Capecitabine-induced oral mucosal hyperpigmentation associated with hand-foot syndrome - A literature review

Abstract Background Capecitabine (Xeloda®) is a cytotoxic, antimetabolite chemotherapeutic agent. Its most common adverse events are diarrhea, hand-foot syndrome (HFS), hyperbilirubinemia, hyperpigmentation, fatigue, abdominal pain, and other gastrointestinal effects. HFS or palmar-plantar erythrodysesthesia (PPE) is an adverse reaction resulting from therapy with chemotherapeutic agents, classified into three degrees. Hyperpigmentation, as an adverse effect of capecitabine, can occur in different locations and with different patterns. The skin, nails and oral mucosal membrane can be affected. Objective The objective of this study was to report and discuss oral hyperpigmentation associated with HFS caused by the use of capecitabine, which is still poorly described in the literature. Methodology A literature review was carried out using the online databases PubMed, Scielo, BVS, Lilacs, Medline, BBO and Google Scholar, associating the descriptors "Capecitabine", "Pigmentation Disorders", "Oral mucosa", "Cancer" and "Hand-Foot Syndrome", which were related and used to exemplify, discuss and report the exposed clinical case. Results This case report corroborates the literature regarding the incidence in females and black skin persons like this patient who was affected by HFS when undergoing antineoplastic therapy with capecitabine and presented hyperpigmentation of the hands, feet and oral mucosa. On the oral mucosa, the hyperpigmented spots were diffuse, showing a blackish color and irregular edges. Their pathophysiology remains unknown. Study limitations Few articles citing capecitabine-associated pigmentation. Conclusions It is hoped that this study may contribute to the identification and correct diagnosis of hyperpigmentation in the oral cavity, as well as call attention to the adverse effects related to capecitabine.

Analysis of association between severity of capecitabine-induced hand-foot syndrome and inflammatory factors / 药学实践杂志

Objective To investigate the correlation between plasma inflammatory factors [IL-1β, IL-6, IL-10, IL-12, IL-17, IL-23, TNF-α, TGF-β, IFN-γ, C-reactive protein (CPR) CCL-5] and hand-foot syndrome in colorectal cancer patients after taking capecitabine. Methods 35 colorectal cancer patients treated with capecitabine were collected and the degree of severity was divided according to the hand-foot syndrome grading diagnostic criteria. The concentrations of inflammatory factors in plasma were determined by ELISA kits. Results The standard curve of all inflammatory cytokines were linear (r>0.9900), and plasma concentrations of inflammatory cytokines in patients with colorectal cancer were determined. The concentration of TNF-α changed obviously, which had reference value. Conclusion The concentrations of different inflammatory factors were different and the concentration of TNF-α was closely correlated with the severity of hand-foot syndrome.

Efficacy and cardiotoxicity observation of different doses of capecitabine in patient-derived tumor xenograft of mice with colorectal cancer / 肿瘤研究与临床

Objective:To explore the correlation of the dose of capecitabine with the efficacy and cardiotoxicity in patient-derived tumor xenograft (PDX) model of mice with colorectal cancer.Methods:The fresh cancer tissues of 1 colorectal cancer patient were transplanted into the bilateral axillary subcutaneous of immunodeficient NOG mice to establish PDX model and passage stably. And then the morphology of tumor cells in primary generation and the second-generation tumor tissues was observed by using HE staining. The expression of tumor markers was detected by using immunohistochemistry method, and the model was evaluated. Mice were intragastrically infused with 200, 300 and 400 mg/kg capecitabine once a day, which were treated as low, middle and high dose groups respectively, 5 rats in each group; in the control group, 0.9% NaCl solution was perfused into the stomach; 14 d in total, use stop for 7 d, consecutively administered in this way. The body weight was measured every day and the tumor volume was measured every 3 days. After 100 days of observation, the mice were killed, and the tumor tissue was taken to measure the tumor weight and then the tumor volume, tumor volume inhibition rate and tumor inhibition rate were calculated. The morphology of tumor tissues was observed by using HE staining. The protein levels of anti-tumor effect indexes like rasP21, cyclooxygenase 2 (COX2), prostaglandin E2 (PGE2), cardiac troponin Ⅰ (cTn-Ⅰ) and brain natriuretic peptide (BNP) in serum of mice were detected by using enzyme linked immunosorbent assay (ELISA).Results:PDX model of mice with colorectal cancer was successfully constructed, and the histological characteristics of the primary tumor in the model were well preserved. During administration, 1 mouse died in the capecitabine high dose group; a slow down in tumor volume growth could be found with the increased dose of capecitabine. There was no statistically significant difference in body weight among 4 groups until all mice were killed ( P > 0.05). The tumor volume and tumor weight in the low, middle and high dose groups were lower than those in the control group (all P < 0.05), and the tumor volume and tumor weight showed an obvious decrease with the increase in dose. The tumor volume inhibition rates of low, middle and high dose groups were 42.61%, 67.61% and 77.27%, respectively, and the tumor inhibition rates were 35.53%, 67.77% and 75.09%, respectively. The serum anti-tumor effect indexes rasP21, COX2 and PGE2 in the middle and high dose groups were decreased compared with those in the control group (all P < 0.05), while cTn-Ⅰ and BNP levels were increased compared with those in the control group (all P < 0.05). Conclusions:The established PDX model of mice with colorectal cancer can better retain the histological characteristics of the original tumor. After treatment of middle and high dose of capecitabine, the tumor inhibition effect is obvious, but the risk of myocardial damage should be noticed.

Carboxylesterase 1 family knockout alters drug disposition and lipid metabolism

The mammalian carboxylesterase 1 (Ces1/CES1) family comprises several enzymes that hydrolyze many xenobiotic chemicals and endogenous lipids. To investigate the pharmacological and physiological roles of Ces1/CES1, we generated Ces1 cluster knockout (Ces1 -/- ) mice, and a hepatic human CES1 transgenic model in the Ces1 -/- background (TgCES1). Ces1 -/- mice displayed profoundly decreased conversion of the anticancer prodrug irinotecan to SN-38 in plasma and tissues. TgCES1 mice exhibited enhanced metabolism of irinotecan to SN-38 in liver and kidney. Ces1 and hCES1 activity increased irinotecan toxicity, likely by enhancing the formation of pharmacodynamically active SN-38. Ces1 -/- mice also showed markedly increased capecitabine plasma exposure, which was moderately decreased in TgCES1 mice. Ces1 -/- mice were overweight with increased adipose tissue, white adipose tissue inflammation (in males), a higher lipid load in brown adipose tissue, and impaired blood glucose tolerance (in males). These phenotypes were mostly reversed in TgCES1 mice. TgCES1 mice displayed increased triglyceride secretion from liver to plasma, together with higher triglyceride levels in the male liver. These results indicate that the carboxylesterase 1 family plays essential roles in drug and lipid metabolism and detoxification. Ces1 -/- and TgCES1 mice will provide excellent tools for further study of the in vivo functions of Ces1/CES1 enzymes.

Effects of disodium cantharidinate on the pharmacokinetic behavior of capecitabine in rats / 中国药房

OBJECTIVE To study the effects of disodium cantharidinate on the pharmacokinetic behavior of capecitabine in rats. METHODS Rats were randomly divided into two control groups and two experimental groups with 6 rats in each group. Two control groups were intraperitoneally injected with normal saline， and two experimental groups were intraperitoneally injected with Disodium cantharidinate injection of 0.5 mL/kg， for 7 consecutive days. Eight days after medication， control group 1 and experimental group 1 were given capecitabine 5 mg/kg intragastrically， while control group 2 and experimental group 2 were given capecitabine 5 mg/kg intravenously. Blood samples were collected at different time points after administration. After extraction with ethyl acetate， the concentration of capecitabine in rat plasma was determined by UPLC-MS/MS method using tolbutamide as the internal standard. The pharmacokinetic parameters were calculated by DAS 2.0 software. RESULTS Compared with control group 1， MRT0－∞， cmax， AUC0－30 h， AUC0－∞ and F of experimental group 1 were increased significantly， while CLz/F was decreased significantly （P＜0.01）. Compared with control group 2， t1/2， MRT0－30 h， MRT0-∞， AUC0－30 h and AUC0－∞ of experimental group 2 were increased significantly （P＜0.01）. CONCLUSIONS Disodium cantharidinate can increase the plasma exposure of capecitabine in rats， improve its oral bioavailability， prolong the average residence time， and reduce its clearance rate.

Isquemia inducida por fluoropirimidinas en un paciente con cáncer de esófago y enfermedad coronaria / Fluoropyrimidine-induced ischemia in a patient with oesophageal cancer

Resumen Los grandes avances terapéuticos de las últimas décadas han prolongado la sobrevida de muchos pacientes con cáncer. Sin embargo, esta mejoría se ha logrado a expensas de un aumento en las complicaciones cardiovasculares secundarias a la quimioterapia y a la radioterapia. Se presenta el caso de un paciente con cáncer esofágico que manifiesta angina inestable como complicación de su enfermedad coronaria multivaso tras iniciar la quimioterapia (capecitabina/oxaliplatino/epirubicina), se discuten los posibles mecanismos que subyacen al evento y se subraya la necesidad de individualizar la estratificación de riesgo previa a la quimioterapia.

Abstract The great therapeutic advances of the last decades have prolonged the survival of many cancer patients. However, these advances have been made at the expense of an increase in cardiovascular complications secondary to chemotherapy and/or radiotherapy. It is presented a patient with oesophageal cancer who manifests unstable angina as a complication of multivessel coronary artery disease after starting chemotherapy with capecitabine/oxaliplatin/epirubicin, discussing the possible mechanisms underlying the event and emphasizing the need to personalize the risk stratification before chemotherapy.

Oral hyperpigmentation as an initial clinical aspect of hand foot syndrome

Abstract Hand-foot syndrome (HFS) is a common adverse effect of anticancer therapy. It is known to cause dermatological symptoms including acral erythema and dysesthesia of the palms and soles of the feet, swelling, pain, itching, and scaling. Some drugs, like capecitabine, are known to trigger this condition. However, pigmentation of the oral mucosa is a rare adverse effect. This study aims to report a case of oral mucosa hyperpigmentation caused by capecitabine therapy before the clinical diagnosis of HFS. A 58-year-old female, diagnosed with invasive breast duct carcinoma, had the central nervous system, liver, skin, and lung metastasis, using capecitabine every day for 14 cycles. Oral examination revealed multifocal black macules on the hard palate, bilateral buccal mucosa, gingival mucosa, and dorsum of the tongue. The clinical hypothesis was oral mucosa hyperpigmentation by capecitabine use and only periodic follow-up was necessary. Hyperpigmentation of oral mucosa by capecitabine is a rare consequence of neoplastic therapy and your association with HFS is unclear, and poorly reported. The report of these events is important to alert oncology health teams about the individual tolerance to capecitabine therapy.

Resumo A síndrome mão-pé (SMP) é um efeito adverso comum da terapia anticâncer. Sabe-se que causa sintomas dermatológicos, incluindo eritema acral e disestesia das palmas das mãos e solas dos pés, inchaço, dor, coceira e descamação. Alguns medicamentos como a capecitabina são conhecidos por desencadear essa condição. No entanto, a pigmentação da mucosa oral é um efeito adverso raro. Este trabalho tem como objetivo relatar um caso de hiperpigmentação da mucosa oral causada pela terapia com capecitabina antes do diagnóstico clínico de SMP. Mulher de 58 anos, com diagnóstico de carcinoma invasivo de ducto mamário, apresentou metástase no sistema nervoso central, fígado, pele e pulmão, em uso de capecitabina todos os dias por 14 ciclos. O exame oral revelou máculas negras multifocais no palato duro, mucosa bucal bilateral, mucosa gengival e dorso de língua. A hipótese clínica foi de hiperpigmentação da mucosa oral pelo uso de capecitabina e apenas o acompanhamento periódico foi necessário. A hiperpigmentação da mucosa oral pela capecitabina é uma consequência rara da terapia neoplásica e sua associação com SMP não é clara e pouco relatada. O relato desses eventos é importante para alertar as equipes de saúde oncológica sobre a tolerância individual à terapia com capecitabina.

A small-scale method of sample preparation suitable for simultaneous HPLC-UV assay of capecitabine and its 5'-DFCR metabolite in mouse blood plasma

Abstract The objective of the study was to develop an easy, cheap, effective, and safe, small-scale method for sample preparation suitable for the simultaneous high-performance liquid chromatography (HPLC)-ultraviolet (UV) assay of capecitabine and its 5′-deoxy-5-fluorocytidine (5′-DFCR) metabolite in mouse blood plasma. The suitability of the proposed method of sample preparation was verified by the optimal effectiveness and efficiency achieved in the overall analytical workflow. The chromatographic separation of capecitabine and its first metabolite was performed on a Hypersil GOLD aQ column with a mobile phase consisting of 1% formic acid, methanol, and water, and run in a gradient elution mode. The absence of interfering endogenous components at the retention times of each analyte was confirmed by the chromatographic analysis of blank matrices and matrices spiked with the corresponding standards. The absence of any tactile matrix effect was also recorded. For the first time, the effect of the vacutainer's anticoagulant on the extraction efficiency of both analytes was evaluated. The method was found to be accurate, precise, and specific. The estimated mean "extraction" efficiencies were ≥90% for each analyte. The lower limit of quantitation for both capecitabine and 5′-DFCR was 0.05 μg/mL.

Pharmacoeconomic evaluation of pyrotinib combined with capecitabine in the second-line treatment of HER- 2 positive patients with advanced breast cancer / 中国药房

OBJECTIVE To evaluate the cost-effectiveness of pyrotinib combined with capecitabine in the second-line treatment of human epidermal growth factor receptor- 2（HER-2）positive advanced breast cancer from the point of view of medical and health system ，and to provide reference for the selection of clinical therapy plan and national health decision. METHODS The dynamic Markov model was constructed on the basis of a multicenter ，open，randomized controlled phase Ⅲ clinical trial in 29 centers in China. The simulation time limit was 8 years，and the cycle was 21 days. The cost-effectiveness of pyrotinib combined with capecitabine （observation group ）were compared with that of lapatinib combined with capecitabine （control group ）in the second-line treatment of HER- 2 positive advanced breast cancer. The incremental cost-utility ratio （ICER）was calculated by using quality-adjusted life year （QALY）as output indicators ，and the sensitivity analysis was carried out to validate the robustness of the results of basic analysis. RESULTS The results of basic analysis showed that compared with control group ，the incremental cost per capita and incremental utility per capita of observation group were 67 953.82 yuan and 0.40 QALYs；ICER was 168 861.89 yuan/QALY，which was lower than the willing to pay （WTP）threshold（217 500 yuan/QALY）represented by 3 times of China ’s per capita GDP in 2020，indicating the treatment plan of the observation group is more cost-effective. The results of single factor sensitivity analysis showed that the proportion of patients treated with trastuzumab or pyrotinib after entering disease progression （PD）status in the control group ，the proportion of patients treated with lapatinib or trastuzumab after entering PD status in the observation group ，the cost of capecitabine and other parameters showed great impact on ICER ，but those parameters didn ’t cause the reverse of basis analysis results. The results of probabilistic sensitivity analysis showed that when the WTP threshold was 217 500 yuan/QALY，the probability that the treatment plan in the observation group was cost-effective was 94.10％. The results of partition survival model analysis were consistent with those of dynamic Markov model. CONCLUSIONS On the premise of taking 3 times of China ’s per capita GDP in 2020 as the WTP lin- threshold， the second-line treatment of HER- 2 positive wang9805@163.com advanced breast cancer with pyrotinib combined with capecitabine is more cost-effective than that with lapatinib combined with capecitabine.

Trial study of capecitabine metronomic chemotherapy combined with exemestane inhibit proliferation of breast cancer cells by PI3K-AKT signaling pathway / 肿瘤研究与临床

Objective:To investigate effects of capecitabine metronomic chemotherapy combined with exemestane on the proliferation of breast cancer MCF-7 cells and PI3-K/AKT signaling pathway.Methods:MCF-7 cells cultured in vitro were divided into the control group (adding DMEM without drugs), 30 μmol/L exemestane group, capecitabine metronomic chemotherapy combined drugs group [30 μmol/L exemestane combined with different concentrations (50, 33, 17 μmol/L) of capecitabine]. CCK-8 assay was used to detect the cell proliferation inhibition rate, the half-maximal inhibitory concentration ( IC50) was calculated, and the changes of cell cycle and apoptosis rate of MCF-7 in different drug groups were assessed by using flow cytometry. The related-protein expression of PI3K-AKT signaling pathway of MCF-7 cells was detected by using Western blot. Results:The IC50 of capecitabine and exemestane on MCF-7 cells for 72 h was 101.2 μmol/L and 60.6 μmol/L, respectively. The proliferation inhibition rate of MCF-7 cells in 30 μmol/L exemestane for 24 h and 48 h combined with 50, 33 and 17 μmol/L capecitabine group was higher than that in 30 μmol/L exemestane group (all P<0.01). The apoptosis rates were (18.1±2.6)%, (34.6±3.0)%, (27.6±1.3)%, (23.1±1.6)%, respectively in 30 μmol/L exemestane group, 30 μmol/L exemestane + 50 μmol/L capecitabine group, 30 μmol/L exemestane + 33 μmol/L capecitabine group, 30 μmol/L exemestane + 17 μmol/L capecitabine group, and the difference was statistically significant ( F = 23.652, P<0.01). Compared with the control group, the proportion of MCF-7 cells in phase G 2 of 30 μmol/L exemestane group was increased [(16.7±2.6)% vs. (10.6±2.2)%], while that in phase G 1 was decreased [(53.3±4.0)% vs. (56.3±3.2)%]. The proportion of MCF-7 cells in phase S of 30 μmol/L exemestane + 50 μmol/L capecitabine group was increased [(39.0±3.6)% vs. (33.1±2.0)%]. MCF-7 cells of 30 μmol/L of exemestane + 33 μmol/L capecitabine group were more blocked in phase S [(51.7±4.1)%], and cells in phase G 2 were nearly disappeared [(1.2±0.5)%]; the cell proportion MCF-7 cells in phase G 2 of 30 μmol/L exemestane plus 17 μmol/L capecitabine group was increased [(26.2±3.1)%]. Western blot analysis showed that low dose capecitabine metronomic chemotherapy promoted exemestane to inhibit the expression of PI3K, motivated AKT serine phosphorylated at protein 473 [the increased expression of p-AKT (473)], promoted S6 protein expression at downstream of signaling pathway and increased its phosphorylation level (the increased expression of p-S6), thereby activating apoptosis signal. Conclusion:Capecitabine metronomic chemotherapy combined with exemestane can synergistically inhibit the proliferation of breast cancer MCF-7 cells and activate apoptosis mechanisms of MCF-7 cells through affecting PI3K-AKT signaling pathway.

A randomized controlled Phase II trial of vinorelbine plus capecitabine versus docetaxel plus capecitabine in anthracycline-pretreated women with metastatic breast cancer

Background: Previous studies have shown that vinorelbine/capecitabine (NX) and docetaxel/capecitabine (TX) chemotherapy has a certain effect in advanced breast cancer. However, there are few clinical studies directly comparing TX and NX regimen chemotherapy, especially in patients with advanced breast cancer previously treated with anthracycline and taxane. The purpose of this Phase II study was to compare survival and side effects between patients with anthracycline- and taxane-resistant advanced breast cancer treated with NX and those treated with TX chemotherapy. Patients and Methods: From February 2012 to March 2014, a total number of 97 patients were randomly assigned to NX (n = 55) or TX (n = 42). Baseline characteristics were relatively well-balanced in the two treatment arms. The clinical trial registration number (clincaltrials.gov) is NCT01635465. Results: After a median follow-up of 46.0 months, there was no significant difference between the NX and TX arms in objective response rate (17.9% vs. 21.1%; P = 0.686) and progression-free survival (6 months vs. 7 months; P = 0.560). The overall survival period of the TX arm was longer than that of the NX arm (32 months vs. 27 months) but without statistical significance. Both regimens were well-tolerated. The main toxicities were neutropenia, leukopenia, and anemia. In the TX arm, hand-foot syndrome occurred more frequently than in the NX arm (P < 0.01), but frequencies of other minor adverse effects were similar between the two arms. Conclusion: NX and TX regimens are both alternative treatments for patients with anthracycline- and taxane-resistant advanced breast cancer, but the safety profile was more favorable and manageable with the NX regimen. Trial Registrations: ClinicalTrials.gov NCT01635465. Registered 09 July 2012

Curative effect of compound carraghenates cream combined with vitamin B6 in the treatment of hand-foot syndrome caused by capecitabine / 中国基层医药

Objective@#To observe the curative effect of compound carraghenates cream(Titanoreine) combined with vitamin B6 in the treatment of hand-foot syndrome caused by capecitabine(Xeloda).@*Methods@#From December 2015 to December 2017, 97 cases of middle and advanced colorectal cancer in the First People's Hospital of Yongkang were selected.All patients were treated by chemotherapy regimens of capecitabine as priority after operation, but later hand-foot syndrome appeared and they were randomly divided into treatment group (48 cases) and control group (49 cases) according to the digital table.In control group, only vitamin B6 30 mg was taken orally, three times daily; while in treatment group, vitamin B6(30 mg) combined with compound carraghenate cream (1g) were taken orally, three times daily after hand-foot syndrome occurred.The improvement, total efficiency, pain score during the treatment process (the first, fifth, ninth day after treatment), adverse reactions were observed before and after treatment in two groups.@*Results@#After treatment, the hand-foot syndrome in the treatment group and the control group was improved, the difference was statistically significant (treatment group: Z=6.477, P=0.000; control group: Z=4.700, P=0.000). The total effective rate of the treatment group was 87.5%(42/48), which was significantly higher than 65.3%(32/49) of the control group (χ2=6.603, P=0.010). The pain score on the ist day after treatment had no statistically significant differences between the two group[treatment group: (2.88±1.82)points, control group: (3.14±1.74)points, t=0.741, P=0.461] The pain scores on 5th and 9th day after treatment in the treatment group were (2.29±1.52)points, (1.23±1.80)points, respectively, which were lower than those in the control group [(2.94±1.38)points, (2.14±1.90)points](t=2.200, 2.430, P=0.030, 0.017). There were no statistically significant differences between the two groups in general conditions and the incidence of adverse reactions after drugs uses(all P<0.05).@*Conclusion@#Compound carraghenate cream combined with vitamin B6 has significant effect in the treatment of hand-foot syndrome caused by capecitabine, which can improve hand-foot syndrome better and help tumor patients to finish the chemotherapy successfully.

Apatinib combined with capecitabine in the treatment of advanced triple-negative breast cancer as third-line therapy: An observational study / 中国临床药理学与治疗学

AIM: To investigate the efficacy and safety of apatinib combined with capecitabine in the treatment of advanced triple-negative breast cancer (TNBC) as third-line therapy. METHODS: Sixty advanced TNBC patients, who have failed to receive second-line palliative chemotherapy, were enrolled in the Department of Oncology, Anqing Hospital Affiliated to Anhui Medical University from February 2016 to September 2019. Patients were divided into observation group (n=30, received apatinib combined with capecitabine) and control group (n=30, received capecitabine) randomly. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), 1-year survival rate, overall survival (OS) and adverse events between the two groups were observed and compared. RESULTS:ORR was 26.67% and DCR was 86.67% in the observation group, while 6.67% and 60.00% in the control group, respectively. ORR and DCR in the observation group were better than those in the control group (P=0.038; 0.020). Meanwhile, the median PFS was 7.0 months in the observation group, while it was 5.0 months in the control group, which indicated that the observation group exhibited a higher PFS than the control group (P=0.000). The 1-year survival rate and the median OS was 55.30% and 13.0 months in the observation group respectively, while those were 46.30% and 12.0 months in the control group respectively, the OS showed no significant differences between the two groups (P=0.258). In addition, we also found that there was significant differences in the adverse reaction such as hypertension between the two groups (P=0.000), yet it was mild and tolerable after symptomatic treatment. CONCLUSION:Apatinib combined with capecitabine in the advanced TNBC maintenance treatment has a certain survival benefit for those who failed in second-line therapy, and adverse reactions are tolerable and controllable.

Efficacy and safety of XELOX therapy in comparison with capecitabine monotherapy in adjuvant chemotherapy for elderly patients with colorectal cancer / 中国临床药理学与治疗学

AIM: To investigate the efficacy and safety of the XELOX therapy (capecitabine plus oxaliplatin) versus capecitabine monotherapy in adjuvant chemotherapy for elderly patients with colorectal cancer. METHODS: This study included 195 elderly patients with early colorectal cancer (60-82 years old) who underwent R0 surgical resection from January 2010 to December 2017 in Zhengzhou People's Hospital. Patients received either adjuvant chemotherapy with capecitabine monotherapy or XELOX therapy after surgery (selective adjuvant chemotherapy based on patient ECOG score, physical status, physician assessment, patient tolerance, and willingness). The baseline clinical data were collected through the hospital case system and patients were followed up according to the trial protocol. Disease-free survival (DFS) and overall survival (OS) were analyzed by Kaplan-Meier survival analysis. Cox risk ratio model was established to evaluate the efficacy of different adjuvant chemotherapy regimens with the same risk factors. Adverse reactions above level 2 (according to CTCAE 4.0) were recorded for safety analysis. RESULTS:The median follow-up of the study was 5.75 years (the follow-up time range: 0.30-7.50 years). The efficacy was evaluated in 195 patients enrolled in the study. The median disease-free survival (mDFS) was 5.0 years in the overall patient population, and the mDFS in the XELOX group was 5.5 years, significantly higher than the mDFS of the capecitabine monotherapy group for 3.6 years (P=0.047, 95%CI: 2.06-5.14). The overall median overall survival (mOS) was 7.1 years, and the mOS of the XELOX group was 7.1 years, significantly higher than the median total of the capecitabine monotherapy group mOS 4.5 years (P=0.021, 95% CI: 3.30-5.70). With the same risk factors, when the patients were younger than 70 years old, both the DFS (HR=0.74, P=0.036) and OS (HR=0.78, P=0.041) patients could benefit from the XELOX regimen; when the patients ≥70 years old, only DFS (HR=0.77, P=0.035) could benefit from the XELOX therapy. Regardless of the patient's comorbidities, the patient's DFS and OS benefit from the XELOX therapy. However, patient's DFS and OS can benefit from XELOX only when the number of lymph nodes examined was less than 12 nodes and the number of cycles of patients receiving adjuvant chemotherapy was ≥6 cycles. In terms of adverse reactions, the incidence of neutropenia (61.54% vs. 39.74%, P=0.003) and neurotoxicity (65.81% vs. 0%) were significantly higher in the XELOX therapy than the capecitabine monotherapy regimen. Other adverse reactions such as diarrhea, stomatitis, thrombocytopenia, hand-foot syndrome, anemia, nausea and vomiting, increased AST/ALT, and hair loss were not significantly different between the two groups (P>0.05). CONCLUSION: The XELOX therapy does not significantly increase adverse events in elderly patients, and elderly patients (age<70 years old) who combine oxaliplatin on the basis of capecitabine can significantly benefit from DFS and OS, but when the patients were≥70 years old, only DFS can benefit, while OS cannot.

Bioequivalence of capecitabine tablets in cancer patients / 中国临床药理学与治疗学

AIM: To evaluate the pharmacokinetics, bioequivalence, and safety of capecitabine tablet in cancer patients following single oral administration. METHODS: Based on an open-randomized two-period crossover designation, subjects were orally given capecitabine tablet (test or reference products, 0.6 g single dosage). Blood samples were then collected and the plasma concentrations of capecitabine and its active metabolite, 5-fluorouracil (5-FU) were examined by HPLC-MS/MS. The bioequivalence between the test and reference formulations were evaluated with the pharmacokinetic parameters determined by the Phoenix WinNonlin 7.0 software. RESULTS: The numbers of the major pharmacokinetic parameters in patients treated with test and reference products were similar. To analyze the numbers of Cmax, tmax, AUC0-t, AUC0-∞, the 90% confidence interval (CI) for Cmax, AUC0-t and AUC0-∞ were 84.48-106.70, 93.03-96.54 and 96.34-102.84, respectively. For the 5-FU, the 90%CI of the for Cmax, AUC0-t and AUC0-∞ were 84.32-99.67, 90.55-98.76 and 96.99-103.48, respectively. Both sets of numbers fell within the bioequivalent limit ranges of 80.00%-125.00%. No serious adverse event was observed. CONCLUSION: The current data indicate that the test and reference formulations of capecitabine tablets were bioequivalent in cancer patients.

Capecitabine maintenance in the treatment of locally advanced nasopharyngeal carcinoma: a retrospective study / 中国肿瘤临床

Objective: The efficacy of sequential capecitabine maintenance chemotherapy after radical chemoradiotherapy for stage N2- 3 nasopharyngeal carcinoma in non- endemic areas of northwest China was retrospectively analyzed to clarify the value of capecitabine maintenance chemotherapy in the treatment of locally advanced nasopharyngeal carcinoma. Methods: From Jannary 2014 to December 2016, patients with stage N2-3 nasopharyngeal carcinoma underwent 2 or 3 cycles of induction chemotherapy combined with concurrent chemoradiotherapy. The study group continued to receive capecitabine for 4 cycles of chemotherapy after radical chemoradiotherapy, whereas the control group was only observed. The survival differences between the two groups were compared, and the toxicity and compliance of the two regimens were evaluated. Result: A total of 179 patients were included in this study, among whom 84 were included in the maintain chemotherapy group and 95 in the control group. The median follow-up time was 44.4 (5.97-70.26) months. The 3-year distant metastasis-free survival rates and 3-year disease-free survival rates were 79.3% and 68.1% (chi-square=3.898, P=0.048) and 75.6% and 64.2% (chi-square=5.428, P=0.020) for the maintain chemotherapy and control groups, respectively. The differences were statistically significant. There was no difference between the two groups in acute and late toxicity (P> 0.05). The toxicity of capecitabine-specific drugs was below grade 2. Conclusions: For N2-3 stage nasopharyngeal carcinoma in non-endemic areas in northwest China, the 3- year distant metastasis- free survival and disease- free survival rates following sequential capecitabine maintenance therapy after radical radiotherapy and chemotherapy are improved. Treatment was well-tolerated, and compliance was good, with no obvious adverse reactions.

The Newly Developed Highly Sensitive Method For The Determination Of Capecitabine By Using Uv-Spectroscopy

Capecitabine is a fluoropyrimidine carbamate, designed as 'pro-drug' to the cytotoxic agent 5-fluorouracil (5-FU) meant to be administered orally. Capecitabine is used as first line monotherapy for metastatic colorectal cancer. In the present study simple, rapid, accurate UV spectrophotometric methods were developed and validated for the estimation of capecitabine in bulk and its formulations as per ICH guidelines. Three solvent systems viz., 0.1N NaOH, 0.1N HCl and Methanol: Water (1:3) were tried. The results suggest that the developed methods shows linearity over the concentration range of 2-24μg/ml with a correlation coefficient of 0.9999. All the developed methods were statistically validated for accuracy, precision, linearity, robustness, and ruggedness as per ICH guidelines. The % RSD values for validated methods were found to be less than 1.5 and methods will find application in routine analysis of drug formulations containing capecitabine.

Randomized Open Label Phase III Trial of Irinotecan Plus Capecitabine versus Capecitabine Monotherapy in Patients with Metastatic Breast Cancer Previously Treated with Anthracycline and Taxane: PROCEED Trial (KCSG BR 11-01) / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: We investigated whether irinotecan plus capecitabine improved progression-free survival (PFS) compared with capecitabine alone in patients with human epidermal growth factor 2 (HER2) negative and anthracycline and taxane pretreated metastatic breast cancer (MBC). MATERIALS AND METHODS: A total of 221 patients were randomly assigned to irinotecan (80 mg/m2, days 1 and 8) and capecitabine (1,000 mg/m2 twice a day, days 1-14) or capecitabine alone (1,250 mg/m2 twice a day, days 1-14) every 3 weeks. The primary endpoint was PFS. RESULTS: There was no significant difference in PFS between the combination and monotherapy arm (median, 6.4 months vs. 4.7 months; hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.63 to 1.11; p=0.84). In patients with triple-negative breast cancer (TNBC, n=90), the combination significantly improved PFS (median, 4.7 months vs. 2.5 months; HR, 0.58; 95% CI, 0.37 to 0.91; p=0.02). Objective response rate was numerically higher in the combination arm, though it failed to reach statistical significance (44.4% vs. 33.3%, p=0.30). Overall survival did not differ between arms (median, 20.4 months vs. 24.0 months; p=0.63). While grade 3 or 4 neutropenia was more common in the combination arm (39.6% vs. 9.0%), hand-foot syndrome was more often observed in capecitabine arm. Quality of life measurements in global health status was similar. However, patients in the combination arm showed significantly worse symptom scales especially in nausea/vomiting and diarrhea. CONCLUSION: Irinotecan plus capecitabine did not prove clinically superior to single-agent capecitabine in anthracycline- and taxane-pretreated HER2 negative MBC patients. Toxicity profiles of the two groups differed but were manageable. The role of added irinotecan in patients with TNBC remains to be elucidated.

Effects of oxaliplalin combined with capecitabine on expressions of tumor-related factors in gastric cancer tissue of rats with experimental gastric cancer and their synergistic anti-tumor effects / 吉林大学学报(医学版)

Objective: To investigate the effects of oxaliplatin combined with capecitabine on the expressions of tumor-related factors in the gastric cancer tissue and the levels of serum inflammatory factors in the rats with experimental gastric cancer, and to elucidate the possible mechanism of their anti-tumor effects. Methods: Sixty Wistar rats were randomly divided into control group∗ model group∗ oxaliplatin group∗ capecitabine group and oxaliplatin combined with capecitabine group (combination group); there were 12 rats in each group. The BGC823 cells were used to establish the experimental gastric cancer models. The experimental rats were given capecitabine (400 mg • kg ) and (or) oxaliplatin (20 mg • kg ) at the same time; the rats in control group and model group were given the normal saline at the same volume for 8 weeks. The average tumor weight was measured after administration. The apoptosis of gastric cancer cells was measured by TUNEL staining. The protein expression levels of P53. signal transduction and activation factor 3 (STAT3) and vascular endothelial growth factor (VEGF) in the gastric cancer tissue of the rats in various groups were detected by Western blotting method. The levels of serum interleukin-6 (IL-6)» interleukin-10 (IL-10) and tumor necrosis factor-a (TNF-a) of the rats in various groups were detected by ELISA. Results: Compared with control group, the protein expression levels of P53» STAT3. and VEGF in the gastric cancer tissue and the levels of serum IL-6. 11,-10. and TNF-a of the rats in model group were significantly increased (P<0. 05). Compared with model group, the average tumor weights and the protein expression levels of P53» STAT3. and VEGF in the gastric cancer tissue and the levels of serum IL-6. IL-10. and TNF-a of the rats in oxaliplatin group, capecitabine group and combination group were significantly decreased (P∗C0. 05); the apoptosis indexes (AI) of gastric cancer cells were significantly increased (P<0. 05). The average tumor weight, the protein expression levels of P53∗ STAT3∗ and VEGF in gastric cancer tissue and the levels of serum IL-6. IL-10. and TNF-a of the rats in combination group were significantly lower than those in capecitabine group and oxaliplatin group ( P-C0. 05). Conclusion: Both oxaliplatin and capecitabine can paly the antitumor effects by reducing the protein expression levels of the tumor-related factors and the serum IL-6. IL-10. and TNF-a levels of the gastric cancer rats, and the anti-tumor effect of combined utilization is better than that of capecitabine or oxaliplatin used alone.

Effect of omeprazole on plasma concentration and adverse reactions of capecitabine in patients with colon cancer / 中华肿瘤杂志

Objective@#To investigate the effect of omeprazole on plasma concentration, efficacy and adverse reactions of capecitabine in patients with colon cancer.@*Methods@#Seventy-two patients with colon cancer treated with capecitabine were analysed retrospective. The patients treated with capecitabine combined with omeprazole were identified as experimental group and the capecitabine treatment alone as control group.The differences of blood concentration and the side effects of capecitabine between these two groups were compared.@*Results@#The plasma concentration of 5-Fluorouracilum in experimental group was (126.25±50.59) μg/ml, without significant difference of (123.09±56.70) μg/ml in control group (P=0.121). The incidence of Ⅲ to Ⅳ degree bone marrow suppression, nausea, vomiting, diarrhea and hand-foot syndrome in experimental group were 13.8%, 0%, 0% and 19.4%, respectively. In control group, the incidence of Ⅲ to Ⅳ degree bone marrow suppression, nausea, vomiting, diarrhea and the hand-foot syndrome were 11.1%, 0%, 0% and 19.4%, respectively, without significant difference of experimental group (P>0.05). The incidence of acid reflux and heartburn in the control group was 72.2%, significantly higher than 44.4% of the experimental group (P<0.05). The objective response rate (ORR) and progression-free survival time (PFS) in these two groups were 30.6% and 33.3%, and 8.0 month and 8.5 month, respectively, without significant difference (P>0.05).@*Conclusion@#The intravenous omeprazole attenuates reflux and heartburn of colon cancer patients treated with capecitabine, without affecting its plasma concentration and side effects and has no impact on the PFS of these patients.