Capecitabine Research Articles

Pharmacogenomic-guided dosing of fluoropyrimidines beyond DPYD: time for a polygenic algorithm?

Fluoropyrimidines are chemotherapeutic agents widely used for the treatment of various solid tumors. Commonly prescribed FPs include 5-fluorouracil (5-FU) and its oral prodrugs capecitabine (CAP) and tegafur. Bioconversion of 5-FU prodrugs to 5-FU and subsequent metabolic activation of 5-FU are required for the formation of fluorodeoxyuridine triphosphate (FdUTP) and fluorouridine triphosphate, the active nucleotides through which 5-FU exerts its antimetabolite actions. A significant proportion of FP-treated patients develop severe or life-threatening, even fatal, toxicity. It is well known that FP-induced toxicity is governed by genetic factors, with dihydropyrimidine dehydrogenase (DPYD), the rate limiting enzyme in 5-FU catabolism, being currently the cornerstone of FP pharmacogenomics. DPYD-based dosing guidelines exist to guide FP chemotherapy suggesting significant dose reductions in DPYD defective patients. Accumulated evidence shows that additional variations in other genes implicated in FP pharmacokinetics and pharmacodynamics increase risk for FP toxicity, therefore taking into account more gene variations in FP dosing guidelines holds promise to improve FP pharmacotherapy. In this review we describe the current knowledge on pharmacogenomics of FP-related genes, beyond DPYD, focusing on FP toxicity risk and genetic effects on FP dose reductions. We propose that in the future, FP dosing guidelines may be expanded to include a broader ethnicity-based genetic panel as well as gene*gene and gender*gene interactions towards safer FP prescription.

95MO Circulating tumor DNA (ctDNA) dynamics in patients (pts) receiving capecitabine (CAPE) for early-stage triple-negative breast cancer (eTNBC) with an incomplete response to neoadjuvant therapy (NAT)

95MO Circulating tumor DNA (ctDNA) dynamics in patients (pts) receiving capecitabine (CAPE) for early-stage triple-negative breast cancer (eTNBC) with an incomplete response to neoadjuvant therapy (NAT)

Hesperetin and Capecitabine Abate 1,2 Dimethylhydrazine-Induced Colon Carcinogenesis in Wistar Rats via Suppressing Oxidative Stress and Enhancing Antioxidant, Anti-Inflammatory and Apoptotic Actions.

Colon cancer is a major cause of cancer-related death, with significantly increasing rates of incidence worldwide. The current study was designed to evaluate the anti-carcinogenic effects of hesperetin (HES) alone and in combination with capecitabine (CAP) on 1,2 dimethylhydrazine (DMH)-induced colon carcinogenesis in Wistar rats. The rats were given DMH at 20 mg/kg body weight (b.w.)/week for 12 weeks and were orally treated with HES (25 mg/kg b.w.) and/or CAP (200 mg/kg b.w.) every other day for 8 weeks. The DMH-administered rats exhibited colon-mucosal hyperplastic polyps, the formation of new glandular units and cancerous epithelial cells. These histological changes were associated with the significant upregulation of colon Ki67 expression and the elevation of the tumor marker, carcinoembryonic antigen (CEA), in the sera. The treatment of the DMH-administered rats with HES and/or CAP prevented these histological cancerous changes concomitantly with the decrease in colon-Ki67 expression and serum-CEA levels. The results also indicated that the treatments with HES and/or CAP showed a significant reduction in the serum levels of lipid peroxides, an elevation in the serum levels of reduced glutathione, and the enhancement of the activities of colon-tissue superoxide dismutase, glutathione reductase and glutathione-S-transferase. Additionally, the results showed an increase in the mRNA expressions of the anti-inflammatory cytokine, IL-4, as well as the proapoptotic protein, p53, in the colon tissues of the DMH-administered rats treated with HES and/or CAP. The TGF-β1 decreased significantly in the DMH-administered rats and this effect was counteracted by the treatments with HES and/or CAP. Based on these findings, it can be suggested that both HES and CAP, singly or in combination, have the potential to exert chemopreventive effects against DMH-induced colon carcinogenesis via the suppression of oxidative stress, the stimulation of the antioxidant defense system, the attenuation of inflammatory effects, the reduction in cell proliferation and the enhancement of apoptosis.

Development and Validation of Novel RP-HPLC Method for the Simultaneous Estimation of Capecitabine and Thymoquinone in the Biodegradable Nanoparticles using Full Factorial Design.

An innovative RP-HPLC technique was devised to simultaneously quantify thymoquinone (TQ) and capecitabine (CAP) in newly designed polymeric nanoparticles. A unique chromatographic approach was created, optimized and validated using Design-Expert® (design of experiment) in compliance with ICH requirements. A 24 factorial design examined the influence of variables on method responses. The method found linear between 0.25 and 16μg/mL, with an R2 value of 0.999. The detection and quantification limits for CAP were 0.05 and 0.16μg/mL, respectively, and 0.12 and 0.38μg/mL for TQ, respectively, and 97-100% recovery in plain drug solution and 100-102% in nanoformulation were achieved. A purposeful modification examined by analysis of variance revealed that the experimental model was significant (P = 0.0001). The total drug content in nanoformulation was 8.68mg, and the entrapment efficiency was 84.79%. Based on the findings, it is possible to infer that the use of the Quality by Design methodology resulted in the development of a more accurate technique capable of producing consistent, dependable, high-quality data and precise in quantifying CAP and TQ in bulk and nanoparticulate systems.

Baicalein prevents capecitabine-induced heart damage in female Wistar rats and enhances its anticancer potential in MCF-7 breast cancer cells

AimWe investigated the ability of baicalein (BAI) to enhance the anticancer potential of capecitabine (CAP) in the MCF-7 cell line and its protective effect on CAP-induced cardiotoxicity in female Wistar rats. Methods and key findingsIn vitro study involved evaluating the effect of BAI and/or CAP on cell viability, cell cycle progression, and BAX and Bcl2 gene expression in MCF-7 cells. Co-treatment of BAI with CAP significantly reduced the viability of MCF-7 cells, improved their cytotoxic effect, markedly elevated the percentage of the sub-G1 population, drastically reduced the G2/M population, and significantly altered the mRNA expression of BAX and Bcl2 genes compared with each treatment alone. In vivo study revealed that the oral administration of CAP (140 mg/kg BW) to adult female rats significantly elevated the levels of serum creatine kinase-myocardial band (CK-MB), lactate dehydrogenase (LDH), tumor necrosis factor (TNF)-α, and interleukin (IL)-1β and cardiac TNF-α, IL-1β malondialdehyde (MDA) concentration, whereas it reduced the serum and cardiac total antioxidant capacity (TAC), level of cardiac glutathione (GSH) and activity of glutathione peroxidase (GPx) with a vast array of circulatory, inflammatory, degenerative, and necrotic alterations in the cardiac tissue. Furthermore, CAP administration significantly upregulated the mRNA expression of NF-κB, TLR4, MyD88, ATF6, CHOP, and JNK genes. Concurrent administration of BAI (200 mg/kg BW) and CAP significantly improved the biochemical alterations and cardiac oxidant/antioxidant status and architecture. In addition, it modulated the TLR4/MyD88/NF-κB pathway and endoplasmic reticulum stress. SignificanceAltogether, BAI can augment the anticancer potential of CAP and alleviate its cardiotoxic effects during cancer treatment.

Severe enterocolitis with capecitabine (CAPE) is not a predictor of gastrointestinal (GI) toxicity with infusional 5-fluorouracil (5-FU)–based regimens: An institutional analysis.

89 Background: Enterocolitis is a potentially fatal toxicity of CAPE. The safety of infusional 5-FU-based regimens in patients developing severe enterocolitis with CAPE is not well established in the literature. Methods: After institutional review board approval, a database search identified patients who received infusional 5-FU-based regimens between January 2015 and July 2022 in a tertiary care cancer center after experiencing severe CAPE-induced enterocolitis, defined as the presence of grade 3 or higher diarrhea and features of enterocolitis on computed tomography (CT) scan. Data on patient characteristics, grade of CAPE-induced diarrhea, clinical course, details of 5-FU-based regimens administered after recovery, and outcomes were collected by retrospective electronic chart review. Results: Among the 791 patients treated with CAPE during the study period, 27 (3.4%) developed grade 3 or higher diarrhea, and 15 of these 27 patients (1.9%) had evidence of enterocolitis on CT scan. All patients were treated with supportive measures. All but 1 patient recovered fully; 1 patient died due to a condition unrelated to CAPE toxicity. After complete recovery, 7 patients aged 46 to 69 years (median, 68 years) received FOLFOX (oxaliplatin and infusional 5-FU). The time interval between recovery from CAPE-induced enterocolitis and the start of infusional 5-FU ranged from 4 to 20 weeks (median, 12 weeks), with 3 patients starting 5-FU within 4-5 weeks of recovery. Standard dose 5-FU (2400 mg/m2 over 46 hours) was given to 2 of the 7 patients; the remaining 5 patients received 50% to 80% of the standard dose at the beginning of treatment, but eventually tolerated the standard dose. All patients tolerated 5-FU infusion without experiencing any grade 2 or higher 5-FU induced GI toxicity. Conclusions: Most patients developing severe enterocolitis with CAPE recover fully with appropriate supportive measures. Infusional 5-FU-based regimens appear to be safe in this patient group. Severe CAPE-induced enterocolitis should not preclude the use of infusional 5-FU-based regimens, especially in curative-intent settings such as adjuvant therapy.

In vitro co-culture systems of hepatic and intestinal cells for cellular pharmacokinetic and pharmacodynamic studies of capecitabine against colorectal cancer

BackgroundAs a prodrug of 5-fluorouracil (5-FU), orally administrated capecitabine (CAP) undergoes preliminary conversion into active metabolites in the liver and then releases 5-FU in the gut to exert the anti-tumor activity. Since metabolic changes of CAP play a key role in its activation, a single kind of intestinal or hepatic cell can never be used in vitro to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) nature. Hence, we aimed to establish a novel in vitro system to effectively assess the PK and PD of these kinds of prodrugs.MethodsCo-culture cellular models were established by simultaneously using colorectal cancer (CRC) and hepatocarcinoma cell lines in one system. Cell Counting Kit-8 (CCK-8) and flow cytometric analysis were used to evaluate cell viability and apoptosis, respectively. Apoptosis-related protein expression levels were measured using western blot analysis. A selective liquid chromatography-tandem mass spectrometry (LC–MS/MS) method was developed for cellular PK in co-culture models.ResultsCAP had little anti-proliferative effect on the five monolayer CRC cell lines (SW480, LoVo, HCT-8, HCT-116 and SW620) or the hepatocarcinoma cell line (HepG2). However, CAP exerted marked anti-tumor activities on each of the CRC cell lines in the co-culture models containing both CRC and hepatocarcinoma cell lines, although its effect on the five CRC cell lines varied. Moreover, after pre-incubation of CAP with HepG2 cells, the culture media containing the active metabolites of CAP also showed an anti-tumor effect on the five CRC cell lines, indicating the crucial role of hepatic cells in the activation of CAP.ConclusionThe simple and cost‑effective co-culture models with both CRC and hepatocarcinoma cells could mimic the in vivo process of a prodrug dependent on metabolic conversion to active metabolites in the liver, providing a valuable strategy for evaluating the PK and PD characteristics of CAP-like prodrugs in vitro at the early stage of drug development.

Real-World Experience of Metronomic Chemotherapy in Metastatic Breast Cancer: Results of a Retrospective Unicenter Study

Introduction: Metronomic chemotherapy (MCT) is increasingly used in oncology due to its favorable therapeutic index. There is still a lack of evidence for MCT in metastatic breast cancer (MBC). In this retrospective unicenter study, we demonstrated real-word data on MCT in MBC. Methods: MBC patients who received metronomic oral cyclophosphamide (CTX) (50 mg daily) and methotrexate (MTX) (2.5 mg every other day), CTX and capecitabine (CAPE) (500 mg thrice daily), CTX, or vinorelbine (VRL) (30 mg daily) alone for at least 4 weeks between 2009 and 2021 were included. The primary endpoint was disease control rate (DCR) ≥24 weeks. Secondary endpoints were progression-free survival (PFS) and overall survival (OS). Patient characteristics and therapy response were analyzed using χ² test. For survival analyses, Kaplan-Meier estimator and log-rank test were used. Results: Seventy-two patients were identified. Sixty-two patients received CTX/MTX, three CTX/CAPE, two CTX, and five VRL. Median age at diagnosis MBC and at start of MCT was 59.0 years and 64.5 years, respectively. 72.2% tumors were hormone receptor positive and 27.8% were triple-negative. 54.2% patients had more than two different metastases. 80.6% patients showed visceral involvement. 31.9% patients achieved DCR ≥24 weeks. Median PFS was 17.0 weeks (95% CI 14.5–19.5) and median OS was 58.0 weeks (95% CI 29.0–87.0). MCT showed similar DCR ≥24 weeks and clinically meaningful but not statistically significant shorter median PFS compared to prior therapy (31.9% versus 32.8% [p = 0.570] and 17.0 weeks versus 20.0 weeks [p = 0.093], respectively) and statistically significant higher DCR ≥24 weeks and longer median PFS compared to subsequent therapy (31.9% versus 17.4% [p = 0.038] and 17.0 weeks versus 12.0 weeks [p = 0.006], respectively). Three (4.2%) patients terminated MCT because of toxicity. Conclusion: In this real-world retrospective study, MCT was effective and well tolerated and may thus represent a valuable treatment option in selected MBC patients.

Efficacy and safety of gemcitabine and capecitabine combination for patients with previously treated advanced primary pulmonary lymphoepithelioma-like carcinoma: a retrospective single-arm cohort study.

Primary pulmonary lymphoepithelioma-like carcinoma (PLELC) is a rare and unique subtype of non-small cell lung cancer (NSCLC). Studies reporting on salvage treatment for pretreated PLELC are limited. Positive interactions between gemcitabine (GEM) and capecitabine (CAP) have been demonstrated in preclinical studies. In addition, the clinical benefit of the combination has been reported for other malignancies. However, the efficacy and safety of the combination for pretreated PLELC remain unclear. Therefore, we conducted this retrospective study to examine the activity and safety of gemcitabine plus capecitabine (GEM/CAP) combination for previously treated PLELC. Patients with PLELC at Sun Yat-sen University Cancer Center who received GEM combined with CAP between May 2013 and January 2021 as the second-line therapy or beyond were retrospectively enrolled. Treatment consisted of intravenous GEM (1,000 mg/m2 on days 1 and 8) and oral CAP (1,000 mg/m2 twice daily on days 1-14) every 3 weeks. Evaluation of response was performed every 2 cycles in accordance with Response Evaluation Criteria in Solid Tumors version 1.1. Safety was assessed in accordance with Common Terminology Criteria for Adverse Events version 5.0. Clinical characteristics were collected from medical records. The survival data were obtained by medical records or telephone. Follow-ups were performed until February 3rd, 2021. A total of 16 patients were enrolled in this study. There were 5, 4, 4, and 3 patients treated with GEM/CAP combination as the second-, third-, fourth-, and fifth-line settings, respectively. There were 8 patients with partial response (PR) (50.00%), 6 with stable disease (SD) (37.50%), 2 with progressive disease (PD) (12.50%), and none with complete response (CR). The objective response rate and disease control rate (DCR) were 50.00% and 87.50%, respectively. The most common hematological and nonhematological adverse events (AEs) at any grade were neutropenia (31.25%) and hand-foot syndrome (43.75%). At a median follow-up of 29.3 months with 95% confidence interval (CI) of 20.3 to 38.3 months, the median progression-free survival (PFS) was 9.3 months (95% CI: 6.5-12.1 months). The median overall survival (OS) was 41.5 months (95% CI: 3.1-79.8 months). This retrospective study demonstrated the potential clinical benefit of GEM in combination with CAP for pretreated PLELC. Future multicenter large-scale, prospective studies are warranted.

Adjuvant therapy in biliary tract cancers: oral fluoropyrimidine as a beginning

Biliary tract cancer is a group of malignant tumours, mostly adenocarcinoma, arising from different sites of the biliary tract with diverse aetiology, molecular profiling, TNM classification, and surgical procedures and outcomes of resectable diseases. 1 Valle JW Kelley RK Nervi B Oh D-Y Zhu AX Biliary tract cancer. Lancet. 2021; 397: 428-444 Summary Full Text Full Text PDF PubMed Scopus (181) Google Scholar Radical surgical resection remains the only curative treatment, but postoperative relapse is common. 1 Valle JW Kelley RK Nervi B Oh D-Y Zhu AX Biliary tract cancer. Lancet. 2021; 397: 428-444 Summary Full Text Full Text PDF PubMed Scopus (181) Google Scholar Developing effective adjuvant therapy is mandatory. However, two modern observation-controlled phase 3 trials, the BCAT trial 2 Ebata T Hirano S Konishi M et al. Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer. Br J Surg. 2018; 105: 192-202 Crossref PubMed Scopus (192) Google Scholar and the PRODIGE 12-ACCORD 18 trial, 3 Edeline J Benabdelghani M Bertaut A et al. Gemcitabine and oxaliplatin chemotherapy or surveillance in resected biliary tract cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): a randomized phase III study. J Clin Oncol. 2019; 37: 658-667 Crossref PubMed Scopus (230) Google Scholar did not show the benefit of adjuvant gemcitabine-based chemotherapy in resected biliary tract cancers. BILCAP 4 Primrose JN Fox RP Palmer DH et al. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol. 2019; 20: 663-673 Summary Full Text Full Text PDF PubMed Google Scholar was the first phase 3 study to support the role of adjuvant chemotherapy, with oral capecitabine, for resected biliary tract cancers. 5 Shroff RT Kennedy EB Bachini M et al. Adjuvant therapy for resected biliary tract cancer: ASCO clinical practice guideline. J Clin Oncol. 2019; 37: 1015-1027 Crossref PubMed Scopus (198) Google Scholar , 6 Yoo C Jeong H Kim KP et al. Adjuvant gemcitabine plus cisplatin (GemCis) versus capecitabine (CAP) in patients (pts) with resected lymph node (LN)-positive extrahepatic cholangiocarcinoma (CCA): a multicenter, open-label, randomized, phase 2 study (STAMP). Proc Am Soc Clin Oncol. 2022; 404019 Google Scholar , 7 Stein A Arnold D Bridgewater J et al. Adjuvant chemotherapy with gemcitabine and cisplatin compared to observation after curative intent resection of cholangiocarcinoma and muscle invasive gallbladder carcinoma (ACTICCA-1 trial)—a randomized, multidisciplinary, multinational phase III trial. BMC Cancer. 2015; 15: 564 Crossref PubMed Google Scholar The recommendation mainly relied on a significant improvement in overall survival by the prespecified sensitivity analysis (hazard ratio [HR]=0·71, 95% CI 0·55–0·92) but not on overall survival (ie, the primary endpoint; HR=0·81, 95% CI 0·63–1·04) in the primary, intention-to-treat analysis, 4 Primrose JN Fox RP Palmer DH et al. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol. 2019; 20: 663-673 Summary Full Text Full Text PDF PubMed Google Scholar and is thus debatable. The adjusted HR for overall survival increased to 0·84 (95% Cl 0·67–1·06) and the HR for recurrence-free survival was 0·81 (95% Cl 0·65–1·01) in the extension report, 8 Bridgewater J Fletcher P Palmer DH et al. Long-term outcomes and exploratory analyses of the randomized phase III BILCAP study. J Clin Oncol. 2022; 40: 2048-2057 Crossref PubMed Scopus (11) Google Scholar which further weakened the recommendation. 9 Edeline J Malka D Capecitabine: still a standard option in the adjuvant setting of biliary tract cancer?. J Clin Oncol. 2022; 40: 3667-3668 Crossref PubMed Scopus (1) Google Scholar Adjuvant S-1 compared with observation in resected biliary tract cancer (JCOG1202, ASCOT): a multicentre, open-label, randomised, controlled, phase 3 trialAlthough long-term clinical benefit would be needed for a definitive conclusion, a significant improvement in survival suggested adjuvant S-1 could be considered a standard of care for resected biliary tract cancer in Asian patients. Full-Text PDF

PH Responsive Hydrogels for the Delivery of Capecitabine: Development, Optimization and Pharmacokinetic Studies.

The objective of the current study was to achieve a sustained release profile of capecitabine (CAP), an anticancer agent frequently administered in conventional dosage form due to its short plasma half-life. A drug-loaded smart pH responsive chitosan/fenugreek-g-poly (MAA) hydrogel was synthesized by an aqueous free radical polymerization technique. The developed network was evaluated for capecitabine loading %, swelling response, morphology, structural and compositional characteristics, and drug release behavior. Significantly higher swelling and in vitro drug release rate were exhibited by formulations at pH 7.4 than at pH 1.2, demonstrating the pH responsive character of hydrogels. Swelling percentage and CAP loading ranged within 74.45-83.54% and 50.13-72.43%, respectively. Maximum release, up to 93%, was demonstrated over 30 h, evidencing the controlled release pattern of CAP from hydrogels. The optimized formulation was further screened for acute oral toxicity studies. No signs of oral, dermal, or ocular toxicities were noticed, confirming safety evidence of the network. Furthermore, pharmacokinetic analysis demonstrated the sustained release response of CAP from hydrogels as confirmed by a significant increase in plasma half-life (t1/2) (13 h) and AUC (42.88 µg h/mL) of CAP. Based on these findings, fabricated hydrogels are strongly recommended as a biocompatible carrier for colorectal delivery of active agents.

Influence of oxidative stress on drug-DNA binding: Microcalorimetric and mechanistic insights with anticancer drugs

Oxidative stress causing the chronic inflammation, mediates to deadly diseases such as cancer, diabetes, cardiovascular disease. Maintaining the ratio of reactive oxygen species generation to scavenging, thus the oxidative stress is important to have healthy cells. Oxidative stress not only causes the deadly diseases but also affect the conformation of biomolecules such as protein and DNA, even at lower concentrations. Binding of drugs to DNA is susceptible to these DNA structural or conformational changes. Here, we have reported the influence of oxidative stress on binding of anti-cancer drugsdoxorubicin hydrochloride (DOX),mitoxantrone dihydrochloride (MTX), capecitabine (CPT), and ethidium bromide (EtBr) with DNA. Quantitative insights of association of these anticancer drugs with DNA in presence of different environments, in vitro (pH – 7.4), cellular (100:1 ratio of GSH to GSSG) and oxidative stress condition (1:1 ratio of GSH to GSSG) have been compared. Microcalorimetry has been used for determination of thermodynamic parameters, binding constant Kb, molar enthalpy of interaction (ΔHm), molar entropy of interaction (ΔSm) & stoichiometry (n). Fluorescence spectroscopy has been used to illustrate the mode of drug-DNA binding and also to complement the ITC results. Insignificant changes in thermodynamic parameters for drug-DNA binding in in vitro and in presence of cellular condition were observed whereas significant decrease in binding affinity and stoichiometry was observed in the presence of oxidative stress conditions. Quantitative understanding of drug-DNA binding and influence of oxidative stress in terms of thermodynamic signature assists in the structure-based drug designing and development.

Preoperative Chemoradiotherapy With Capecitabine With or Without Temozolomide in Patients With Locally Advanced Rectal Cancer: A Prospective, Randomised Phase II Study Stratified by O6-Methylguanine DNA Methyltransferase Status: KCSG-CO17-02

AimsTo evaluate the clinical efficacy of adding temozolomide (TMZ) to preoperative capecitabine (CAP)-based chemoradiotherapy in patients with locally advanced rectal cancer (LARC) and validate O6-methylguanine DNA methyltransferase (MGMT) methylation status as a predictive marker for TMZ combined regimens. Materials and methodsLARC patients with clinical stage II (cT3-4N0) or III (cTanyN+) disease were enrolled. They were stratified into unmethylated MGMT (uMGMT) and methylated MGMT (mMGMT) groups by methylation-specific polymerase chain reaction before randomisation and were then randomly assigned (1:1) to one of four treatment arms: uMGMT/CAP (arm A), uMGMT/TMZ + CAP (arm B), mMGMT/CAP (arm C) and mMGMT/TMZ + CAP (arm D). The primary end point was the pathological complete response (pCR) rate. ResultsBetween November 2017 and July 2020, 64 patients were randomised. Slow accrual caused early study termination. After excluding four ineligible patients, 60 were included in the full analysis set. The pCR rate was 15.0% (9/60), 0%, 14.3%, 18.8% and 26.7% for the entire cohort, arms A, B, C and D, respectively (P = 0.0498 between arms A and D). The pCR rate was 9.7% in the CAP group (arms A + C), 20.7% in the TMZ + CAP group (arms B + D), 6.9% in the uMGMT group (arms A + B) and 22.6% in the mMGMT group (arms C + D). Grade 1–2 nausea or vomiting was significantly more frequent in the TMZ + CAP treatment groups (arms B + D) than in the CAP treatment groups (arms A + C, P < 0.001) with no difference in grade 3 adverse events. There were no grade 4 or 5 adverse events. ConclusionThe addition of TMZ to CAP-based chemoradiotherapy tended to improve pCR rates, particularly in those with mMGMT LARC. MGMT status may warrant further investigation as a predictive biomarker for chemotherapeutic agents and radiotherapy.

An HP-TLC densitometric method and fingerprinting for estimating capecitabine and thymoquinone simultaneously and its application in nanoscience using Box–Behnken design

World Health Organization estimates that 10% of medications are of inferior quality, thus dangerous to human health. One way to avoid such a problem is to create an adequate, economical, and competitive analytical system. As a result, the study’s goal is to create a High-Performance Thin Layer Chromatography (HP-TLC) method for determining capecitabine (CAP) and thymoquinone (TQ) simultaneously. To the best of our knowledge, no such method for determining CAP and TQ simultaneously exists today. The method was created by implementing an analytical quality-by-design approach based on the Box–Behnken design (BBD) to optimize the chromatographic conditions and a combination of factors such as toluene volume (A), solvent front (B), and chamber saturation time (C), all of which were likely to affect the R f of CAP and TQ, respectively, later validated using TLC-silica coated plate 60 F254. The validated parameters were within an acceptable range, according to ICH guidelines. BBD design revealed that the volume of toluene and solvent front had a greater effect on all of the responses studied and thus needs to be controlled. The developed method of the analysis was found to be facile, dependable, expeditious, cost-effective, and could be used to quantify CAP and TQ in Nanoformulation.

215 (PB095) - OQL036 topical gel inhibits the skin toxicity associated with 5-fluorouracil/capecitabine: results from in vitro and in vivo preclinical studies

Background: Hand-Foot Syndrome (HFS) is a dermatological toxicity induced by capecitabine (CAP)/fluorouracil (5FU). HFS is related to damage of palmar/plantar epidermal/dermal cells by 5FU, and inflammation-mediated by cyclooxygenase-2 pathways. We hypothesize applying OQL036 a topical gel prodrug metabolizing to thymidine (TdR) and naproxen (NAP) may alleviate HFS toxicity associated with CAP/5FU.

Preparation of Molecularly Imprinted Polymer Microspheres for Selective Solid-Phase Extraction of Capecitabine in Urine Samples.

Molecularly imprinted solid-phase extraction to treat biological samples has attracted considerable attention. Herein, molecularly imprinted polymer (MIP) microspheres with porous structures were prepared by a combined suspension-iniferter polymerization method using capecitabine (CAP) as a template molecule. This material was subsequently used as a solid-phase extraction agent to separate and enrich drug molecules in urine samples. UV analysis revealed that methacrylate (MAA) was an ideal functional monomer, and 1H Nuclear Magnetic Resonance (1H NMR), Ultraviolet (UV), and Fourier transform-infrared (FT-IR) spectroscopic analyses were used to study the interaction forces between MAA and CAP, demonstrating that hydrogen bonding was the primary interaction force. MIPs with outstanding selectivity were successfully prepared, and the analysis of their surface morphology and chemical structure revealed a spherical morphology with small holes distributed across a rough surface. This surface morphology significantly reduced the mass transfer resistance of template molecules, providing an ideal template recognition effect. Using the molecularly imprinted solid-phase extraction method, CAP and the structural analog cytidine (CYT) were pretreated in urine samples and quantified by HPLC. The results showed that CAP and CYT recoveries reached 97.2% and 39.8%, respectively, with a limit of detection of 10.0–50.0 µg·mL−1. This study provides a novel approach to drug molecule pretreatment that can be applied in drug separation and functional materials science fields.

Cost-Effectiveness of Pharmacologic Treatment Options for Women With Endocrine-Refractory or Triple-Negative Metastatic Breast Cancer.

Treatments for endocrine-refractory or triple-negative metastatic breast cancer (mBC) are modestly effective at prolonging life and improving quality of life but can be extremely expensive. Given these tradeoffs in quality of life and cost, the optimal choice of treatment sequencing is unclear. Cost-effectiveness analysis can explicitly quantify such tradeoffs, enabling more informed decision making. Our objective was to estimate the societal cost-effectiveness of different therapeutic alternatives in the first- to third-line sequences of single-agent chemotherapy regimens among patients with endocrine-refractory or triple-negative mBC. Using three dynamic microsimulation models of 10,000 patients each, three cohorts were simulated, based upon prior chemotherapy exposure: (1) unexposed to either taxane or anthracycline, (2) taxane- and anthracycline-exposed, and (3) taxane-exposed/anthracycline-naive. We focused on the following single-agent chemotherapy regimens as reasonable and commonly used options in the first three lines of therapy for each cohort, based upon feedback from oncologists treating endocrine-refractory or triple-negative mBC: (1) for taxane- and anthracycline-unexposed patients, paclitaxel, capecitabine (CAPE), or pegylated liposomal doxorubicin; (2) for taxane- and anthracycline-exposed patients, Eribulin, CAPE, or carboplatin; and (3) for taxane-exposed/anthracycline-naive patients, pegylated liposomal doxorubicin, CAPE, or Eribulin. In each cohort, accumulated quality-adjusted life-years were similar between regimens, but total societal costs varied considerably. Sequences beginning first-line treatment with paclitaxel, carboplatin, and CAPE, respectively, for cohorts 1, 2, and 3, had lower costs and similar or slightly better outcomes compared with alternative options. In this setting where multiple single-agent chemotherapy options are recommended by clinical guidelines and share similar survival and adverse event trajectories, treatment sequencing approaches that minimize costs early may improve the value of care.

The efficacy and safety of gemcitabine-based combination therapy vs. gemcitabine alone for the treatment of advanced pancreatic cancer: a systematic review and meta-analysis.

BackgroundGemcitabine (GEM) is used as a standard first-line drug to effectively alleviate symptoms and prolong survival time for advanced pancreatic cancer. Most randomized controlled trials (RCTs) show that GEM-based combination therapy is better than GEM alone, while some RCTs have the opposite conclusion. This study aimed to investigate whether GEM-based combination therapy would be superior to GEM alone by a systematic review and meta-analysis.MethodsAccording to the PICOS principles, RCTs (S) focused on comparing GEM-based combination therapy (I) vs. GEM alone (C) for advanced pancreatic cancer (P) were collected from eight electronic databases, outcome variables mainly include survival status and adverse events (AEs) (O). Review Manager 5.4 was used to evaluate the pooled effects of the results among selected articles. Pooled estimate of hazard ratio (HR) and odds ratio (OR) with 95% confidence interval (CI) were used as measures of effect sizes. Quality assessment for individual study was performed using the Cochrane tool for risk of bias.ResultsA total of 17 studies including 5,197 patients were selected in this analysis. The pooled results revealed that GEM-based combination therapy significantly improved the overall survival (OS; HR =0.84; 95% CI: 0.79 to 0.90; P<0.00001), progression-free survival (PFS; HR =0.78; 95% CI: 0.72 to 0.84; P<0.00001), overall response rate (ORR; OR =1.92; 95% CI: 1.61 to 2.30; P<0.00001), 1-year survival rate (OR =1.44; 95% CI: 1.02 to 2.03; P=0.04), respectively. Subgroup analysis showed that the efficacy of GEM plus capecitabine (CAP) and GEM plus S-1 was better than that of GEM alone, while GEM plus cisplatin (CIS) did not achieve an improved effect. GEM-based combination therapy can significantly increase the incidence of AEs, such as leukopenia (P<0.001), neutropenia (P<0.001), anemia (P<0.05), nausea (P<0.001), diarrhea (P<0.05), and stomatitis (P<0.001). No publication bias existed in our meta-analysis (P>0.10).DiscussionOur study supported that GEM-based combination therapy was more beneficial to improve patient’s survival than GEM alone, while there was no additional benefits in GEM plus CIS. We also found that GEM-based combination therapy increased the incidence of AEs. Clinicians need to choose the appropriate combination therapy according to the specific situation.

Hybrid laser activated phycocyanin/capecitabine treatment of cancerous MCF7 cells.

Laser-induced fluorescence is recently used as an efficient technique in cancer diagnosis and non-invasive treatment. Here, the synergic therapeutical efficacies of the Capecitabine (CAP) chemodrug, photosensitive Phycocyanin (PC) and graphene oxide (GO) under laser irradiation were investigated. The therapeutical efficacies of diverse concentrations of CAP (0.001-10 mg/ml) and PC (0.5-10 mg/ml) alone and with laser irradiation on human breast adenocarcinoma (MCF-7) cells were examined. The interactional effects of 100 mW SHG Nd:YAG laser at 532nm and GaAs laser at 808 nm ranging power of 150 mW- 2.2W were considered. The contribution of graphene oxide (GO) in biocompatible concentrations of 2.5-20 ng/ml and thermal characteristics of laser exposure at 808 nm on GO + fluorophores have been studied. The effects of the bare and laser-excited CAP + PC on cell mortality have been obtained. Despite the laser irradiation could not hold up the cell proliferation in the absence of drug interaction considerably; however, the viability of the treated cells (by a combination of fluorophores) under laser exposure at 808 nm was significantly reduced. The laser at 532 nm excited the fluorescent PC in (CAP + PC) to trigger the photodynamic processes via oxygen generation. Through the in-vitro experiments of laser-induced fluorescence (LIF) spectroscopy of PC + CAP, the PC/CAP concentrations of the maximum fluorescence signal and spectral shifts have been characterized. The synergic effects of the laser exposures and (CAP + PC) treatment at different concentrations were confirmed. It has been shown here that the laser activation of (CAP + PC) can induce the mortality of the malignant cells by reducing the chemotherapeutic dose of CAP to avoid its non-desirable side effects and by approaching the minimally invasive treatment. Elevation of the laser intensity/exposure time could contribute to the therapeutic efficacy. Survival of the treated cells with a combination of GO and fluorophores could be reduced under laser exposure at 808 nm compared to the same combination therapy in the absence of GO. This survey could benefit the forthcoming clinical protocols based on laser spectroscopy for in-situ imaging/diagnosis/treatment of adenocarcinoma utilizing PC + CAP + GO.

PNA-Modified Liposomes Improve the Delivery Efficacy of CAPIRI for the Synergistic Treatment of Colorectal Cancer.

Tumor-associated antigen mucin 1 (MUC1) is highly expressed in colorectal cancer and is positively correlated with advanced stage at diagnosis and poor patient outcomes. The combination of irinotecan and capecitabine is standard chemotherapy for metastatic colorectal cancer and is known as XELIRI or CAPIRI, which significantly prolongs the progression-free survival and overall survival of colorectal cancer patients compared to a single drug alone. We previously reported that peanut agglutinin (PNA)-conjugated liposomes showed enhanced drug delivery efficiency to MUC1-positive liver cancer cells. In this study, we prepared irinotecan hydrochloride (IRI) and capecitabine (CAP)-coloaded liposomes modified by peanut agglutinin (IRI/CAP-PNA-Lips) to target MUC1-positive colorectal cancer. The results showed that IRI/CAP-PNA-Lips showed an enhanced ability to target MUC1-positive colorectal cancer cells compared to unmodified liposomes. Treatment with IRI/CAP-PNA-Lips also increased the proportion of apoptotic cells and inhibited the proliferation of colorectal cancer cells. The targeting specificity for tumor cells and the antitumor effects of PNA-modified liposomes were significantly increased in tumor-bearing mice with no severe cytotoxicity to normal tissues. These results suggest that PNA-modified liposomes could provide a new delivery strategy for the synergistic treatment of colorectal cancer with clinical chemotherapeutic agents.