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"An anthracycline which is the 4'-epi-isomer of doxorubicin. The compound exerts its antitumor effects by interference with the synthesis and function of DNA." (MeSH 2013)

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Latest Research Publications

Web Resources: Epirubicin (6 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Lian F, Chen W, Liu Y, et al.
Intra-arterial chemotherapy combined with intravesical chemotherapy is effective in preventing recurrence in non-muscle invasive bladder cancer.
J Cancer Res Clin Oncol. 2019; 145(6):1625-1633 [PubMed] Related Publications
OBJECTIVE: To evaluate the efficacy and safety of intra-arterial chemotherapy (IAC) combined with intravesical chemotherapy (IC) in non-muscle invasive bladder cancer (NMIBC) and identify the risk factors for recurrence and progression.
METHODS: This is a retrospective cohort study of NMIBC patients in south China. Ninety-nine patients underwent IAC combined with transurethral resection of bladder tumor (TURBT) and IC, and 50 patients underwent TURBT plus IC without IAC. The 5-year outcomes of the two groups were compared. Cox regression was used to evaluate risk factors. Kaplan-Meier curves were used to assess the significant differences of recurrence-free survival and progression-free survival.
RESULTS: At 5 years, IAC significantly reduced the recurrence of high-grade NMIBC, 54.5% (18/33) in the non-IAC group vs 30.5% (18/59) in the IAC group (p = 0.028). IAC significantly reduced the recurrence of high-risk NMIBC, 56.3% (18/32) in the non-IAC group vs 26.1% (18/69) in the IAC group (p = 0.007). IAC significantly reduced the recurrence of intermediate-risk NMIBC, 44.4% (8/18) in the non-IAC group vs 22.2% (6/27) in the IAC group (p = 0.030). Tumors numbering from 2 to 7 had the highest recurrence rate (18.1%, 27/149). In this aspect, there was a significantly lower recurrence rate in the IAC group (30.8%, 12/30) than in the non-IAC group (68.2%, 15/22) (p = 0.007). No significant difference was found in the progression rate between the two groups. Only two cases (2/99, 2.0%) in the IAC group showed progression. The results of univariate and multivariate analyses suggested that the number of tumors, grade and risk level were risk factors for recurrence. No difference was found with respect to gender, age, tumor diameter, and T category. In the Kaplan-Meier plot, recurrence-free survival was significantly associated with treatment strategies (p < 0.01). Recurrence-free survival was shorter in the non-IAC group (12.73 ± 7.56 months) than in the IAC group (17.88 ± 12.26 months).
CONCLUSIONS: Combined IAC is a promising procedure to prevent recurrence and may be useful to suppress progression in NMIBC patients. The independent risk factors for the recurrence of NMIBC were multifocal tumors, grade and risk level. Intra-arterial chemotherapy is an effective and safe procedure and may be a promising choice in areas where BCG is not available or for patients who are intolerant to BCG.

Wang L, Pei J, Cong Z, et al.
Development of anisamide-targeted PEGylated gold nanorods to deliver epirubicin for chemo-photothermal therapy in tumor-bearing mice.
Int J Nanomedicine. 2019; 14:1817-1833 [PubMed] Free Access to Full Article Related Publications
Background: Gold nanorods (AuNRs), due to the optical and electronic properties namely the surface plasma resonance, have been developed to achieve the light-mediated photothermal therapy (PTT) for cancer. However, PTT alone may suffer from inefficient tumor killing. Recently, the combination of PTT and chemotherapy has been utilized to achieve synergistic anticancer effects.
Methods: In this study, AuNRs capped with hexadecyltrimethylammonium bromide (CTAB), poly(acrylic acid) (PAA), and PEGylated anisamide (a ligand known to target the sigma receptor) have been developed to produce a range of negatively charged anisamide-targeted PEGylated AuNRs (namely Au-CTAB-PAA-PEG-AA) for the combination of PTT and chemotherapy (termed as chemo-photothermal therapy [CPTT]). Epirubicin (EPI, an anthracycline drug) was efficiently loaded onto the surface of Au
Results: The resultant complex demonstrated pH-dependent drug release, facilitated nucleus trafficking of EPI, and induced antiproliferative effects in human prostate cancer PC-3 cells. When Au
Conclusion: These results demonstrate a promising strategy for clinical application of CPTT in cancer.

Suo N, Wang M, Jin Y, et al.
Magnetic multiwalled carbon nanotubes with controlled release of epirubicin: an intravesical instillation system for bladder cancer.
Int J Nanomedicine. 2019; 14:1241-1254 [PubMed] Free Access to Full Article Related Publications
Background: Traditional intravesical instillation treatment in bladder cancer has limited efficacy, which results in a high frequency of recurrence.
Purpose: The aim of this study was to report on an epirubicin (EPI)-loaded magnetic multi-walled carbon nanotube (mMWCNTs-EPI) system for intravesical instillation in place of the current formulation.
Methods: The mMWCNTs-EPI system was formulated with carboxylated MWCNTs, Fe
Results: Under the effect of external magnets, the mMWCNTs-EPI system showed sustained release and prolonged retention behavior and better antitumor activity than free EPI. The mMWCNTs-EPI system had higher efficiency in enhancing cytotoxicity and inhibiting proliferation in vitro and in vivo than free EPI. Our studies also revealed the atoxic nature of mMWCNTs.
Conclusion: These findings suggested that mMWCNTs are effective intravesical instillation agents with great potential for clinical application.

Lucatelli P, Ginnani Corradini L, De Rubeis G, et al.
Balloon-Occluded Transcatheter Arterial Chemoembolization (b-TACE) for Hepatocellular Carcinoma Performed with Polyethylene-Glycol Epirubicin-Loaded Drug-Eluting Embolics: Safety and Preliminary Results.
Cardiovasc Intervent Radiol. 2019; 42(6):853-862 [PubMed] Free Access to Full Article Related Publications
PURPOSE: To report technical success, safety profile and oncological results of balloon-occluded transcatheter arterial chemoembolization using a balloon micro-catheter and epirubicin-loaded polyethylene-glycol (PEG) microsphere (100 ± 25 µm and 200 ± 50 µm) in patients with hepatocellular carcinoma (HCC).
MATERIALS AND METHODS: This is a single-centre, single-arm, retrospective study with 6-month follow-up. Twenty-two patients (Child-Pugh A 68% [15/22], B in 32% [7/22]; age 67.05 ± 14 years) with 29 HCC were treated in 24 procedures. Technical success is defined: ability to place the balloon micro-catheter within the required vascular segment, balloon-occluded arterial stump pressure drops and assessment of microsphere deposition. Laboratory assessment pre/post-procedural and complications were analysed, respectively, according to Common Terminology Criteria for Adverse Events (CTCAEv5) and CIRSE system. Postembolization syndrome (PES) was defined as fever and/or nausea and/or pain onset. Oncological results were evaluated using m-RECIST criteria with CT/MRI imaging at 1 and 3-6 months. In partial responder patients, pre/post-procedural tumour volume was compared.
RESULTS: Pre-planned feeder was reached in all cases. Pressure drop average was 51.1 ± 21.6 mmHg. Exclusive target embolization was achieved in 14/24 procedures (58.3%). Laboratory test modifications were all grade 1. 4/24 adverse events occurred (17%): pseudo-aneurysm of the feeder (grade 3), liver abscess (grade 2) and 2 asymptomatic segmentary biliary tree dilatations (grade 2). PES occurred in 8/24 (33%). The complete response at 1 and 3-6 months was 44.8% (13/29) and 52.9% (9/17), respectively. The partial response at 1 and 3-6 months was 55% (16/29) and 4/17 (23.5%), respectively. Among partial responder patients, the average percentage of tumour volume reduction was 64.9 ± 27.3%.
CONCLUSION: Epirubicin-loaded PEG microsphere b-TACE is technically feasible, safe and effective procedure for HCC treatment.

Lucatelli P, Argirò R, De Rubeis G, et al.
Polyethylene Glycol Epirubicin-Loaded Transcatheter Arterial Chemoembolization Procedures Utilizing a Combined Approach with 100 and 200 μm Microspheres: A Promising Alternative to Current Standards.
J Vasc Interv Radiol. 2019; 30(3):305-313 [PubMed] Related Publications
PURPOSE: To report clinical effectiveness, toxicity profile, and prognostic factors of combined 100 μm ± 25 and 200 μm ± 50 epirubicin-loaded polyethylene glycol (PEG) microsphere drug-eluting embolic transcatheter arterial chemoembolization protocol in patients with hepatocellular carcinoma.
MATERIALS AND METHODS: In this prospective, single-center, single-arm study with 18 months of follow-up, 36 consecutive patients (mean age 69.9 y ± 10.8; 26 men, 10 women; 54 naïve lesions) were treated. Embolization was initiated with 100 μm ± 25 microspheres, and if stasis (10 heart beats) was not achieved, 200 μm ± 50 microspheres were administered. Each syringe (2 mL) of PEG microsphere was loaded with 50 mg of epirubicin. Results were evaluated using Modified Response Evaluation Criteria In Solid Tumors with multidetector computed tomography/magnetic resonance imaging at 1, 3-6, 9-12, and 15-18 months. Toxicity profile was assessed by laboratory testing before and after the procedure. Complications were recorded. Postembolization syndrome (PES) was defined as onset of fever/nausea/pain after the procedure. Patient/lesion characteristics and treatment results were correlated with predicted outcome using regression analysis. Child-Pugh score was A in 86.1% of patients (31/36) and B in 13.9% (5/36).
RESULTS: In 10 of 21 lesions, < 2 cm in diameter (47.5%) stasis was achieved with 100 μm ± 25 microspheres only, whereas all other lesions required adjunctive treatment with 200 μm ± 50 microspheres. Reported adverse events were grade 1 acute liver bile duct injury (3/39 cases, 7.7%) and PES (grade 2; 3/39 cases, 7.7%). Complete response (CR) at 1, 3-6, 9-12, and 15-18 months was 61.1%, 65.5%, 63.63%, and 62.5%. Objective response (CR + partial response) at 1, 3-6, 9-12, and 15-18 months was 83.3%, 65.85%, 63.63%, and 62.5%. No single factor (laboratory testing, etiology, patient status, hepatic status, tumor characteristics, administration protocol) predicted outcomes except for albumin level at baseline for CR (P < .05, odds ratio = 1.09).
CONCLUSIONS: The combined microsphere sizing strategy was technically feasible and yielded promising results in terms of effectiveness and toxicity.

Yazdian-Robati R, Arab A, Ramezani M, et al.
Smart aptamer-modified calcium carbonate nanoparticles for controlled release and targeted delivery of epirubicin and melittin into cancer cells in vitro and in vivo.
Drug Dev Ind Pharm. 2019; 45(4):603-610 [PubMed] Related Publications
To explore the effect of combination therapy of epirubicin (Epi) and melittin (Mel) to cancer cells, calcium carbonate nanoparticles (CCN), as carriers, were developed which were modified with MUC1-Dimer aptamers as targeting agents. Both Epi and Mel were delivered at the same time to cancer cells overexpressing the target of MUC1 aptamer, mucin 1 glycoproteins (MCF7 and C26 cells). CCN were prepared with a water-in-oil emulsion method. Epi and Mel were separately encapsulated in CCN and the nanoparticles were modified with MUC1-Dimer aptamers. In vitro studies, including MTT assay, flow cytometry analysis and fluorescence imaging were applied to investigate the targeting and cell proliferation inhibition capabilities of MUC1-Dimer aptamer-CCN-Mel complex and MUC1-Dimer aptamer-CCN-Epi complex in the target (MCF-7 and C26 cells) and nontarget (HepG2) cells. Also, the function of the developed complexes was analyzed using in vivo tumor growth inhibition. The release of Epi from MUC1-Dimer aptamer-CCN-Epi complex was pH-sensitive. Cellular uptake studies showed more internalization of the MUC1-Dimer aptamer-CCN-Epi complex into MCF-7 and C26 cells (target) compared to HepG2 cells (nontarget). Interestingly, the MUC1-Dimer aptamer-CCN-Mel complex and MUC1-Dimer aptamer-CCN-Epi complex indicated very low toxicity as compared to target cells. Moreover, co-delivery of Epi and Mel using the mixture of MUC1-Dimer aptamer-CCN-Mel complex and MUC1-Dimer aptamer-CCN-Epi complex exhibited strong synergistic cytotoxicity in MCF-7 and C26 cells. Furthermore, the presented complexes had a better function to control tumor growth in vivo compared to free Epi.

Li H, Hu B, Guo Z, et al.
Correlation of UGT2B7 Polymorphism with Cardiotoxicity in Breast Cancer Patients Undergoing Epirubicin/Cyclophosphamide-Docetaxel Adjuvant Chemotherapy.
Yonsei Med J. 2019; 60(1):30-37 [PubMed] Free Access to Full Article Related Publications
PURPOSE: The present study aimed to investigate correlations between uridine glucuronosyltransferase 2B7 (UGT2B7) -161 single nucleotide polymorphism C to T (C>T) and the occurrence of cardiotoxicity in Chinese breast cancer (BC) patients undergoing epirubicin/cyclophosphamide-docetaxel (EC-D) adjuvant chemotherapy.
MATERIALS AND METHODS: 427 BC patients who had underwent surgery were consecutively enrolled in this prospective cohort study. All patients were scheduled to receive EC-D adjuvant chemotherapy regimen, and they were divided into UGT2B7 -161 CC (n=141), UGT2B7 -161 CT (n=196), and UGT2B7 -161 TT (n=90) groups according to their genotypes. Polymerase chain reaction was performed for determination of UGT2B7 -161 genotypes. Cardiotoxicity was defined as an absolute decline in left ventricular ejection fraction (LVEF) of at least 10% points from baseline to a value less than 53%, heart failure, acute coronary artery syndrome, or fatal arrhythmia.
RESULTS: LVEF values were lower at cycle (C) 4, C8, 3 months after chemotherapy (M3), M6, M9, and M12 compared to C0 (all
CONCLUSION: A UGT2B7 -161 T allele serves as a potential biomarker for predicting a low occurrence of cardiotoxicity in BC patients undergoing EC-D adjuvant chemotherapy.

Liu H, Xie MR, Gao H, Li J
Influence of pharmorubicin on the left ventricular ejection fraction of patients with breast cancer: A mechanism study.
J Cancer Res Ther. 2018; 14(Supplement):S1183-S1187 [PubMed] Related Publications
Aims: Breast cancer is a great public health problem. It remains unclear how pharmorubicin induces cardiac dysfunction in patients with breast cancer. Our study was aimed to explore the influence of pharmorubicin on the left ventricular ejection fraction (EF) of patients with breast cancer and its potential mechanism.
Materials and Methods: Patients with breast cancer were enrolled at the same hospital. Group I consisted of 135 samples, who were under treatment of pharmorubicin (200 mg/m
Results: The ultrasound results showed that pharmorubicin treatment significantly jeopardized cardiac function, verified by decrease of both EF and fractional shortening (FS) (P < 0. 05). Moreover, such effect was dose-dependent. Oxygen free radical level was remarkably increased after pharmorubicin treatment (P < 0. 05), verified by flow cytometry. Adjunctive therapy of NAC decreased oxygen free radical level and improved cardiac function of patients with breast cancer, suggesting NAC ameliorated side effect of pharmorubicin treatment.
Conclusions: Pharmorubicin treatment decreased EF and FS of patients with breast cancer through increasing oxygen free radical level in hemocytes. Adjunctive therapy of NAC could be a potential treatment to ameliorated side effect pharmorubicin treatment.

Bahreyni A, Alibolandi M, Ramezani M, et al.
A novel MUC1 aptamer-modified PLGA-epirubicin-PβAE-antimir-21 nanocomplex platform for targeted co-delivery of anticancer agents in vitro and in vivo.
Colloids Surf B Biointerfaces. 2019; 175:231-238 [PubMed] Related Publications
Conventional chemotherapy suffers from several drawbacks, including toxic side effects together with the development of resistance to the chemical agents. Therefore, exploring alternative therapeutic approaches as well as developing targeted delivery systems are in demand. Oligonucleotide-based therapy has emerged as a promising and alternative procedure for treating malignancies involving gene-related diseases. In the current study, a targeted delivery system was designed to target cancer cells based on two biocompatible polymers of poly (β amino ester) (PβAE) and poly (d, l-lactide-co-glycolide) (PLGA). In this system, antimir-21 as an inhibitor of microRNA-21 (miR-21) which is an oncomiR overexpressed in several human cancers was condensed with PβAE polymer and then PLGA was electrostatically deposited on this complex and provided a reservoir for positively charged drug, epirubicin (Epi). At the final stage, MUC1 aptamer as a targeting agent was covalently attached to the nanoparticles for selectively guided therapeutic delivery. The obtained results demonstrated that the fabricated MUC1 aptamer-modified nanocomplex could efficiently be internalized into MCF7 (human breast carcinoma cell) and C26 (murine colon carcinoma cell) cells through interaction between MUC1 aptamer and its receptor on the surfaces of these cell lines and decline cell viability in these cells but not in CHO cells (Chinese hamster ovary cell) as nontarget cells (MUC1 negative cells). The safety of PLGA-Epi-PβAE-antimir-21 nanocomplex and synergetic effect of Epi and antimir-21 in reducing cell viability of target cells were confirmed by treating MCF-7 and CHO cells with nanocomplex and MUC1 aptamer-modified nanocomplex. Moreover, it was demonstrated that MUC1 aptamer-modified nanocomplex could remarkably inhibit tumor growth in tumor-bearing mice compared with Epi alone.

Pan XK, Su F, Xu LH, et al.
DJ-1 Alters Epirubicin-induced Apoptosis via Modulating Epirubicinactivated Autophagy in Human Gastric Cancer Cells.
Curr Med Sci. 2018; 38(6):1018-1024 [PubMed] Related Publications
Epirubicin, which is a conventional chemotherapeutic drug for gastric cancer, has innate and adaptive chemoresistance. Recent studies revealed that epirubicin could induce autophagy as a defensive mechanism in drug resistance of mammary carcinoma. Another study implied that DJ-1 may be a chemoresistance-related gene. But the association between DJ-1 and drug resistance of epirubicin in gastric cancer is still ambiguous. In the present report, we explored whether and how DJ-1 conduced to epirubicin-induced apoptosis in gastric cancer. Epirubicin dose-dependently increased the expression of DJ-1 and induced autophagy. Knockdown of DJ-1 notably enhanced epirubicin-induced cell apoptosis, whereas overexpression of DJ-1 attenuated epirubicin-induced cell apoptosis. Further studies revealed that down-regulation of DJ-1 modulated epirubicinactivated autophagy which augmented epirubicin-induced apoptosis. In conclusion, our results validated that DJ-1 reduced epirubicin-induced apoptosis in gastric cancer cells via modulating epirubicin-activated autophagy.

Zhang X, Pan Y, Fu H, Zhang J
Nucleolar and Spindle Associated Protein 1 (NUSAP1) Inhibits Cell Proliferation and Enhances Susceptibility to Epirubicin In Invasive Breast Cancer Cells by Regulating Cyclin D Kinase (CDK1) and DLGAP5 Expression.
Med Sci Monit. 2018; 24:8553-8564 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Differentially expressed genes (DEGs) of IBC were selected from the Gene Expression Omnibus (GEO) chip data: GSE21422 and GSE21974. Network analysis of the DEGs and IBC-related genes was performed in STRING database to find the core gene. Thus, this study aimed to determine the role of NUSAP1 in invasive breast cancer (IBC) and to investigate its effect on drug susceptibility to epirubicin (E-ADM). MATERIAL AND METHODS The mRNA expression of NUSAP1 was determined by quantitative polymerase chain reaction (q-PCR). The protein expression was detected by Western blotting. Cell growth and growth cycle were detected by MTT assay and flow cytometry, respectively. Cell migration and invasion were tested by Transwell assay. RESULTS Through use of gene network analysis, we found that NUSAP1 interacts with IBC-related genes. NUSAP1 presented high expression in IBC tissue samples and MCF-7 cells. NUSAP1 overexpression promoted the growth, migration, and invasion of MCF-7 cells. While NUSAP1 gene silencing downregulated the expression of genes associated with cell cycle progression in G2/M phase, cyclin D kinase (CDK1) and DLGAP5 arrested cells in G2/M phase and significantly inhibited the growth, migration, and invasion of MCF-7 cells. si-NUSAP1 increased the susceptibility of MCF-7 cells to E-ADM-induced apoptosis. CONCLUSIONS Our study provides evidence that downregulation of NUSAP1 can inhibit the proliferation, migration, and invasion of IBC cells by regulating CDK1 and DLGAP5 expression and enhances the drug susceptibility to E-ADM.

Gomhor J Alqaraghuli H, Kashanian S, Rafipour R, et al.
Development and characterization of folic acid-functionalized apoferritin as a delivery vehicle for epirubicin against MCF-7 breast cancer cells.
Artif Cells Nanomed Biotechnol. 2018; 46(sup3):S847-S854 [PubMed] Related Publications
Epirubicin (Epr) is an effective chemotherapeutic drug; however, the clinical amenability of Epr is limited by its highly toxic interaction with normal cells. This toxicity can be decreased by utilizing nanocarriers and targeted drug delivery systems. This work describes an approach for the delivery of Epr via encapsulation in the horse spleen apoferritin (HsAFr) cavity. The encapsulation was achieved by the disassembling of apoferritin into subunits at pH 2 followed by its reformation at pH 7.4 in the presence of Epr. The surface of HsAFr-encapsulated Epr was modified with folic acid (FA) for optimal targeting of breast cancer cells (MCF-7). The use of FA to functionalize HsAFr could enhance the cellular uptake efficiency via FA-receptor-mediated endocytosis. UV-vis spectroscopy, fluorescence spectroscopy, circular dichroism (CD) and transmission electron microscopy (TEM) were utilized for structural characterization of the HsAFr-Epr and HsAFr-Epr-FA complexes. The comparison of the anti-cancer activities across the HsAFr-Epr-FA complex and the free Epr drug was performed using the MTT viability assay on MCF-7.

van Ramshorst MS, van der Voort A, van Werkhoven ED, et al.
Neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2 blockade for HER2-positive breast cancer (TRAIN-2): a multicentre, open-label, randomised, phase 3 trial.
Lancet Oncol. 2018; 19(12):1630-1640 [PubMed] Related Publications
BACKGROUND: The optimal chemotherapy backbone for dual HER2 blockade in the neoadjuvant setting for early breast cancer is unknown. We investigated whether the addition of anthracyclines would improve pathological complete response compared with a carboplatin-taxane regimen, when given in combination with the HER2-targeted agents trastuzumab and pertuzumab.
METHODS: The TRAIN-2 study is an open-label, randomised, controlled, phase 3 trial being done in 37 hospitals in the Netherlands. We recruited patients aged 18 years or older with previously untreated, histologically confirmed stage II-III HER2-positive breast cancer. Patients were randomly allocated using central randomisation software (1:1 ratio) with minimisation without a random component, stratified by tumour stage, nodal stage, oestrogen receptor status, and age, to receive 5-fluorouracil (500 mg/m
FINDINGS: Between Dec 9, 2013, and Jan 14, 2016, 438 patients were enrolled and randomly assigned to the two treatment groups (219 patients to each group), of whom 418 were evaluable for the primary endpoint (212 in the anthracycline group and 206 in the non-anthracycline group). The median follow-up for all patients was 19 months (IQR 16-23 months). A pathological complete response was recorded in 141 (67%, 95% CI 60-73) of 212 patients in the anthracycline group and in 140 (68%, 61-74) of 206 in the non-anthracycline group (p=0·95). One patient randomly allocated to the non-anthracycline group did receive anthracyclines and was thus included in the anthracycline group for safety analyses; therefore, for the safety analyses there were 220 patients in the anthracycline group and 218 in the non-anthracycline group. Serious adverse events were reported in 61 (28%) of 220 patients in the anthracycline group and in 49 (22%) of 218 in the non-anthracycline group. The most common adverse events of any cause were grade 3 or worse neutropenia (in 131 [60%] of 220 patients in the anthracycline group vs 118 [54%] of 218 in the non-anthracycline group), grade 3 or worse diarrhoea (26 [12%] vs 37 [18%]), and grade 2 or worse peripheral neuropathy (66 [30%] vs 68 [31%]), with no substantial differences between the groups. Grade 3 or worse febrile neutropenia was more common in the anthracycline group than in the non-anthracycline group (23 [10%] vs three [1%], p<0·0001). Symptomatic left ventricular systolic dysfunction was rare in both groups (two [1%] of 220 vs 0 of 218). One patient in the anthracycline group died because of a pulmonary embolism, which was possibly treatment related.
INTERPRETATION: In view of the high proportion of pathological complete responses recorded in both groups and the fact that febrile neutropenia was more frequent in the anthracycline group, omitting anthracyclines from neoadjuvant treatment regimens might be a preferred approach in the presence of dual HER2 blockade in patients with early HER2-positive breast cancer. Long-term follow-up is required to confirm these results.
FUNDING: Roche Netherlands.

Hong J, Maacha S, Belkhiri A
Transcriptional upregulation of c-MYC by AXL confers epirubicin resistance in esophageal adenocarcinoma.
Mol Oncol. 2018; 12(12):2191-2208 [PubMed] Free Access to Full Article Related Publications
AXL receptor tyrosine kinase is overexpressed in esophageal adenocarcinoma (EAC) and several other types of malignancies; hence, it may be a valuable therapeutic target. Herein, we investigated the role of AXL in regulating c-MYC expression and resistance to the chemotherapeutic agent epirubicin in EAC. Using in vitro EAC cell models, we found that AXL overexpression enhances epirubicin resistance in sensitive cells. Conversely, genetic knockdown or pharmacological inhibition of AXL sensitizes resistant cells to epirubicin. Notably, we showed that inhibition or knockdown of c-MYC markedly sensitizes AXL-dependent resistant cells to epirubicin, and our data demonstrated that AXL promotes epirubicin resistance through transcriptional upregulation of c-MYC. We showed that AXL overexpression significantly increased transcriptional activity, mRNA, and protein levels of c-MYC. Conversely, AXL knockdown reversed these effects. Mechanistic investigations indicated that AXL upregulates c-MYC expression through activation of the AKT/β-catenin signaling pathway. Data from a tumor xenograft mouse model indicated that inhibition of AXL with R428 in combination with epirubicin synergistically suppresses tumor growth and proliferation. Our results demonstrate that AXL promotes epirubicin resistance through transcriptional upregulation of c-MYC in EAC. Our findings support future clinical trials to assess the therapeutic potential of R428 in epirubicin-resistant tumors with overexpression of AXL and activation of c-MYC.

Shirono T, Iwamoto H, Niizeki T, et al.
Epirubicin is More Effective than Miriplatin in Balloon-Occluded Transcatheter Arterial Chemoembolization for Hepatocellular Carcinoma.
Oncology. 2019; 96(2):79-86 [PubMed] Related Publications
BACKGROUND: Transcatheter arterial chemoembolization (TACE) is a standard therapy used in the treatment of intermediate hepatocellular carcinoma (HCC). Recently, balloon-occluded TACE (B-TACE) has been developed.
PURPOSE: This study aimed to clarify the effects of B-TACE in patients with HCC, with a focus on which drug is suitable to suspend in Lipiodol for B-TACE.
METHODS: We retrospectively evaluated 35 patients with HCC treated with B-TACE. Factors associated with enhanced time to progression (TTP) after B-TACE were evaluated using univariate and multivariate analyses.
RESULTS: A total of 35 patients with HCC (40 nodules) were treated with B-TACE between June 2013 and August 2016. Epirubicin was used in 25 nodules and miriplatin was used in 15 nodules. Epirubicin (15.1 months) was significantly better than miriplatin (3.2 months) in prolonging the local TTP after B-TACE (p = 0.0293). Epirubicin showed a positive tendency in TE4 (100% tumor necrosis) rate when compared with miriplatin (p = 0.058). Achievement of TE4 was the only significant factor associated with better TTP after B-TACE. Epirubicin- and TACE-naïve statuses were significant factors in achieving TE4 with B-TACE.
CONCLUSION: To enhance the TTP with B-TACE, TE4 should be achieved. Epirubicin is a more optimal anticancer drug (as a Lipiodol suspension) than miriplatin for achieving TE4 with B-TACE.

Salinas Y, Hoerhager C, García-Fernández A, et al.
Biocompatible Phenylboronic-Acid-Capped ZnS Nanocrystals Designed As Caps in Mesoporous Silica Hybrid Materials for on-Demand pH-Triggered Release In Cancer Cells.
ACS Appl Mater Interfaces. 2018; 10(40):34029-34038 [PubMed] Related Publications
Biocompatible ZnS-based nanocrystals capped with 4-mercaptophenylboronic acid (ZnS@B) have been size-designed as excellent pH-responsive gatekeepers on mesoporous silica nanoparticles (MSNs), which encapsulate fluorophore safranin O (S2-Saf) or anticancer drug epirubicin hydrochloride (S2-Epi) for delivery applications in cancer cells. In this novel hybrid system, the gate mechanism consists of reversible pH-sensitive boronate ester moieties linking the nanocrystals directly to the alcohol groups from silica surface scaffold, avoiding tedious intermediate functionalization steps. The ∼3 nm size of the ZnS@B nanocrystals was tailored to allow efficient sealing of the pore voids and achieve a "zero premature cargo release" at neutral pH (7.4). The system selectively released the cargo in acidic conditions (pH 5.4 and 3.0) because of the hydrolysis of the boronate esters, which unblocked the pore voids. Delivery of the cargo by off-on cycles was demonstrated by changes in pH from 7.4 to 3.0, showing its potential pH-switching behavior. Cellular uptake of these nanocarriers within human cervix adenocarcinoma (HeLa) cells was achieved and the controlled release of the chemotherapeutic drug epirubicin was shown to occur within the endogenous endosomal/lysosomal acidified cancer cell microenvironment and further diffused into the cytosol. Cytotoxicity tests done on the mesoporous support without cargo and covalently linked with ZnS@B nanocrystals as caps were negative, suggesting that the proposed system is biocompatible and can be considered as a very promising drug nanocarrier.

Campone M, Lacroix-Triki M, Roca L, et al.
UCBG 2-08: 5-year efficacy results from the UNICANCER-PACS08 randomised phase III trial of adjuvant treatment with FEC100 and then either docetaxel or ixabepilone in patients with early-stage, poor prognosis breast cancer.
Eur J Cancer. 2018; 103:184-194 [PubMed] Related Publications
PURPOSE: UNICANCER-PACS08 compared adjuvant FEC (5-FU; epirubicin; cyclophosphamide) then docetaxel to FEC then ixabepilone in poor prognosis early breast cancer (BC). We evaluated whether replacing docetaxel with ixabepilone would increase 5-year disease-free survival (DFS).
PATIENTS AND METHODS: Triple-negative breast cancer (TNBC) or oestrogen receptor (ER)+/progesterone receptor (PR)-/HER2- BC patients were randomised to receive standard FEC (3 cycles) followed by 3 cycles of either docetaxel (100 mg/m
RESULTS: Seven hundred sixty-two patients were enrolled between October 2007 and September 2010. Baseline characteristics were balanced between arms. Median follow-up was 66.7 months. Median DFS was not reached; 5-year DFS rate was 76% with docetaxel and 79% with ixabepilone (hazard ratio [HR] = 0.80; 95% confidence interval [CI] = 0.58-1.10; p = 0.175). Median overall survival (OS) was not reached; 5-year OS rate was 86% versus 84% (HR = 0.97; 95% CI = 0.66-1.42; p = 0.897). TNBC patients treated with ixabepilone had a 23% lower risk of relapse compared to docetaxel (HR for DFS = 0.77; 95% CI = 0.53-1.11; p = 0.168). DFS was longer with ixabepilone than docetaxel in patients with grade II-III lymphocytic infiltration (HR = 0.55; 95% CI = 0.29-1.05; p = 0.063). All patients experienced ≥1 adverse events (AEs): 75% reported grade III-IV AEs and two (<1%) had grade V AEs (both with neutropenia and infection receiving ixabepilone).
CONCLUSION: After adjuvant FEC, ixabepilone was comparable to docetaxel for treating poor prognosis early BC patients. The benefit of ixabepilone in subgroups (patients with TNBC and grade II-III lymphocytic infiltration) requires further evaluation.

Buhl ASK, Christensen TD, Christensen IJ, et al.
Predicting efficacy of epirubicin by a multigene assay in advanced breast cancer within a Danish Breast Cancer Cooperative Group (DBCG) cohort: a retrospective-prospective blinded study.
Breast Cancer Res Treat. 2018; 172(2):391-400 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Anthracyclines remain a cornerstone in the treatment of primary and advanced breast cancer (BC). This study has evaluated the predictive value of a multigene mRNA-based drug response predictor (DRP) in the treatment of advanced BC with epirubicin. The DRP is a mathematical method combining in vitro sensitivity and gene expression with clinical genetic information from > 3000 clinical tumor samples.
METHODS: From a DBCG cohort, 140 consecutive patients were treated with epirubicin between May 1997 and November 2016. After patient informed consent, mRNA was isolated from archival formalin-fixed paraffin-embedded primary breast tumor tissue and analyzed using Affymetrix arrays. Using time to progression (TTP) as primary endpoint, the efficacy of epirubicin was analyzed according to DRP combined with clinicopathological data collected retrospectively from patients' medical records. Statistical analysis was done using Cox proportional hazards model stratified by treatment line.
RESULTS: Median TTP was 9.3 months. The DRP was significantly associated to TTP (P = 0.03). The hazard ratio for DRP scores differing by 50 percentage points was 0.55 (95% CI -0.93, one-sided). A 75% DRP was associated with a median TTP of 13 months compared to 7 months following a 25% DRP. Multivariate analysis showed that DRP was independent of age and number of metastases.
CONCLUSION: The current study prospectively validates the predictive capability of DRP regarding epirubicin previously shown retrospectively allowing the patients predicted to be poor responders to choose more effective alternatives. Randomized prospective studies are needed to demonstrate if such an approach will lead to increased overall survival.

Sun WL, Wang L, Luo J, et al.
Ambra1 modulates the sensitivity of breast cancer cells to epirubicin by regulating autophagy via ATG12.
Cancer Sci. 2018; 109(10):3129-3138 [PubMed] Free Access to Full Article Related Publications
The sensitivity of breast cancer cells to epirubicin (EPI) is closely related to the efficacy of the drug and the prognosis of patients. A growing body of research has suggested that autophagy is involved in the treatment of a variety of cancers, including breast cancer, and modifies the sensitivity of anticancer drugs. However, the mechanism by which autophagy participates in cancer therapy and modulates drug sensitivity has not been fully elucidated. In this study, we showed that the expression of Autophagy/Beclin 1 regulator 1 (Ambra1), a key protein of autophagy, was negatively correlated with EPI sensitivity in breast cancer cells. In addition, it altered the sensitivity of breast cancer cells to EPI by regulating EPI-induced autophagy. As a potential mechanism, we demonstrated that autophagy-related protein 12 (ATG12) was a downstream protein that Ambra1-regulated EPI-induced autophagy. Therefore, Ambra1 plays an important role in regulating the sensitivity of breast cancer cells to EPI. And the regulatory effect of Ambra1 on EPI sensitivity is achieved through the regulation of autophagy by targeting ATG12. Overall, we propose a novel mechanism by which autophagy modulates the sensitivity of breast cancer cells to EPI. ATG12 is a novel targeting protein of Ambra1 in regulating EPI-induced autophagy. In addition, the important role of Ambra1 in modulating the sensitivity of breast cancer cells to EPI is confirmed in vivo. This finding indicates that Ambra1 might be a target for developing breast cancer treatments.

Zhang W, Qiao B, Fan J
Overexpression of miR-4443 promotes the resistance of non-small cell lung cancer cells to epirubicin by targeting INPP4A and regulating the activation of JAK2/STAT3 pathway.
Pharmazie. 2018; 73(7):386-392 [PubMed] Related Publications
We aimed to elucidate the roles and regulatory mechanism of miR-4443 in regulating the resistance of non-small cell lung cancer (NSCLC) cells to epirubicin (EPI). Fifty-four advanced NSCLC patients were classified as ''insensitive'' or ''sensitive'' according to patient's responses following EPI-based chemotherapy and then the expression of miR-4443 was determined. The EPI-resistant H1299 cells were collected and transfected with miR-4443 mimics, whereas parental H1299 cells were transfected with miR-4443 inhibitors. The inhibition of growth (IC50), cell cycle or apoptosis of different transfected groups were investigated. Additionally, the potential target of miR-3188 was identified and verified by luciferase reporter assay. Besides, the regulatory relationship between miR-3188 and JAK2/STAT3 pathway was explored. miR-4443 was highly expressed in insensitive NSCLC patients to EPT-based chemotherapy and EPI-resistant H1299 cells. Inhibition of miR-4443 increased the sensitivity of EPI-resistant H1299 cells to EPI by decreasing IC50 of EPI, inducing cell apoptosis and G0/G1 cell cycle arrest, while overexpression of miR-4443 promoted the resistance of parental H1299 cells to EPI. Furthermore, inositol polyphosphate 4-phosphatase type I gene (INPP4A) was a target of miR-4443 and its expression could be negatively regulated by miR-4443. Overexpression of miR-4443 promoted the resistance of parental H1299 cells to EPI by targeting INPP4A. Besides, overexpression of miR-4443 activated JAK2/STAT3 pathway in parental H1299 cells to EPI. Overexpression of miR-4443 may promote the resistance of NSCLC cells to EPI by targeting INPP4A and regulating the activation of JAK2/STAT3 pathway. miR-4443 may serve as a drug target for NSCLC.

Fan Z, Chang Y, Cui C, et al.
Near infrared fluorescent peptide nanoparticles for enhancing esophageal cancer therapeutic efficacy.
Nat Commun. 2018; 9(1):2605 [PubMed] Free Access to Full Article Related Publications
Various types of nanoparticles have been proposed for targeted drug delivering, imaging, and tracking of therapeutic agents. However, highly biocompatible nanoparticles with structure-induced fluorescence and capability to conjugate with biomarkers and drugs remain lacking. This research proposes and synthesizes fluorescent nanoparticles (f-PNPs) assembled by cyclic peptides to combine imaging and drug delivering for esophageal cancer (EC). To achieve tumor targeting, f-PNPs are first conjugated with RGD moieties to selectively target EC cells via α

Felipe AV, Oliveira J, Moraes AA, et al.
Reversal of Multidrug Resistance in an Epirubicin-Resistant Gastric Cancer Cell Subline
Asian Pac J Cancer Prev. 2018; 19(5):1237-1242 [PubMed] Free Access to Full Article Related Publications
Background: Gastric cancer is one of the most common malignancies worldwide. Epirubicin (EPI) is used extensively in the treatment of multiple cancers despite its tendency to induce multidrug resistance though overexpression of the ABCB1 efflux pump. However, this overexpression can be disrupted using short interfering RNAs (siRNAs). Objective and Methods: The aim of this study was to explore approaches to reverse EPI resistance and thus increase the success of chemotherapy treatment in an EPI-resistant gastric cancer cell subline (AGS/EPI). Methods: The study focused on effects of ABCB1 knockdown by siRNA technology using TaqMan gene expression assays with quantitative real-time reverse-transcription PCR (qRT-PCR). MTT assays were performed to evaluate viability and prolifer in subline. ABCB1 protein localization and EPI intracellular fluorescence intensity in AGS/EPI cells were detected by confocal microscopy. Results: The siRNA efficiently downregulated ABCB1 mRNA in AGS/EPI cells. Thus MDR reversal was clearly demonstrated in the AGS/EPI cells, offering the possibility of future in vitro chemoresistance assays for the GC field. Conclusions: ABCB1 knockdown decreased EPI efflux and increased EPI sensitivity in AGS/EPI cells. This result provides a novel strategy for targeted gene therapy to reverse EPI resistance in gastric cancer.

Xu X, Zhang L, He X, et al.
TGF-β plays a vital role in triple-negative breast cancer (TNBC) drug-resistance through regulating stemness, EMT and apoptosis.
Biochem Biophys Res Commun. 2018; 502(1):160-165 [PubMed] Related Publications
Triple negative breast cancer (TNBC) is the most malignant subtype of breast cancer in which the cell surface lacks usual targets for drug to exhibit its effects. Epirubicin (Epi) is widely used for TNBC, but a substantial number of patients develop Epi resistance that is usually associated with poor prognosis. Transforming growth factor (TGF-β) is a multifunctional cytokine. In recent study, it appears that TGF-β influences the cancer stem cell population, thus, the drug resistance of cancer may also be affected. We used epirubicin to treat MDA-MB-231 (MB-231) cells and found that TGF-β and breast cancer stem cell markers CD44

Shi F, Li M, Wang J, et al.
Induction of multiple myeloma cancer stem cell apoptosis using conjugated anti-ABCG2 antibody with epirubicin-loaded microbubbles.
Stem Cell Res Ther. 2018; 9(1):144 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Multiple myeloma (MM) currently remains largely incurable. Cancer stem cells (CSCs) are believed to be responsible for drug resistance and eventual relapse. In this study, we exploited a novel agent to evaluate its inhibitory effect on MM CSCs.
METHODS: Epirubicin (EPI)-loaded lipid microbubbles (MBs) conjugated with anti-ABCG2 monoclonal antibody (EPI-MBs + mAb) were developed and their effect on MM 138
RESULTS: EPI-MBs + mAb combined with ultrasound led to a significant decrease in the clone formation ability and the mitochondrial membrane potential along with an increase in MM CSC apoptosis. Moreover, treatment with EPI-MBs + mAb with ultrasound exposure remarkably inhibited the growth of MM CSC-derived tumors in xenograft nonobese diabetic/severe combined immunodeficient mice compared with a single agent or EPI-MBs + mAb without ultrasound exposure. The inhibitive efficacy was also correlated with an increased expression of caspase-3, Bax, and TUNEL and decreased expressions of PCNA, Bcl-2, and CD31.
CONCLUSIONS: Our findings reveal that the EPI-MBs + mAb combined with therapeutic ultrasound may confer an effective approach for treatment of MM by induction of an apoptotic pathway in MM CSCs.

Lim ST, Park CH, Kim SY, et al.
The effect of adjuvant chemotherapy on survival in Korean patients with node negative T1c, triple negative breast cancer.
PLoS One. 2018; 13(5):e0197523 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The present study investigated the prognostic role of adjuvant systemic chemotherapy in patients with node negative, T1c triple negative breast cancer (TNBC) from a nationwide cohort. In addition, the prognostic effect between 3 different chemotherapy regimens were compared in node-negative T1c TNBC patients by subgroup analysis.
METHODS: From the Korean breast cancer registry database, 1,151 T1c node negative TNBC patients were included in this study. Patients were categorized into four treatment groups according to chemotherapy regimen: (1) no chemotherapy, (2) adriamycin plus cyclophosphamide (AC), (3) adriamycin/epirubicin plus cyclophosphamide plus 5-FU (FAC/FEC), and (4) cyclophosphamide plus 5-FU plus methotrexate (CMF). Overall survival (OS) was evaluated between each patient group.
RESULTS: Of the 1,151 T1c node negative TNBC patients, 1,006 received adjuvant chemotherapy, while 145 received no chemotherapy. Among the patients receiving adjuvant chemotherapy the distribution of regimens was: 586 AC, 168 FAC/FEC (126 FAC, 42 FEC), and 252 CMF. The mean follow-up time of the full study cohort was 87.98 ± 33.56 months (range = 6-192 months). Patients in the no chemotherapy group showed significantly worse OS compared to each chemotherapy regimen group. However, when OS was compared between each chemotherapy regimen, no significant difference was found.
CONCLUSIONS: This study showed that adjuvant systemic chemotherapy improved OS in T1c node negative TNBC patients, regardless of chemotherapy between AC, FAC/FEC, and CMF regimens.

Ma G, Huang H, Li M, et al.
Plasma CCL5 promotes EMT-medicated epirubicin-resistance in locally advanced breast cancer.
Cancer Biomark. 2018; 22(3):405-415 [PubMed] Related Publications
Neoadjuvant chemotherapy (NCT) is the standard treatment for locally advanced breast cancer (LABC). Pathological complete response (pCR) is commonly used as a valid predictor of NCT long-term outcomes. Blood-based tumor biomarkers have the potential to predict response to NCT at early stage non-invasively. We believed plasma CCL5 could be a potential marker to predict NCT of LABC. Its efficiency and possible mechanism was studied in this work. Human Cytokine Antibody Microarray was applied to screen different cytokine concentration in plasma between low histological regression (Low-R) and high histological regression (High-R) patients. LABC patients were divided into two groups according to pathological reactivity. The concentration of plasma CCL5 in different groups was determined by ELISA analysis. CCK8 assay was performed to analyze epirubicin susceptibility of breast cancer cells. Transwell assay was performed to determine the effect of CCL5 on breast cancer cells' migration and invasion. qRT-PCR and western blot were used to verify the EMT (epithelial-mesenchymal transition) markers in CCL5-treated and epirubicin-treated breast cancer cells. The concentration of plasma CCL5 of Low-R group was higher than High-R group before NCT. The plasma levels of CCL5 were significantly reduced after NCT in the group of high histological regression (High-R). Epirubicin susceptibility decreased in the breast cancer cells treated by recombinant CCL5. Migration and invasion were significantly enhanced in breast cancer cells treated by recombinant CCL5. E-cadherin expression was decreased whereas vimentin increased significantly in CCL5-treated breast cancer cells. The phosphorylation of ezrin in Y-567 and its downstream protein cortactin increased significantly in CCL5-treated breast cancer cells. Plasma CCL5 level could be a promised candidate to predict chemotherapy response of breast cancer. Plasma CCL5 plays an important role in EMT process of breast cancer.

Li N, Han D, Sun J, et al.
Subtypes of MDSCs in mechanisms and prognosis of gastric cancer and are inhibited by epirubicin and paclitaxel.
Discov Med. 2018; 25(137):99-112 [PubMed] Related Publications
Myeloid-derived suppressor cells (MDSCs) are thought to play a critical immunosuppressive role in tumorigenesis. In this project, we aimed to investigate subset alteration of MDSCs in gastric cancer (GC), and the effects of epirubicin (EPI) and paclitaxel (TAX) on MDSCs. The frequencies of MDSC subsets in peripheral blood were observed by using flow cytometry after treatment with EPI- or TAX- based chemotherapy in GC patients. After treatment with EPI or TAX in vitro, the subsets, apoptosis, cell cycle, and MAPK and NF-κB protein expressions of mouse bone marrow MDSCs were analyzed. The frequency of MDSCs in the peripheral blood of GC patients was higher than that in healthy controls. Granulocyte-type MDSCs (G-MDSCs) were significantly more than monocyte-type MDSCs (M-MDSCs) in GC patients. The frequencies of MDSC subsets in the peripheral blood decreased after EPI- or TAX-based chemotherapy. High levels of MDSC subsets were correlated with low cancer differentiation degree. High level of M-MDSCs was related to lymph node metastasis, and was negatively correlated with the overall survival of GC patients. After treatment with EPI or TAX, levels of mouse bone marrow MDSC subsets decreased significantly in vitro. Arg-1 secretion and expression of total and phosphorylated MAPK and NF-κB by MDSCs decreased. EPI or TAX decreases the levels of MDSCs, inhibits the proliferation and function of MDSCs in vitro, and induces their apoptosis via the MAPK and NF-κB signaling pathways.

Li J, Duan B, Guo Y, et al.
Baicalein sensitizes hepatocellular carcinoma cells to 5-FU and Epirubicin by activating apoptosis and ameliorating P-glycoprotein activity.
Biomed Pharmacother. 2018; 98:806-812 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) has a dismal prognosis in part because of multi-drug resistance (MDR). Baicalein is a flavonoid extracted from Radix Scutellariae with anti-HCC activity. We tested the effects of Baicalein on multi-drug resistant HCC cells (Bel7402/5-FU) known to be resistant to the anticancer drugs 5-FU and Epirubicin. Flow cytometry analysis showed that treatment with 5??g/ml and 10??g/ml Baicalein resulted in increases in the intra-cellular concentrations of Rho123 and Epirubicin in the corresponding group of cells compared to untreated cells, illustrating that Baicalein reverses MDR in Bel7402/5-FU cells. Bel7402/5-FU cells displayed increased P-glycoprotein (P-gp)-mediated drug efflux. However, this efflux was inhibited in cells pre-incubated in Baicalein for 48?h. Moreover, Baicalein induced apoptosis and autophagy and decreased P-gp and Bcl-xl expression levels. All of these results indicate that Baicalein can reverse P-gp-mediated MDR in HCC and may thus be useful for the treatment of drug-resistant HCC.

Bai Z, Qin Y, Zhu G, et al.
Efficacy and safety of epirubicin applied in transcatheter arterial chemoembolization for hepatocellular carcinoma: A meta-analysis.
J Cancer Res Ther. 2018; 14(1):133-138 [PubMed] Related Publications
Objectives: This study was aimed to evaluate the efficacy and safety of epirubicin applied in transcatheter arterial chemoembolization (TACE) for the treatment of hepatocellular carcinoma (HCC).
Materials and Methods: Studies were searched in Embase, PubMed, and Springer until August 10, 2016. All the studies were screened with inclusion and exclusion criteria. The quality assessment of the eligible studies was performed with the Newcastle-Ottawa Scale and the Jadad Scale. Response rate, recurrence, mortality, and thrombocytopenia were evaluated with risk ratios (RRs) with 95% confidence intervals (CIs). The heterogeneity and publication bias were assessed.
Results: Ten eligible studies were included with a total of 993 objects. The data were extracted and summarized. The overall results were calculated including response rate (RR = 0.98, 95% CI: 0.83-1.15), recurrence (RR = 0.75, 95% CI: 0.58-0.96), mortality (RR = 0.71, 95% CI: 0.39-1.28), and thrombocytopenia (RR = 0.42, 95% CI: 0.09-1.93), without significant heterogeneity. There was a significant heterogeneity for mortality; thus, the random effects model was used. No publication bias was observed in this study.
Conclusions: The results of meta-analysis indicated that epirubicin applied in TACE has an obvious efficacy for the treatment of HCC, with significantly decreased recurrence while without superiority of safety.

Banke A, Fosbøl EL, Møller JE, et al.
Long-term effect of epirubicin on incidence of heart failure in women with breast cancer: insight from a randomized clinical trial.
Eur J Heart Fail. 2018; 20(10):1447-1453 [PubMed] Related Publications
AIMS: Anthracycline-based chemotherapy improves survival in breast cancer patients but is associated with increased risk of heart failure (HF). However, the risk of late-onset HF is debatable and mainly based on observational studies. The aim of this study was to evaluate the effect of anthracycline-based chemotherapy on long-term risk of clinical HF.
METHODS AND RESULTS: Between 1990 and 1998 the Danish Breast Cancer Cooperative Group (DBCG) 89D trial randomized 980 Danish women with early breast cancer to adjuvant cyclophosphamide, epirubicin, and fluorouracil or cyclophosphamide, methotrexate, and fluorouracil. Incident HF was the primary endpoint obtained from Danish administrative registries. Follow-up ended at December 2014. The risk of HF was evaluated in a cumulative incidence analysis and a Fine-Gray proportional hazards model. Median follow-up time was 16.9 years [interquartile range (IQR) 3.7-20.9]. In the epirubicin treatment group, 23 new cases of HF were identified vs. 9 in the non-epirubicin group corresponding to incidence rates per 1000 patient-years of 3.7 [95% confidence interval (CI) 2.5-5.6] vs. 1.4 (95% CI 0.7-2.7). The cumulative incidence of HF was higher in the epirubicin treatment group compared with the non-epirubicin group (P < 0.01), yielding a hazard ratio of 3.00 (95% CI 1.39-6.49, P < 0.01) for HF associated with epirubicin. The median dose of epirubicin was 451.9 mg/m
CONCLUSIONS: Anthracycline-based chemotherapy is associated with a three-fold increased risk of late-onset clinical HF relative to non-anthracycline chemotherapy in this randomized clinical trial, but overall risk is low.

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