Pub Date : 2014-01-24eCollection Date: 2014-01-01DOI: 10.2147/CE.S40698
Philippe Lagacé-Wiens, Andrew Walkty, James A Karlowsky
Avibactam (NXL104, AVE1330A) is a semi-synthetic, non-β-lactam, β-lactamase inhibitor that is active against Ambler class A, class C, and some class D serine β-lactamases. In this review, we summarize the in vitro data, pharmacology, mechanisms of action and resistance, and clinical trial data relating to the use of this agent combined with ceftazidime for the treatment of Gram-negative bacterial infections. The addition of avibactam to ceftazidime improves its in vitro activity against Enterobacteriaceae and Pseudomonas aeruginosa. Avibactam does not improve the activity of ceftazidime against Acinetobacter spp., Burkholderia spp., or most anaerobic Gram-negative rods. Pharmacodynamic data indicate that ceftazidime-avibactam is bactericidal at concentrations achievable in human serum. Animal studies demonstrate that ceftazidime-avibactam is effective in ceftazidime-resistant Gram-negative septicemia, meningitis, pyelonephritis, and pneumonia. Limited clinical trials published to date have reported that ceftazidime-avibactam is as effective as therapy with a carbapenem in complicated urinary tract infection and complicated intra-abdominal infection (combined with metronidazole) including infection caused by cephalosporin-resistant Gram-negative isolates. Safety and tolerability of ceftazidime-avibactam in clinical trials has been excellent, with few serious drug-related adverse events reported. Given the abundant clinical experience with ceftazidime and the significant improvement that avibactam provides in its activity against contemporary β-lactamase-producing Gram-negative pathogens, it is likely this new combination agent will play a role in the empiric treatment of complicated urinary tract infections (monotherapy) and complicated intra-abdominal infections (in combination with metronidazole) caused or suspected to be caused by antimicrobial-resistant pathogens (eg, extended spectrum beta-lactamase-, AmpC-, or Klebsiella pneumoniae carbapenemase-producing Enterobacteriaceae and multidrug-resistant P. aeruginosa). Potential future uses also include hospital-acquired pneumonia (in combination with antistaphylococcal and antipneumococcal agents) or treatment of skin and soft tissue infections caused by antimicrobial-resistant Gram-negative pathogens (eg, diabetic foot infections), but further clinical trials are required.
{"title":"Ceftazidime-avibactam: an evidence-based review of its pharmacology and potential use in the treatment of Gram-negative bacterial infections.","authors":"Philippe Lagacé-Wiens, Andrew Walkty, James A Karlowsky","doi":"10.2147/CE.S40698","DOIUrl":"https://doi.org/10.2147/CE.S40698","url":null,"abstract":"<p><p>Avibactam (NXL104, AVE1330A) is a semi-synthetic, non-β-lactam, β-lactamase inhibitor that is active against Ambler class A, class C, and some class D serine β-lactamases. In this review, we summarize the in vitro data, pharmacology, mechanisms of action and resistance, and clinical trial data relating to the use of this agent combined with ceftazidime for the treatment of Gram-negative bacterial infections. The addition of avibactam to ceftazidime improves its in vitro activity against Enterobacteriaceae and Pseudomonas aeruginosa. Avibactam does not improve the activity of ceftazidime against Acinetobacter spp., Burkholderia spp., or most anaerobic Gram-negative rods. Pharmacodynamic data indicate that ceftazidime-avibactam is bactericidal at concentrations achievable in human serum. Animal studies demonstrate that ceftazidime-avibactam is effective in ceftazidime-resistant Gram-negative septicemia, meningitis, pyelonephritis, and pneumonia. Limited clinical trials published to date have reported that ceftazidime-avibactam is as effective as therapy with a carbapenem in complicated urinary tract infection and complicated intra-abdominal infection (combined with metronidazole) including infection caused by cephalosporin-resistant Gram-negative isolates. Safety and tolerability of ceftazidime-avibactam in clinical trials has been excellent, with few serious drug-related adverse events reported. Given the abundant clinical experience with ceftazidime and the significant improvement that avibactam provides in its activity against contemporary β-lactamase-producing Gram-negative pathogens, it is likely this new combination agent will play a role in the empiric treatment of complicated urinary tract infections (monotherapy) and complicated intra-abdominal infections (in combination with metronidazole) caused or suspected to be caused by antimicrobial-resistant pathogens (eg, extended spectrum beta-lactamase-, AmpC-, or Klebsiella pneumoniae carbapenemase-producing Enterobacteriaceae and multidrug-resistant P. aeruginosa). Potential future uses also include hospital-acquired pneumonia (in combination with antistaphylococcal and antipneumococcal agents) or treatment of skin and soft tissue infections caused by antimicrobial-resistant Gram-negative pathogens (eg, diabetic foot infections), but further clinical trials are required. </p>","PeriodicalId":10764,"journal":{"name":"Core Evidence","volume":"9 ","pages":"13-25"},"PeriodicalIF":0.0,"publicationDate":"2014-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/CE.S40698","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32086589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Objective: To perform a systematic review and meta-analysis of randomized controlled trials that compared the efficacy of targeted therapy to conventional chemotherapy (CT) in patients with metastatic triple-negative breast cancer (TNBC).
Methods: Several databases were searched, including Medline, Embase, LILACS, and CENTRAL. The primary end point was progression-free survival (PFS). We performed a meta-analysis of the published data. The results are expressed as hazard ratio (HR) or risk ratio, with their corresponding 95% confidence intervals (95% CIs).
Results: The final analysis included twelve trials comprising 2,054 patients with TNBC, which compared conventional CT alone against CT combined with targeted therapy (bevacizumab [Bev], sorafenib [Sor], cetuximab, lapatinib, and iniparib). PFS was superior in previously untreated patients with TNBC who received Bev plus CT compared to CT alone (fixed effect, HR 0.62, 95% CI 0.51-0.75; P<0.00001). Also, PFS was higher in one study that tested Bev plus CT combination in previously treated patients (HR 0.49, 95% CI 0.33-0.74; P=0.0006). Sor plus CT was also tested as first-line and second-line treatments. The pooled data of PFS favored the combination CT plus Sor (fixed effect, HR 0.69, 95% CI 0.49-0.98; P=0.04). Comparisons of iniparib plus CT also had a better PFS than CT alone (fixed effect, HR 0.75, 95% CI 0.62-0.90; P=0.002).
Conclusion: Targeted therapy, when associated with conventional CT, demonstrated gains in the PFS of patients with TNBC.
目的:对转移性三阴性乳腺癌(TNBC)患者进行靶向治疗与常规化疗(CT)疗效比较的随机对照试验进行系统回顾和荟萃分析。方法:检索Medline、Embase、LILACS、CENTRAL等数据库。主要终点为无进展生存期(PFS)。我们对发表的数据进行了荟萃分析。结果用风险比(HR)或风险比表示,并给出相应的95%置信区间(95% ci)。结果:最终分析包括12项试验,包括2054例TNBC患者,比较了常规CT单独与CT联合靶向治疗(贝伐单抗[Bev],索拉非尼[Sor],西妥昔单抗,拉帕替尼和伊尼帕里)。未经治疗的TNBC患者接受Bev + CT治疗的PFS优于单独接受CT治疗(固定效应,HR 0.62, 95% CI 0.51-0.75;结论:当与常规CT相结合时,靶向治疗显示了TNBC患者PFS的增加。
{"title":"Targeted therapy in triple-negative metastatic breast cancer: a systematic review and meta-analysis.","authors":"Otávio Clark, Tobias Engel Ayer Botrel, Luciano Paladini, Mariana Bhering Andrade Ferreira","doi":"10.2147/CE.S52197","DOIUrl":"https://doi.org/10.2147/CE.S52197","url":null,"abstract":"<p><strong>Objective: </strong>To perform a systematic review and meta-analysis of randomized controlled trials that compared the efficacy of targeted therapy to conventional chemotherapy (CT) in patients with metastatic triple-negative breast cancer (TNBC).</p><p><strong>Methods: </strong>Several databases were searched, including Medline, Embase, LILACS, and CENTRAL. The primary end point was progression-free survival (PFS). We performed a meta-analysis of the published data. The results are expressed as hazard ratio (HR) or risk ratio, with their corresponding 95% confidence intervals (95% CIs).</p><p><strong>Results: </strong>The final analysis included twelve trials comprising 2,054 patients with TNBC, which compared conventional CT alone against CT combined with targeted therapy (bevacizumab [Bev], sorafenib [Sor], cetuximab, lapatinib, and iniparib). PFS was superior in previously untreated patients with TNBC who received Bev plus CT compared to CT alone (fixed effect, HR 0.62, 95% CI 0.51-0.75; P<0.00001). Also, PFS was higher in one study that tested Bev plus CT combination in previously treated patients (HR 0.49, 95% CI 0.33-0.74; P=0.0006). Sor plus CT was also tested as first-line and second-line treatments. The pooled data of PFS favored the combination CT plus Sor (fixed effect, HR 0.69, 95% CI 0.49-0.98; P=0.04). Comparisons of iniparib plus CT also had a better PFS than CT alone (fixed effect, HR 0.75, 95% CI 0.62-0.90; P=0.002).</p><p><strong>Conclusion: </strong>Targeted therapy, when associated with conventional CT, demonstrated gains in the PFS of patients with TNBC.</p>","PeriodicalId":10764,"journal":{"name":"Core Evidence","volume":"9 ","pages":"1-11"},"PeriodicalIF":0.0,"publicationDate":"2014-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/CE.S52197","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32072872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2013-01-01Epub Date: 2013-05-16DOI: 10.2147/CE.S34068
Julio C Chavez, Eva Sahakian, Javier Pinilla-Ibarz
Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with a variable course, and remains an incurable disease. Frequent relapses and eventual resistance to fludarabine characterize symptomatic CLL and portends a dismal prognosis for patients. Growing evidence has shown that signaling pathways such as the B cell receptor and NFkB are implicated in the survival and proliferation of the CLL cells which are ultimately associated with persistence of the disease. The Bruton's tyrosine kinase pathway regulates downstream activation of the B cell receptor and has emerged as an attractive target. Ibrutinib inhibits the Bruton's tyrosine kinase pathway, and consequently induces apoptosis of B cells. Phase I and II studies have shown impressive response rates with an excellent safety profile in patients with refractory/relapsed CLL and elderly treatment-naïve CLL patients. This paper reviews the preclinical and clinical data for ibrutinib when used in the treatment of CLL. Recent studies showing the benefit of combination therapy using ibrutinib, monoclonal antibodies, and chemoimmunotherapy are also discussed.
{"title":"Ibrutinib: an evidence-based review of its potential in the treatment of advanced chronic lymphocytic leukemia.","authors":"Julio C Chavez, Eva Sahakian, Javier Pinilla-Ibarz","doi":"10.2147/CE.S34068","DOIUrl":"https://doi.org/10.2147/CE.S34068","url":null,"abstract":"<p><p>Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with a variable course, and remains an incurable disease. Frequent relapses and eventual resistance to fludarabine characterize symptomatic CLL and portends a dismal prognosis for patients. Growing evidence has shown that signaling pathways such as the B cell receptor and NFkB are implicated in the survival and proliferation of the CLL cells which are ultimately associated with persistence of the disease. The Bruton's tyrosine kinase pathway regulates downstream activation of the B cell receptor and has emerged as an attractive target. Ibrutinib inhibits the Bruton's tyrosine kinase pathway, and consequently induces apoptosis of B cells. Phase I and II studies have shown impressive response rates with an excellent safety profile in patients with refractory/relapsed CLL and elderly treatment-naïve CLL patients. This paper reviews the preclinical and clinical data for ibrutinib when used in the treatment of CLL. Recent studies showing the benefit of combination therapy using ibrutinib, monoclonal antibodies, and chemoimmunotherapy are also discussed.</p>","PeriodicalId":10764,"journal":{"name":"Core Evidence","volume":"8 ","pages":"37-45"},"PeriodicalIF":0.0,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/CE.S34068","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31466348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2013-01-01Epub Date: 2013-07-11DOI: 10.2147/CE.S36744
Brendan T Bowman, Mitchell H Rosner
Hyponatremia is the most common electrolyte abnormality seen in clinical practice. Most cases of euvolemic or hypervolemic hyponatremia involve arginine vasopressin (AVP). AVP leads to a concentrated urine and negative free water clearance. Given this primary role of AVP, antagonizing its effect through blockade of its receptor in the distal tubule is an attractive therapeutic target. Lixivaptan is a newer, non-peptide, vasopressin type 2 receptor antagonist. Recent studies have demonstrated efficacy. This review summarizes the clinical pharmacology and data for this new agent.
{"title":"Lixivaptan - an evidence-based review of its clinical potential in the treatment of hyponatremia.","authors":"Brendan T Bowman, Mitchell H Rosner","doi":"10.2147/CE.S36744","DOIUrl":"10.2147/CE.S36744","url":null,"abstract":"<p><p>Hyponatremia is the most common electrolyte abnormality seen in clinical practice. Most cases of euvolemic or hypervolemic hyponatremia involve arginine vasopressin (AVP). AVP leads to a concentrated urine and negative free water clearance. Given this primary role of AVP, antagonizing its effect through blockade of its receptor in the distal tubule is an attractive therapeutic target. Lixivaptan is a newer, non-peptide, vasopressin type 2 receptor antagonist. Recent studies have demonstrated efficacy. This review summarizes the clinical pharmacology and data for this new agent. </p>","PeriodicalId":10764,"journal":{"name":"Core Evidence","volume":"8 ","pages":"47-56"},"PeriodicalIF":0.0,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/CE.S36744","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31597324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2013-01-01Epub Date: 2013-04-04DOI: 10.2147/CE.S34747
Ali R Golshayan, Emmanuel S Antonarakis
Introduction: Enzalutamide is an oral androgen receptor (AR) signaling inhibitor that was specifically engineered to overcome castration-resistant prostate cancer (CRPC) harboring AR amplification or overexpression. Enzalutamide has demonstrated significant activity in men with metastatic CRPC.
Aims: To update the evidence and provide an overview of the available data on enzalutamide.
Evidence review: Peer reviewed articles published and listed in Medline Search were reviewed. In addition, relevant ASCO and ESMO abstracts were searched. The activity of enzalutamide is mediated by potently antagonizing the full-length AR, impairing translocation of the AR from the cytoplasm into the nucleus, and inhibiting the transcriptional activity of the AR by modulating the interaction of the AR with androgen-response elements in gene promoter regions. Enzalutamide has a favorable safety profile and the most common adverse events include fatigue, hot flashes and headache; 1% of patients experienced seizure.
Place in therapy: The AFFIRM phase III study evaluated the clinical utility of treatment with enzalutamide in men with docetaxel-refractory metastatic CRPC. Enzalutamide improved overall survival compared to placebo, with a median overall survival of 18.4 months versus 13.6 months respectively.
Conclusion: Enzalutamide has demonstrated impressive efficacy in men with metastatic CRPC, moving swiftly from a phase I/II study to two pivotal phase III trials testing this agent in both chemotherapy-pretreated as well as chemotherapy-naïve CRPC patients. Ongoing studies are aiming to explore the utility of enzalutamide in earlier stages of the disease, and to investigate the optimal sequencing and combination of enzalutamide with other standard and novel therapies for prostate cancer.
{"title":"Enzalutamide: an evidence-based review of its use in the treatment of prostate cancer.","authors":"Ali R Golshayan, Emmanuel S Antonarakis","doi":"10.2147/CE.S34747","DOIUrl":"https://doi.org/10.2147/CE.S34747","url":null,"abstract":"<p><strong>Introduction: </strong>Enzalutamide is an oral androgen receptor (AR) signaling inhibitor that was specifically engineered to overcome castration-resistant prostate cancer (CRPC) harboring AR amplification or overexpression. Enzalutamide has demonstrated significant activity in men with metastatic CRPC.</p><p><strong>Aims: </strong>To update the evidence and provide an overview of the available data on enzalutamide.</p><p><strong>Evidence review: </strong>Peer reviewed articles published and listed in Medline Search were reviewed. In addition, relevant ASCO and ESMO abstracts were searched. The activity of enzalutamide is mediated by potently antagonizing the full-length AR, impairing translocation of the AR from the cytoplasm into the nucleus, and inhibiting the transcriptional activity of the AR by modulating the interaction of the AR with androgen-response elements in gene promoter regions. Enzalutamide has a favorable safety profile and the most common adverse events include fatigue, hot flashes and headache; 1% of patients experienced seizure.</p><p><strong>Place in therapy: </strong>The AFFIRM phase III study evaluated the clinical utility of treatment with enzalutamide in men with docetaxel-refractory metastatic CRPC. Enzalutamide improved overall survival compared to placebo, with a median overall survival of 18.4 months versus 13.6 months respectively.</p><p><strong>Conclusion: </strong>Enzalutamide has demonstrated impressive efficacy in men with metastatic CRPC, moving swiftly from a phase I/II study to two pivotal phase III trials testing this agent in both chemotherapy-pretreated as well as chemotherapy-naïve CRPC patients. Ongoing studies are aiming to explore the utility of enzalutamide in earlier stages of the disease, and to investigate the optimal sequencing and combination of enzalutamide with other standard and novel therapies for prostate cancer.</p>","PeriodicalId":10764,"journal":{"name":"Core Evidence","volume":"8 ","pages":"27-35"},"PeriodicalIF":0.0,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/CE.S34747","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31361419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2013-01-01Epub Date: 2013-09-30DOI: 10.2147/CE.S50474
Tobias Engel Ayer Botrel, Luciano Paladini, Otávio Augusto C Clark
Background: This paper reports a systematic review and meta-analysis of all randomized controlled trials comparing the efficacy of lapatinib plus chemotherapy or endocrine therapy (CET) versus CET alone in human epidermal growth factor receptor 2-overexpressing (HER-2+) locally advanced or metastatic breast cancer.
Methods: Several databases were searched, including MEDLINE, EMBASE, LILACS, and CENTRAL. The primary endpoints were progression-free survival and overall survival. The side effects of each treatment were analyzed. The data extracted from the studies were combined by using the hazard ratio or risk ratio with their corresponding 95% confidence interval (CI).
Results: A total of 113 references were identified and screened. The final analysis included four trials comprising 1,073 patients with HER-2+. The overall response rate was higher in patients who received the combination of CET plus lapatinib (risk ratio 0.78; 95% CI 0.71-0.85; P < 0.00001) but with significant heterogeneity (χ(2) = 15.61, df = 3; P = 0.001; I(2) = 81%). This result remained favorable to the use of lapatinib when a random-effects model analysis was performed (risk ratio 0.76; 95% CI 0.62-0.94; P = 0.01). Progression-free survival was also higher in patients who received CET plus lapatinib (hazard ratio 0.57; 95% CI 0.49-0.66; P < 0.00001) with no heterogeneity detected on this analysis (χ(2) = 3.05; df = 3; P = 0.38; I(2) = 1%). Overall survival was significantly longer in patients who received CET plus lapatinib (hazard ratio 0.80; 95% CI 0.69-0.92; P = 0.002) without heterogeneity on this analysis (χ(2) = 1.26; df = 3; P = 0.74; I(2) = 0%). Regarding adverse events and severe toxicities (grade ≥3), the group receiving CET plus lapatinib had higher rates of neutropenia (risk ratio 2.08; 95% CI 1.64-2.62; P < 0.00001), diarrhea (risk ratio 4.82; 95% CI 3.14-7.41; P < 0.00001), and rash (risk ratio 8.03; 95% CI 2.46-26.23; P = 0.0006).
Conclusion: The combination of CET plus lapatinib increased the overall response rate, progression-free survival, and overall survival in patients with HER-2+ locally advanced or metastatic breast cancer.
背景:本文报道了一项系统回顾和荟萃分析,比较了拉帕替尼联合化疗或内分泌治疗(CET)与单独使用CET治疗人表皮生长因子受体2过表达(HER-2+)局部晚期或转移性乳腺癌的疗效。方法:检索MEDLINE、EMBASE、LILACS、CENTRAL等数据库。主要终点为无进展生存期和总生存期。分析各治疗方法的副作用。从研究中提取的数据通过使用风险比或风险比及其相应的95%置信区间(CI)进行合并。结果:共筛选文献113篇。最终的分析包括四项试验,包括1073名HER-2+患者。接受CET +拉帕替尼联合治疗的患者总体缓解率更高(风险比0.78;95% ci 0.71-0.85;P < 0.00001),但异质性显著(χ(2) = 15.61, df = 3;P = 0.001;I(2) = 81%)。当进行随机效应模型分析时,这一结果仍然有利于拉帕替尼的使用(风险比0.76;95% ci 0.62-0.94;P = 0.01)。接受CET +拉帕替尼治疗的患者无进展生存率也更高(风险比0.57;95% ci 0.49-0.66;P < 0.00001),本分析未发现异质性(χ(2) = 3.05;Df = 3;P = 0.38;I(2) = 1%)。接受CET +拉帕替尼治疗的患者总生存期明显延长(风险比0.80;95% ci 0.69-0.92;P = 0.002),本分析无异质性(χ(2) = 1.26;Df = 3;P = 0.74;I(2) = 0%)。在不良事件和严重毒性(≥3级)方面,接受CET +拉帕替尼组中性粒细胞减少率较高(风险比2.08;95% ci 1.64-2.62;P < 0.00001)、腹泻(风险比4.82;95% ci 3.14-7.41;P < 0.00001),皮疹(风险比8.03;95% ci 2.46-26.23;P = 0.0006)。结论:CET联合拉帕替尼可提高HER-2+局部晚期或转移性乳腺癌患者的总缓解率、无进展生存期和总生存期。
{"title":"Lapatinib plus chemotherapy or endocrine therapy (CET) versus CET alone in the treatment of HER-2-overexpressing locally advanced or metastatic breast cancer: systematic review and meta-analysis.","authors":"Tobias Engel Ayer Botrel, Luciano Paladini, Otávio Augusto C Clark","doi":"10.2147/CE.S50474","DOIUrl":"10.2147/CE.S50474","url":null,"abstract":"<p><strong>Background: </strong>This paper reports a systematic review and meta-analysis of all randomized controlled trials comparing the efficacy of lapatinib plus chemotherapy or endocrine therapy (CET) versus CET alone in human epidermal growth factor receptor 2-overexpressing (HER-2+) locally advanced or metastatic breast cancer.</p><p><strong>Methods: </strong>Several databases were searched, including MEDLINE, EMBASE, LILACS, and CENTRAL. The primary endpoints were progression-free survival and overall survival. The side effects of each treatment were analyzed. The data extracted from the studies were combined by using the hazard ratio or risk ratio with their corresponding 95% confidence interval (CI).</p><p><strong>Results: </strong>A total of 113 references were identified and screened. The final analysis included four trials comprising 1,073 patients with HER-2+. The overall response rate was higher in patients who received the combination of CET plus lapatinib (risk ratio 0.78; 95% CI 0.71-0.85; P < 0.00001) but with significant heterogeneity (χ(2) = 15.61, df = 3; P = 0.001; I(2) = 81%). This result remained favorable to the use of lapatinib when a random-effects model analysis was performed (risk ratio 0.76; 95% CI 0.62-0.94; P = 0.01). Progression-free survival was also higher in patients who received CET plus lapatinib (hazard ratio 0.57; 95% CI 0.49-0.66; P < 0.00001) with no heterogeneity detected on this analysis (χ(2) = 3.05; df = 3; P = 0.38; I(2) = 1%). Overall survival was significantly longer in patients who received CET plus lapatinib (hazard ratio 0.80; 95% CI 0.69-0.92; P = 0.002) without heterogeneity on this analysis (χ(2) = 1.26; df = 3; P = 0.74; I(2) = 0%). Regarding adverse events and severe toxicities (grade ≥3), the group receiving CET plus lapatinib had higher rates of neutropenia (risk ratio 2.08; 95% CI 1.64-2.62; P < 0.00001), diarrhea (risk ratio 4.82; 95% CI 3.14-7.41; P < 0.00001), and rash (risk ratio 8.03; 95% CI 2.46-26.23; P = 0.0006).</p><p><strong>Conclusion: </strong>The combination of CET plus lapatinib increased the overall response rate, progression-free survival, and overall survival in patients with HER-2+ locally advanced or metastatic breast cancer.</p>","PeriodicalId":10764,"journal":{"name":"Core Evidence","volume":"8 ","pages":"69-78"},"PeriodicalIF":0.0,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/CE.S50474","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31799855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2013-01-01Epub Date: 2013-03-14DOI: 10.2147/CE.S42568
Carolyn A Goard, Aaron D Schimmer
Obatoclax mesylate is an intravenously-administered drug under investigation in Phase I and II clinical trials as a novel anticancer therapeutic for hematological malignancies and solid tumors. Obatoclax was developed as a pan-inhibitor of antiapoptotic members of the B cell chronic lymphocytic leukemia/lymphoma 2 (BCL-2) family of proteins, which control the intrinsic or mitochondrial pathway of apoptosis. Resistance to apoptosis through dysregulation of BCL-2 family members is commonly observed in hematological malignancies, and can be linked to therapeutic resistance and poor clinical outcomes. By inhibiting pro-survival BCL-2 family proteins, including MCL-1, obatoclax is proposed to (1) trigger cell death as a single agent, and (2) potentiate the anticancer effects of other therapeutics. Preclinical investigations have supported these proposals and have provided evidence suggestive of a promising therapeutic index for this drug. Phase I trials of obatoclax mesylate in leukemia and lymphoma have defined well-tolerated regimens and have identified transient neurotoxicity as the most common adverse effect of this drug. In these studies, a limited number of objective responses were observed, along with hematological improvement in a larger proportion of treated patients. Published Phase II evaluations in lymphoma and myelofibrosis, however, have not reported robust single-agent activity. Emerging evidence from ongoing preclinical and clinical investigations suggests that the full potential of obatoclax mesylate as a novel anticancer agent may be realized (1) in rational combination treatments, and (2) when guided by molecular predictors of therapeutic response. By understanding the molecular underpinnings of obatoclax response, along with optimal therapeutic regimens and indications, the potential of obatoclax mesylate for the treatment of hematological malignancies may be further clarified.
甲磺酸 Obatoclax 是一种静脉注射药物,作为一种治疗血液恶性肿瘤和实体瘤的新型抗癌疗法,目前正在进行 I 期和 II 期临床试验。Obatoclax 是作为 B 细胞慢性淋巴细胞白血病/淋巴瘤 2(BCL-2)家族蛋白的抗凋亡泛抑制剂而开发的,这些蛋白控制着细胞凋亡的内在或线粒体途径。在血液恶性肿瘤中经常可以观察到通过 BCL-2 家族成员失调而导致的凋亡抵抗,这可能与治疗抵抗和临床疗效不佳有关。通过抑制包括 MCL-1 在内的促生存 BCL-2 家族蛋白,obatoclax 可(1)作为单药引发细胞死亡,(2)增强其他疗法的抗癌效果。临床前研究支持这些建议,并提供证据表明这种药物具有良好的治疗指数。甲磺酸 obatoclax 治疗白血病和淋巴瘤的 I 期试验确定了耐受性良好的治疗方案,并发现短暂的神经毒性是这种药物最常见的不良反应。在这些研究中,观察到了数量有限的客观反应,较大比例的治疗患者的血液学状况有所改善。然而,已发表的淋巴瘤和骨髓纤维化二期评估报告并未显示出强大的单药活性。正在进行的临床前和临床研究的新证据表明,甲磺酸奥巴曲克作为一种新型抗癌药的全部潜力可能在以下两个方面得以实现:(1) 合理的联合治疗;(2) 以治疗反应的分子预测指标为指导。通过了解 Obatoclax 反应的分子基础以及最佳治疗方案和适应症,可以进一步阐明甲磺酸 obatoclax 治疗血液恶性肿瘤的潜力。
{"title":"An evidence-based review of obatoclax mesylate in the treatment of hematological malignancies.","authors":"Carolyn A Goard, Aaron D Schimmer","doi":"10.2147/CE.S42568","DOIUrl":"10.2147/CE.S42568","url":null,"abstract":"<p><p>Obatoclax mesylate is an intravenously-administered drug under investigation in Phase I and II clinical trials as a novel anticancer therapeutic for hematological malignancies and solid tumors. Obatoclax was developed as a pan-inhibitor of antiapoptotic members of the B cell chronic lymphocytic leukemia/lymphoma 2 (BCL-2) family of proteins, which control the intrinsic or mitochondrial pathway of apoptosis. Resistance to apoptosis through dysregulation of BCL-2 family members is commonly observed in hematological malignancies, and can be linked to therapeutic resistance and poor clinical outcomes. By inhibiting pro-survival BCL-2 family proteins, including MCL-1, obatoclax is proposed to (1) trigger cell death as a single agent, and (2) potentiate the anticancer effects of other therapeutics. Preclinical investigations have supported these proposals and have provided evidence suggestive of a promising therapeutic index for this drug. Phase I trials of obatoclax mesylate in leukemia and lymphoma have defined well-tolerated regimens and have identified transient neurotoxicity as the most common adverse effect of this drug. In these studies, a limited number of objective responses were observed, along with hematological improvement in a larger proportion of treated patients. Published Phase II evaluations in lymphoma and myelofibrosis, however, have not reported robust single-agent activity. Emerging evidence from ongoing preclinical and clinical investigations suggests that the full potential of obatoclax mesylate as a novel anticancer agent may be realized (1) in rational combination treatments, and (2) when guided by molecular predictors of therapeutic response. By understanding the molecular underpinnings of obatoclax response, along with optimal therapeutic regimens and indications, the potential of obatoclax mesylate for the treatment of hematological malignancies may be further clarified.</p>","PeriodicalId":10764,"journal":{"name":"Core Evidence","volume":"8 ","pages":"15-26"},"PeriodicalIF":0.0,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3601645/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31325463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2013-01-01Epub Date: 2013-03-07DOI: 10.2147/CE.S41178
Tobias Engel Ayer Botrel, Otávio Clark, Antônio Carlos Lima Pompeo, Francisco Flávio Horta Bretas, Marcus Vinicius Sadi, Ubirajara Ferreira, Rodolfo Borges Dos Reis
Background: The purpose of this work was to conduct a systematic review and meta-analysis of all randomized controlled trials comparing the efficacy and side effect profile of hypofractionated versus conventional external-beam radiation therapy for prostate cancer.
Methods: Several databases were searched, including Medline, EmBase, LiLACS, and Central. The endpoints were freedom from biochemical failure and side effects. We performed a meta-analysis of the published data. The results are expressed as the hazard ratio (HR) or risk ratio (RR), with the corresponding 95% confidence interval (CI).
Results: The final analysis included nine trials comprising 2702 patients. Freedom from biochemical failure was reported in only three studies and was similar in patients who received hypofractionated or conventional radiotherapy (fixed effect, HR 1.03, 95% CI 0.88-1.20; P = 0.75), with heterogeneity [χ(2) = 15.32, df = 2 (P = 0.0005); I2 = 87%]. The incidence of acute adverse gastrointestinal events was higher in the hypofractionated group (fixed effect, RR 2.02, 95% CI 1.45-2.81; P < 0.0001). We also found moderate heterogeneity on this analysis [χ(2) = 7.47, df = 5 (P = 0.19); I2 = 33%]. Acute genitourinary toxicity was similar among the groups (fixed effect, RR 1.19, 95% CI 0.95-1.49; P = 0.13), with moderate heterogeneity [χ(2) = 5.83, df = 4 (P = 0.21); I2 = 31%]. The incidence of all late adverse events was the same in both groups (fixed effect, gastrointestinal toxicity, RR 1.17, 95% CI 0.79-1.72, P = 0.44; and acute genitourinary toxicity, RR 1.16, 95% CI 0.80-1.68, P = 0.44).
Conclusion: Hypofractionated radiotherapy in localized prostate cancer was not superior to conventional radiotherapy and showed higher acute gastrointestinal toxicity in this meta-analysis. Because the number of published studies is still small, future assessments should be conducted to clarify better the true role of hypofractionated radiotherapy in patients with prostate cancer.
背景:本研究的目的是对所有随机对照试验进行系统回顾和荟萃分析,比较低分割与常规外束放射治疗前列腺癌的疗效和副作用。方法:检索Medline、EmBase、LiLACS、Central等数据库。终点是没有生化失败和副作用。我们对发表的数据进行了荟萃分析。结果用风险比(HR)或风险比(RR)表示,并给出相应的95%置信区间(CI)。结果:最终分析包括9项试验,2702例患者。只有3项研究报告了生化失败的自由,在接受低分割或常规放疗的患者中也有类似的情况(固定效应,HR 1.03, 95% CI 0.88-1.20;P = 0.75),异质性[χ(2) = 15.32, df = 2 (P = 0.0005);I2 = 87%]。急性胃肠道不良事件的发生率在低分割组较高(固定效应,RR 2.02, 95% CI 1.45-2.81;P < 0.0001)。我们还发现该分析存在中度异质性[χ(2) = 7.47, df = 5 (P = 0.19);I2 = 33%]。两组间急性泌尿生殖系统毒性相似(固定效应,RR 1.19, 95% CI 0.95-1.49;P = 0.13),异质性中等[χ(2) = 5.83, df = 4 (P = 0.21);I2 = 31%]。两组的所有晚期不良事件发生率相同(固定效应,胃肠道毒性,RR 1.17, 95% CI 0.79-1.72, P = 0.44;急性泌尿生殖系统毒性,RR 1.16, 95% CI 0.80-1.68, P = 0.44)。结论:在本荟萃分析中,低分割放疗治疗局限性前列腺癌并不优于常规放疗,而且显示出更高的急性胃肠道毒性。由于已发表的研究数量仍然很少,未来的评估应该进行,以更好地阐明低分割放疗在前列腺癌患者中的真正作用。
{"title":"Hypofractionated external-beam radiation therapy (HEBRT) versus conventional external-beam radiation (CEBRT) in patients with localized prostate cancer: a systematic review and meta-analysis.","authors":"Tobias Engel Ayer Botrel, Otávio Clark, Antônio Carlos Lima Pompeo, Francisco Flávio Horta Bretas, Marcus Vinicius Sadi, Ubirajara Ferreira, Rodolfo Borges Dos Reis","doi":"10.2147/CE.S41178","DOIUrl":"https://doi.org/10.2147/CE.S41178","url":null,"abstract":"<p><strong>Background: </strong>The purpose of this work was to conduct a systematic review and meta-analysis of all randomized controlled trials comparing the efficacy and side effect profile of hypofractionated versus conventional external-beam radiation therapy for prostate cancer.</p><p><strong>Methods: </strong>Several databases were searched, including Medline, EmBase, LiLACS, and Central. The endpoints were freedom from biochemical failure and side effects. We performed a meta-analysis of the published data. The results are expressed as the hazard ratio (HR) or risk ratio (RR), with the corresponding 95% confidence interval (CI).</p><p><strong>Results: </strong>The final analysis included nine trials comprising 2702 patients. Freedom from biochemical failure was reported in only three studies and was similar in patients who received hypofractionated or conventional radiotherapy (fixed effect, HR 1.03, 95% CI 0.88-1.20; P = 0.75), with heterogeneity [χ(2) = 15.32, df = 2 (P = 0.0005); I2 = 87%]. The incidence of acute adverse gastrointestinal events was higher in the hypofractionated group (fixed effect, RR 2.02, 95% CI 1.45-2.81; P < 0.0001). We also found moderate heterogeneity on this analysis [χ(2) = 7.47, df = 5 (P = 0.19); I2 = 33%]. Acute genitourinary toxicity was similar among the groups (fixed effect, RR 1.19, 95% CI 0.95-1.49; P = 0.13), with moderate heterogeneity [χ(2) = 5.83, df = 4 (P = 0.21); I2 = 31%]. The incidence of all late adverse events was the same in both groups (fixed effect, gastrointestinal toxicity, RR 1.17, 95% CI 0.79-1.72, P = 0.44; and acute genitourinary toxicity, RR 1.16, 95% CI 0.80-1.68, P = 0.44).</p><p><strong>Conclusion: </strong>Hypofractionated radiotherapy in localized prostate cancer was not superior to conventional radiotherapy and showed higher acute gastrointestinal toxicity in this meta-analysis. Because the number of published studies is still small, future assessments should be conducted to clarify better the true role of hypofractionated radiotherapy in patients with prostate cancer.</p>","PeriodicalId":10764,"journal":{"name":"Core Evidence","volume":"8 ","pages":"1-13"},"PeriodicalIF":0.0,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/CE.S41178","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31425734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2013-01-01Epub Date: 2013-09-25DOI: 10.2147/CE.S35675
Stefan Josef Schaller, Heidrun Fink
Sugammadex is the first clinical representative of a new class of drugs called selective relaxant binding agents. It has revolutionized the way anesthesiologists think about drug reversal. Sugammadex selectively binds rocuronium or vecuronium, thereby reversing their neuromuscular blocking action. Due to its 1:1 binding of rocuronium or vecuronium, it is able to reverse any depth of neuromuscular block. So far, it has been approved for use in adult patients and for pediatric patients over 2 years. Since its approval in Europe, Japan, and Australia, further insight on its use in special patient populations and specific diseases have become available. Due to its pharmacodynamic profile, sugammadex, in combination with rocuronium, may have the potential to displace succinylcholine as the "gold standard" muscle relaxant for rapid sequence induction. The use of rocuronium or vecuronium, with the potential of reverse of their action with sugammadex, seems to be safe in patients with impaired neuromuscular transmission, ie, neuromuscular diseases, including myasthenia gravis. Data from long-term use of sugammadex is not yet available. Evidence suggesting an economic advantage of using sugammadex and justifying its relatively high cost for an anesthesia-related drug, is missing.
{"title":"Sugammadex as a reversal agent for neuromuscular block: an evidence-based review.","authors":"Stefan Josef Schaller, Heidrun Fink","doi":"10.2147/CE.S35675","DOIUrl":"10.2147/CE.S35675","url":null,"abstract":"<p><p>Sugammadex is the first clinical representative of a new class of drugs called selective relaxant binding agents. It has revolutionized the way anesthesiologists think about drug reversal. Sugammadex selectively binds rocuronium or vecuronium, thereby reversing their neuromuscular blocking action. Due to its 1:1 binding of rocuronium or vecuronium, it is able to reverse any depth of neuromuscular block. So far, it has been approved for use in adult patients and for pediatric patients over 2 years. Since its approval in Europe, Japan, and Australia, further insight on its use in special patient populations and specific diseases have become available. Due to its pharmacodynamic profile, sugammadex, in combination with rocuronium, may have the potential to displace succinylcholine as the \"gold standard\" muscle relaxant for rapid sequence induction. The use of rocuronium or vecuronium, with the potential of reverse of their action with sugammadex, seems to be safe in patients with impaired neuromuscular transmission, ie, neuromuscular diseases, including myasthenia gravis. Data from long-term use of sugammadex is not yet available. Evidence suggesting an economic advantage of using sugammadex and justifying its relatively high cost for an anesthesia-related drug, is missing. </p>","PeriodicalId":10764,"journal":{"name":"Core Evidence","volume":"8 ","pages":"57-67"},"PeriodicalIF":0.0,"publicationDate":"2013-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/0c/18/ce-8-057.PMC3789633.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31783574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pancreatic exocrine insufficiency (PEI) is often observed in patients with pancreatic diseases, including chronic pancreatitis, cystic fibrosis, and tumors, or after surgical resection. PEI often results in malnutrition, weight loss and steatorrhea, which together increase the risk of morbidity and mortality. Therefore, nutritional interventions, such as low-fat diets and pancreatic enzyme replacement therapy (PERT), are needed to improve the clinical symptoms, and to address the pathophysiology of pancreatic exocrine insufficiency. PERT with delayed-release pancrelipase is now becoming a standard therapy for pancreatic exocrine insufficiency because it significantly improves the coefficients of fat and nitrogen absorption as well as clinical symptoms, without serious treatment-emergent adverse events. The major adverse events were tolerable gastrointestinal tract symptoms, such as stomach pain, nausea, and bloating. Fibrosing colonopathy, a serious complication, is associated with high doses of enzymes. Several pancrelipase products have been approved by the US Food and Drug Administration in recent years. Although many double-blind, placebo-controlled trials of pancrelipase products have been conducted in recent years, these studies have enrolled relatively few patients and have often been less than a few weeks in duration. Moreover, few studies have addressed the issue of pancreatic diabetes, a type of diabetes that is characterized by frequent hypoglycemia, which is difficult to manage. In addition, it is unclear whether PERT improves morbidity and mortality in such settings. Therefore, large, long-term prospective studies are needed to identify the optimal treatment for pancreatic exocrine insufficiency. The studies should also examine the extent to which PERT using pancrelipase improves mortality and morbidity. The etiology and severity of pancreatic exocrine insufficiency often differ among patients with gastrointestinal diseases or diabetes (type 1 and type 2), and among elderly subjects. Finally, although there is currently limited clinical evidence, numerous extrapancreatic diseases and conditions that are highly prevalent in the general population may also be considered potential targets for PERT and related treatments.
{"title":"Pancrelipase: an evidence-based review of its use for treating pancreatic exocrine insufficiency.","authors":"Kei Nakajima, Haruki Oshida, Toshitaka Muneyuki, Masafumi Kakei","doi":"10.2147/CE.S26705","DOIUrl":"https://doi.org/10.2147/CE.S26705","url":null,"abstract":"<p><p>Pancreatic exocrine insufficiency (PEI) is often observed in patients with pancreatic diseases, including chronic pancreatitis, cystic fibrosis, and tumors, or after surgical resection. PEI often results in malnutrition, weight loss and steatorrhea, which together increase the risk of morbidity and mortality. Therefore, nutritional interventions, such as low-fat diets and pancreatic enzyme replacement therapy (PERT), are needed to improve the clinical symptoms, and to address the pathophysiology of pancreatic exocrine insufficiency. PERT with delayed-release pancrelipase is now becoming a standard therapy for pancreatic exocrine insufficiency because it significantly improves the coefficients of fat and nitrogen absorption as well as clinical symptoms, without serious treatment-emergent adverse events. The major adverse events were tolerable gastrointestinal tract symptoms, such as stomach pain, nausea, and bloating. Fibrosing colonopathy, a serious complication, is associated with high doses of enzymes. Several pancrelipase products have been approved by the US Food and Drug Administration in recent years. Although many double-blind, placebo-controlled trials of pancrelipase products have been conducted in recent years, these studies have enrolled relatively few patients and have often been less than a few weeks in duration. Moreover, few studies have addressed the issue of pancreatic diabetes, a type of diabetes that is characterized by frequent hypoglycemia, which is difficult to manage. In addition, it is unclear whether PERT improves morbidity and mortality in such settings. Therefore, large, long-term prospective studies are needed to identify the optimal treatment for pancreatic exocrine insufficiency. The studies should also examine the extent to which PERT using pancrelipase improves mortality and morbidity. The etiology and severity of pancreatic exocrine insufficiency often differ among patients with gastrointestinal diseases or diabetes (type 1 and type 2), and among elderly subjects. Finally, although there is currently limited clinical evidence, numerous extrapancreatic diseases and conditions that are highly prevalent in the general population may also be considered potential targets for PERT and related treatments.</p>","PeriodicalId":10764,"journal":{"name":"Core Evidence","volume":"7 ","pages":"77-91"},"PeriodicalIF":0.0,"publicationDate":"2012-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/CE.S26705","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"30869663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}