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Journal of Managed Care & Specialty... Feb 2021Several immuno-oncology (IO) agents targeting programmed death-1 or programmed death-ligand 1 (PD-1/L1) are approved second-line therapy options for patients with...
Several immuno-oncology (IO) agents targeting programmed death-1 or programmed death-ligand 1 (PD-1/L1) are approved second-line therapy options for patients with locally advanced or metastatic urothelial carcinoma (la/mUC) previously treated with platinum-based chemotherapy or first-line options in patients ineligible for cisplatin whose tumors express PD-L1 or for any platinum-based chemotherapy regardless of PD-L1 expression levels. However, literature on the epidemiology of la/mUC is limited, and real-world treatment patterns are not well established, especially with respect to therapies used following IO. To (a) report the epidemiology of urothelial carcinoma (UC) and la/mUC; (b) identify and summarize the published literature on la/mUC treatment patterns, including IO and post-IO treatment; and (c) identify evidence gaps. A systematic literature review was conducted using Cochrane dual-reviewer methodology and the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols. Literature databases and selected congress abstracts (2017-2018) were searched for retrospective studies published January 2013-August 2018 in English reporting epidemiological and treatment data (all lines of therapy) for adult patients with la/mUC. Among 6,584 database references and 1,832 congress abstracts screened, 45 publications (29 manuscripts, 1 poster, 15 abstracts; reporting 37 unique studies) were retained. All studies related to treatment patterns, and the majority were from the United States (n = 17), Japan (n = 8), and the United Kingdom (n = 5). Epidemiological data were not identified among the searches thus online registries were leveraged. Among the identified publications, 21 (20 unique) reported on cisplatin versus non-cisplatin regimens, 14 (8 unique) on IO, and 9 (7 unique) on vinflunine. Cisplatin use varied both within and among countries (ranging from 18.4% in 1 U.S. study to 87.9% in 1 Japanese study). The use of IO was higher in later lines of therapy, ranging from 1.4% to 7.9% as first-line therapy to 57.8% as second-line and 64.4% as third-line therapy. Among studies reporting IO discontinuation rates, 41.4%-71% of patients were reported to discontinue IO across the studies, and the median time to discontinuation ranged from 2.7 to 5.8 months. Only 25%-35.5% of patients received subsequent therapy following IO discontinuation; post-IO treatments varied widely. Additional published data on the country-specific epidemiology of UC and la/mUC are needed, including rates of progression from early-stage disease to la/mUC. There was large variation in treatment rates, particularly cisplatin use, within and across countries. The few published real-world IO studies reported high levels of discontinuation with only a small percentage of patients receiving subsequent therapy. As IO therapies continue to be granted regulatory approval in countries outside the United States and novel therapies gain approval in the post-IO setting, the treatment paradigm for patients with la/mUC is shifting, and future studies with more recent data will be required. This study was funded by Astellas/Seagen. Hepp is an employee of and owns stock in Seagen. Shah was a contractor for Astellas Pharma at the time of the study and owns stock in Pfizer. Smoyer is an employee and shareholder of Envision Pharma Group, paid consultants to Seagen. Vadagam was an employee of Envision Pharma Group, paid consultants to Seagen, at the time of the study. Parts of these data have been presented at the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) 2019 Annual Meeting; May 18-22, 2019; New Orleans, LA.
Topics: Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Carcinoma, Transitional Cell; Cisplatin; Humans; Immune Checkpoint Inhibitors; Medical Oncology; Neoplasm Staging; Practice Patterns, Physicians'; Professional Practice Gaps; Programmed Cell Death 1 Receptor; Urinary Bladder Neoplasms
PubMed: 33355035
DOI: 10.18553/jmcp.2020.20285 -
Medicine Nov 2015Several individual studies have reported the diagnostic accuracy of presepsin (sCD14-ST) for sepsis, but the results are inconsistent.The present systematic review and... (Meta-Analysis)
Meta-Analysis Review
Several individual studies have reported the diagnostic accuracy of presepsin (sCD14-ST) for sepsis, but the results are inconsistent.The present systematic review and meta-analysis pooled data to better ascertain the value of circulatory presepsin as a biomarker for sepsis.Studies published in English before November 7, 2014 and assessing the diagnostic accuracy of presepsin for sepsis were retrieved from medical databases.The quality of eligible studies was assessed using a revised Quality Assessment for Studies of Diagnostic Accuracy (QUADAS-2). The overall diagnostic accuracy of presepsin for sepsis was pooled according to a bivariate model. Publication bias was assessed using Deek funnel plot asymmetry test.Eleven studies satisfied the inclusion criteria. The overall diagnostic sensitivity of presepsin for sepsis was 0.83 (95% CI: 0.77-0.88), and specificity was 0.78 (95% CI: 0.72-0.83). The area under the summary receiver operating characteristic curve was 0.88 (95% CI: 0.84-0.90). The pretest probability of sepsis was 0.56 among all subjects. When presepsin was introduced as the diagnostic test for sepsis, the posttest probabilities were 0.81 for a positive result and 0.19 for a negative. The major design deficits of the included studies were lack of prespecified thresholds and patient selection bias. The publication bias was negative.Presepsin is an effective adjunct biomarker for the diagnosis of sepsis, but is insufficient to detect or rule out sepsis when used alone.
Topics: Biomarkers; Emergency Service, Hospital; Humans; Lipopolysaccharide Receptors; Peptide Fragments; ROC Curve; Sensitivity and Specificity; Sepsis
PubMed: 26632748
DOI: 10.1097/MD.0000000000002158 -
European Journal of Hospital Pharmacy :... Jan 2023To investigate the efficacy and safety of programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) plus cytotoxic T lymphocyte antigen-4 (CTLA-4) antibodies... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
To investigate the efficacy and safety of programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) plus cytotoxic T lymphocyte antigen-4 (CTLA-4) antibodies ± other therapies in patients with advanced lung cancer.
METHODS
In accordance with the retrieval strategy, we searched electronic databases for randomised controlled trials testing PD-1/PD-L1 plus CTLA-4 antibodies in patients with lung cancer; RR (for objective response rate (ORR), overall survival (OS), progression-free survival (PFS), and immune-related adverse events (irAEs)) from individual studies were calculated and pooled by using random-effects models or fixed-effects models; heterogeneity and publication bias analyses were also performed, using Review Manager 5.3 and Stata 15.1 for statistical analysis.
RESULTS
We included six studies. Four different immune checkpoint inhibitors (nivolumab, pembrolizumab, durvalumab, tremelimumab) were used. Dual checkpoint inhibitors ± other therapies for advanced lung cancer showed significant improvements in ORR (RR 1.49, 95% CI 1.11 to 1.98; p=0.007), OS (HR 0.72, 95% CI 0.63 to 0.83; p<0.00001), and PFS (HR 0.72, 95% CI 0.63 to 0.82; p<0.00001). The subgroup analyses were consistent with the pooled results. The PD-L1 ≥1% (HR 0.67, 95% CI 0.54 to 0.82; p<0.0001) subgroup differences indicated a statistically significant subgroup effect, but the PD-L1 <1% subgroup (HR 0.88, 95% CI 0.75 to 1.05; p=0.15) was not statistically significant. The incidence of adverse events (grade ≥3) was lower than that of the control group (RR 0.90, 95% CI 0.80 to 1.02; p=0.09), but was not significant.
CONCLUSIONS
PD-1/PD-L1 inhibitors combined with CTLA-4 inhibitors ± other therapies can improve the ORR, OS and PFS of patients with advanced or metastatic lung cancer, but the incidence of adverse reactions is high although generally tolerable.
PROSPERO REGISTRATION
CRD42020149216.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Programmed Cell Death 1 Receptor; CTLA-4 Antigen; B7-H1 Antigen; Lung Neoplasms
PubMed: 34497128
DOI: 10.1136/ejhpharm-2021-002803 -
Current Oncology (Toronto, Ont.) Nov 2023: The purpose of this study was to evaluate the efficacy and safety of programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors for the treatment of... (Meta-Analysis)
Meta-Analysis Review
: The purpose of this study was to evaluate the efficacy and safety of programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors for the treatment of metastatic urothelial carcinoma (mUC). A literature search was conducted of PubMed, EMBASE, and the Cochrane Library and was limited to the English literature. Randomized controlled trials (RCTs) published up to July 2022 were considered for inclusion. The outcomes were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and grade ≥ 3 treatment-related AEs (TRAE). Subgroup analysis was performed based on the PD-L1 expression status, and the differences between first- and second-line PD-1/PD-L1 inhibitors were estimated. We included five RCTs comprising 3584 patients in the analysis. Compared with chemotherapy alone, the use of PD-1/PD-L1 inhibitors as monotherapy did not significantly prolong OS [hazard ratios (HR), 0.90; 95% CI, 0.81-1.00] or PFS (HR, 1.12; 95% CI, 0.95-1.32). However, the PD-1/PD-L1 inhibitor combined with chemotherapy significantly improved both OS (HR, 0.85; 95% CI, 0.74-0.96) and PFS (HR, 0.80; 95% CI, 0.71-0.90). Additionally, subgroup analysis showed that in mUC with PD-L1 expression ≥ 5%, treatment with the PD-1/PD-L1 inhibitor alone did not reduce the risk of death. Safety analysis showed that the PD-1/PD-L1 inhibitor alone did not significantly increase the incidence rates of grade ≥ 3 TRAEs. The results show that use of the PD-1/PD-L1 inhibitor alone as first-line treatment is similar to chemotherapy in terms of both survival and response rates. However, the PD-1/PD-L1 inhibitor plus chemotherapy has a significant benefit in terms of PFS or OS. Nonetheless, more RCTs are warranted to evaluate efficiency and safety in the combination regimen of chemotherapy and PD-1/PD-L1 inhibitors.
Topics: Humans; Immune Checkpoint Inhibitors; B7-H1 Antigen; Programmed Cell Death 1 Receptor; Progression-Free Survival; Carcinoma
PubMed: 37999142
DOI: 10.3390/curroncol30110722 -
ESMO Open Feb 2022Recently, several randomized controlled trials (RCTs) investigated immunotherapy-based regimens versus chemotherapy alone in patients with advanced esophageal squamous... (Meta-Analysis)
Meta-Analysis
Efficacy and activity of PD-1 blockade in patients with advanced esophageal squamous cell carcinoma: a systematic review and meta-analysis with focus on the value of PD-L1 combined positive score.
BACKGROUND
Recently, several randomized controlled trials (RCTs) investigated immunotherapy-based regimens versus chemotherapy alone in patients with advanced esophageal squamous cell carcinoma (ESCC). Here we conducted a systematic review and meta-analysis on the efficacy and activity of programmed cell death protein 1 blockade in these patients, with focus on the value of programmed death-ligand 1 combined positive score (CPS) for selecting patients who may benefit the most.
METHODS
RCTs investigating treatment with or without immune checkpoint inhibitors for advanced ESCC were selected. The hazard ratio (HR) and the odds ratio were used to compare the treatment effect on survival outcomes and tumor response, respectively, for immunotherapy-based regimens compared with standard chemotherapy, overall and according to geographic region or treatment line. We carried out a subgroup analysis comparing patients with CPS ≥10 or <10 and the evidence for treatment effect was evaluated by interaction test.
RESULTS
A total of 5257 patients and 10 RCTs were included. Overall, the HR for overall survival benefit with immunotherapy-based regimens was 0.71 [95% confidence interval (CI) 0.66-0.76] compared with chemotherapy alone; such effect was independent from geographical region (Asia versus rest of the world) and treatment line (upfront versus second/further lines). The HR for progression-free survival benefit and the odds ratio for overall response rate increase were 0.78 (95% CI 0.66-0.93) and 1.50 (95% CI 1.22-1.83), respectively. The HR for overall survival benefit with immunotherapy-based treatment was 0.60 (95% CI 0.51-0.70) for CPS ≥10 subgroup versus 0.83 (95% CI 0.69-1.00) for CPS <10 (P for interaction 0.009).
CONCLUSIONS
Immune checkpoint inhibitors have a consistent benefit in reducing the risk of death for ESCC patients which is dependent on programmed death-ligand 1 CPS status. Further investigations of biomarkers for immunotherapy in the subgroup of patients with CPS <10 are needed.
Topics: B7-H1 Antigen; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Humans; Programmed Cell Death 1 Receptor
PubMed: 35093742
DOI: 10.1016/j.esmoop.2021.100380 -
Blood Advances Mar 2022Chimeric antigen receptor T-cell (CAR-T) therapy has transformed treatment paradigms for relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) in...
Chimeric antigen receptor T-cell (CAR-T) therapy has transformed treatment paradigms for relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) in children and younger adults. We performed a systematic review to investigate the published literature on efficacy and toxicity of CAR-T therapy in adults with r/r B-ALL. We searched MEDLINE, Embase, and the Cochrane Library for prospective interventional studies and included published studies of ≥5 patients with median age at enrollment of ≥18 years. Risk of bias was assessed with a modified Institute of Health Economics tool. A total of 2566 records were assessed; 16 studies involving 489 patients were included in the final analysis. The mean complete remission (CR) rate was 81% and the measurable residual disease (MRD)-negative remission rate was 81% at 4 weeks after CAR-T infusion. With median follow-up across studies of 24 months, the cumulative 12-month probabilities of progression-free survival (PFS) and overall survival (OS) were 37% (95% CI, 26-48) and 57% (95% CI, 49-65), respectively. Relapse occurred in 40.3% of cases; target antigen was retained in 73.2% of relapses. Across studies, any grade of cytokine release syndrome (CRS) occurred in 82% of patients (95% CI, 61-95) and grade 3 or higher CRS in 27% (95% CI, 18-36). Neurotoxicity of any grade occurred in 34% of patients (95% CI, 24-47) and grade 3 or higher in 14% (95% CI, 1-25). In summary, CAR-T therapy achieves high early remission rates in adults with r/r B-ALL and represents a significant improvement over traditional salvage chemotherapy. Relapses are common and durable response remains a challenge.
Topics: Acute Disease; Adult; Antigens, CD19; Burkitt Lymphoma; Cell- and Tissue-Based Therapy; Child; Cytokine Release Syndrome; Humans; Lymphoma, B-Cell; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prospective Studies; Receptors, Chimeric Antigen; Recurrence
PubMed: 34610109
DOI: 10.1182/bloodadvances.2020003482 -
BMC Medicine Sep 2015Targeting CTLA-4 is a recent strategic approach in cancer control: blocking CTLA-4 enhances an antitumor immunity by promoting T-cell activation and cytotoxic... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Targeting CTLA-4 is a recent strategic approach in cancer control: blocking CTLA-4 enhances an antitumor immunity by promoting T-cell activation and cytotoxic T-lymphocyte proliferation. This induction of a tolerance break against the tumor may be responsible for immune-related adverse events (irAEs). Our objective was to assess the incidence and nature of irAEs in oncologic patients receiving anti-CTLA-4 antibodies (ipilimumab and tremelimumab).
METHODS
A systematic search of literature up to February 2014 was performed in MEDLINE, EMBASE, and Cochrane databases to identify relevant articles. Paired reviewers independently selected articles for inclusion and extracted data. Pooled incidence was calculated using R(©), package meta.
RESULTS
Overall, 81 articles were included in the study, with a total of 1265 patients from 22 clinical trials included in the meta-analysis. Described irAEs consisted of skin lesions (rash, pruritus, and vitiligo), colitis, and less frequently hepatitis, hypophysitis, thyroiditis, and some rare events such as sarcoidosis, uveitis, Guillain-Barré syndrome, immune-mediated cytopenia and polymyalgia rheumatic/Horton. The overall incidence of all-grade irAEs was 72 % (95 % CI, 65-79 %). The overall incidence of high-grade irAEs was 24 % (95 % CI, 18-30 %). The risk of developing irAEs was dependent of dosage, with incidence of all-grade irAEs being evaluated to 61 % (95 % CI, 56-66 %) for ipilimumab 3 mg/kg and 79 % (95 % CI, 69-89 %) for ipilimumab 10 mg/kg. Death due to irAEs occurred in 0.86 % of patients. The median time of onset of irAEs was about 10 weeks (IQR, 6-12) after the onset of treatment, corresponding with the first three cycles but varied according to the organ system involved. Such immune activation could also be indicative for tumor-specific T-cell activation and irAE occurrence was associated with clinical response to CTLA-4 blocking in 60 % of patients.
CONCLUSION
The price of potential long-term survival to metastatic tumors is an atypical immune toxicity, reflecting the mechanism of action of anti-CTLA-4 antibodies. A better knowledge of these irAEs and its management in a multidisciplinary approach will help to reduce morbidity and therapy interruptions.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; CTLA-4 Antigen; Humans; Immunologic Factors; Immunotherapy; Ipilimumab; Neoplasms
PubMed: 26337719
DOI: 10.1186/s12916-015-0455-8 -
JOP : Journal of the Pancreas Jan 2013The discovery and subsequent ultrastructural characterization of the interstitial Cajal like cells (now called telocytes) in virtually every anatomic sites of the human... (Review)
Review
CONTEXT
The discovery and subsequent ultrastructural characterization of the interstitial Cajal like cells (now called telocytes) in virtually every anatomic sites of the human body, by Laurentiu M Popescu and co-workers, have dramatically improved the understanding the function of these cells and pathogenesis of extragastrointestinal stromal tumors (EGIST). Pancreatic extragastrointestinal stromal tumors (pEGIST), phenotypically similar to pancreatic interstitial Cajal like cells, are extremely rare with an unpredictable biological behavior.
OBJECTIVE
To review the clinicopathological, radiological, immunohistochemical, and therapeutic outcome data of all reported cases of pEGIST, and highlight the developments in the field of pancreatic interstitial Cajal like cells/telocytes.
METHODS
A systematic review of English literature (January 2000 to July 2012) was done by using the search engine of PubMed, PubMed Central, Google Scholar, and the Directory of Open Access Journals.
RESULTS
There have been 19 reported cases of pEGIST during the last decade, over an age range of 31 to 84 years (mean: 56 years) with equal gender predilection ((male:female ratio: 9:10). Preoperative radiological characteristics have been mostly nondiagnostic though these were used, in some, for tissue diagnosis. Majority of pEGIST were localized to pancreatic head (8/19, 42.1%), and 15 of 19 patients (78.9%) were symptomatic at first presentation. The mean size ranged from 2.5 to 35cm (mean: 14 cm). Histomorphological features were that of predominantly spindle cell tumor which consistently expressed c-KIT/CD117 and CD34 by immunohistochemistry, making these two as the most sensitive markers at this site.
RESULTS
from studies involving discovery on gastrointestinal stromal tumor 1 (DOG-1), the most specific biomarker of GIST/EGIST, has been inconclusive and this was found to be positive in one case only. Neoadjuvant chemotherapy with imatinib mesylate and sunitinib were used in few cases, and genetic analysis of c-KIT proto-oncogene was done in two. By univariate analysis, none of the clinicopathological parameters, except surgical resection with microscopic free margin (R0 resection) (P<0.05), were found to be an important indicators of outcome.
CONCLUSION
The biological behavior of pEGIST, at present, seems unpredictable which requires indefinite period of follow-up. Large number of such cases with genetic analysis supplemented with immunohistochemistry studies will hopefully throw more light in these tumors.
Topics: Antigens, CD34; Female; Gastrointestinal Stromal Tumors; Humans; Immunohistochemistry; Interstitial Cells of Cajal; Male; Pancreas; Pancreatic Neoplasms; Proto-Oncogene Mas; Proto-Oncogene Proteins c-kit
PubMed: 23306329
DOI: 10.6092/1590-8577/1293 -
Scientific Reports Feb 2017The outcomes of studies analyzing the prognostic role of CTLA-4 in cancers are controversial. Therefore, the aim of our meta-analysis was to clarify the correlation... (Meta-Analysis)
Meta-Analysis Review
The outcomes of studies analyzing the prognostic role of CTLA-4 in cancers are controversial. Therefore, the aim of our meta-analysis was to clarify the correlation between CTLA-4 expression and OS in different cancer cases. Relevant literature was searched using PubMed, EMBASE, Web of Science, and the Cochrane Library. The clinicopathological features, hazard ratio (HR) and 95% confidence intervals (CI) were collected from these studies and were analyzed using Stata version 12.0 software. The pooled HR values showed no significant correlation between CTLA-4 expression levels and OS in relation to tumors (HR: 1.24, 95% CI: 0.98-1.56, I2 = 71.7%, P = 0.000). Further subgroup analyses were conducted and categorized by experimental methods, CTLA-4 sources and cancer types. The survey showed a significant correlation (HR: 1.47, 95% CI: 1.14-1.89) between high expression of CTLA-4 and OS in the SNP subgroup, and subgroups analyzing by PCR (HR: 1.50, 95% CI: 1.20-1.86) and flow cytometry (HR: 2.76, 95% CI: 1.49-5.14). In addition, our analysis observed significant differences between patients and controls in inCTLA-4+CD4+ lymphocytes, surCTLA-4+CD4+ lymphocytes, inCTLA-4+CD8+ lymphocytes, and surCTLA-4+CD8+ lymphocytes. Knowledge of the effects of CTLA-4 could potentially be used to effectively guide appropriate prognosis and therapeutic strategies in cancer patients.
Topics: CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; CTLA-4 Antigen; Databases, Factual; Humans; Neoplasms; Polymorphism, Single Nucleotide; Prognosis; Proportional Hazards Models; Survival Rate
PubMed: 28211499
DOI: 10.1038/srep42913 -
Current Oncology (Toronto, Ont.) Sep 2022Chinese national guidelines recommend various systemic therapies for patients with advanced hepatocellular carcinoma (HCC), but optimal treatment selection remains... (Review)
Review
Chinese national guidelines recommend various systemic therapies for patients with advanced hepatocellular carcinoma (HCC), but optimal treatment selection remains uncertain. To summarize the evidence supporting the systemic treatment of Chinese patients with advanced HCC, we performed a systematic review using a literature search of PubMed, Embase, China National Knowledge Infrastructure, and the Chinese Scientific Journal Database between 1 January 2009 and 15 June 2021, and abstracts from ASCO 2020, ASCO GI 2021, ESMO 2020, and ESMO GI 2020. The inclusion criteria were: Chinese patients aged ≥18 years with advanced HCC; first- or second-line systemic therapy; an evaluation of the efficacy or safety outcomes; and a randomized controlled, non-randomized controlled, prospective, or retrospective design. Thirty reports were identified for the following therapies: the single-agent tyrosine kinase inhibitor (TKI; = 10), single-agent programmed death-1 (PD-1) inhibitor ( = 4), chemotherapy ( = 5), PD-1/programmed death-ligand 1 (PD-L1) inhibitor plus TKI ( = 6), PD-1/PD-L1 inhibitor plus bevacizumab or biosimilar ( = 4), and PD-1/PD-L1 inhibitor plus chemotherapy ( = 1). The heterogeneity between the studies precluded statistical analysis and the data were summarized using tables. In the first-line setting, evidence supported the use of atezolizumab or sintilimab plus bevacizumab or a biosimilar. There remains insufficient evidence to determine the optimal approved TKI-based therapeutic option, and active controlled trials in the second-line setting were lacking.
Topics: Humans; Adolescent; Adult; Carcinoma, Hepatocellular; B7-H1 Antigen; Bevacizumab; Programmed Cell Death 1 Receptor; Immune Checkpoint Inhibitors; Biosimilar Pharmaceuticals; Retrospective Studies; Prospective Studies; Liver Neoplasms; Protein Kinase Inhibitors
PubMed: 36290852
DOI: 10.3390/curroncol29100575