Meta-analysis Of Survival Data Research Articles

Venetoclax with Hypomethylating Agents in Newly Diagnosed Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis of Survival Data from Real-World Studies.

In recent years, the association of venetoclax (VEN) with hypomethylating agents (HMAs) significantly improved the outcome of patients with newly diagnosed acute myeloid leukemia (AML) who were unfit for intensive chemotherapy and became the standard of care after the publication of the pivotal RCT VIALE-A. However, it is still not clear to what extent the results observed in the VIALE-A apply to a real-world setting. For this reason, we carried out a systematic review and meta-analysis of real-world studies on newly diagnosed patients with AML, ineligible for intensive induction chemotherapy, receiving first-line VEN+HMA. We then compared their results in term of survival with those from the VIALE-A. Kaplan-Meier curves were extracted from all included studies and individual survival data was reconstructed. We then estimated a pooled survival curve and compared it with the results of the VIALE-A using the log-rank test. We also conducted a secondary analysis including only studies considering VEN plus azacytidine (AZA) as treatment, as this was the schedule originally used in the VIALE-A. Nineteen real-world studies met the inclusion criteria and were included in the systematic review. Most of them reported a worse survival than the VIALE-A. The pooled survival curve was similar to that reported in the VIALE-A during the first three months of treatment but diverged thereafter (p-value = 0.0001). The pooled median survival among the real-world studies was 9.37 months (95%CI 8.81-10.5), substantially lower than that reported in the VIALE-A (14.7 months; 95%CI 11.9-18.7). Results slightly increased when the analysis was restricted to the studies using VEN+AZA as treatment (median survival: 11.5 months; 95%CI 10.2-14.8). Survival of newly diagnosed AML patients treated with VEN+HMAs in a real-world setting seems to be lower than previously reported in the VIALE-A, while the effect of VEN+AZA is more in line with expected results. Future studies are needed to evaluate whether this apparent discrepancy is due to the different characteristics of enrolled patients or to a non-optimal adherence to therapy, and whether alternative regimens can provide better results in terms of safety and effectiveness.

Survival Modelling For Data From Combined Cohorts: Opening the Door to Meta Survival Analyses and Survival Analysis using Electronic Health Records.

Non-parametric estimation of the survival function using observed failure time data depends on the underlying data generating mechanism, including the ways in which the data may be censored and/or truncated. For data arising from a single source or collected from a single cohort, a wide range of estimators have been proposed and compared in the literature. Often, however, it may be possible, and indeed advantageous, to combine and then analyze survival data that have been collected under different study designs. We review non-parametric survival analysis for data obtained by combining the most common types of cohort. We have two main goals: (i) To clarify the differences in the model assumptions, and (ii) to provide a single lens through which some of the proposed estimators may be viewed. Our discussion is relevant to the meta analysis of survival data obtained from different types of study, and to the modern era of electronic health records.

Efficacy and safety of neoadjuvant concurrent chemoradiotherapy followed by surgery versus surgery alone in the treatment of resectable esophageal squamous cell carcinoma: a Meta-analysis

Objective To systematically evaluate the efficacy and safety between neoadjuvant concurrent chemoradiotherapy followed by surgery and surgery alone in the treatment of resectable esophageal squamous cell carcinoma. Methods Literature review was performed from Embase, PubMed, Web of Science, Cochrane Library, CBM, Wanfang Data, CNKI and Chongqing VIP. The randomized controlled clinical trials of concurrent chemoradiotherapy followed by surgery versus surgery alone in the treatment of resectable esophageal squamous cell carcinoma were retrieved. The meta-analysis of survival data, R0 resection rate, incidences of postoperative complications and peritreatment mortality was conducted by using RevMan 5.3 software. Results A total of 1450 patients from 11 controlled clinical trials were included in this meta-analysis. The results of the meta-analysis showed that concurrent chemoradiotherapy followed by surgery group had significantly higher 2-and 5-year overall survival rate (RR=1.14, 95%CI: 1.05-1.23, P=0.00) and progression-free survival rate (RR=1.56, 95%CI: 1.05-2.32, P=0.03). R0 resection rate were also improved in concurrent chemoradiotherapy followed by surgery group (RR=1.10, 95%CI: 1.05-1.14, P=0.00). Compared with the surgery alone group, the incidence of arrhythmia in the concurrent chemoradiotherapy plus surgery group was significantly higher (RR=2.45, 95%CI: 1.37-4.38, P=0.00). However, there was no significant difference in the overall incidence of postoperative complications (RR=1.12, 95%CI: 0.79-1.59, P=0.51) and incidence of peritreatment mortality (RR=1.78, 95%CI: 0.90-3.52, P=0.10) between two groups. Conclusions Neoadjuvant concurrent chemoradiotherapy followed by surgery improves the survival and R0 resection rate over surgery alone among patients with resectable esophageal squamous cell carcinoma, whereas it does not increase the risk of postoperative complications. Consequently, neoadjuvant concurrent chemoradiotherapy followed by surgery is an optimal treatment for patients with resectable esophageal squamous cell carcinoma. Key words: Esophageal neoplasm/neoadjuvant chemoradiotherapy; Esophageal neoplasm/surgery; Prognosis; Meta-analysis

MiR-140-3p functions as a tumor suppressor in squamous cell lung cancer by regulating BRD9

Squamous cell lung cancer (SqCLC) is among the most malignant lung cancers worldwide, lacking biomarkers for diagnostic and targets for treatment. In this study, we observed that miR-140-3p was expressed at low levels both in SqCLC cell lines and patient samples, while overexpression of miR-140-3p dramatically reduced the cell proliferation and invasion in SqCLC cells and Patient derived xenograft (PDX) models. Our further investigation indicated miR-140-3p negatively affected the tumorigenesis of SqCLC by down-regulating the expression of BRD9, an oncogene in SqCLC. Inhibition of BRD9 repressed SqCLC tumorigenesis by regulating c-myc expression. Meanwhile, BRD9 expression is up-regulated and negatively correlated with miR-140-3p in clinical samples; a meta-analysis of survival data indicates that SqCLC patients with high levels of BRD9 in their tumors have a worse prognosis. Collectively, our study suggests the prognostic and therapeutic roles of miR-140-3p and BRD9 axis in squamous cell lung cancer.

Detecting small-study effects and funnel plot asymmetry in meta-analysis of survival data: A comparison of new and existing tests.

Small‐study effects are a common threat in systematic reviews and may indicate publication bias. Their existence is often verified by visual inspection of the funnel plot. Formal tests to assess the presence of funnel plot asymmetry typically estimate the association between the reported effect size and their standard error, the total sample size, or the inverse of the total sample size. In this paper, we demonstrate that the application of these tests may be less appropriate in meta‐analysis of survival data, where censoring influences statistical significance of the hazard ratio. We subsequently propose 2 new tests that are based on the total number of observed events and adopt a multiplicative variance component. We compare the performance of the various funnel plot asymmetry tests in an extensive simulation study where we varied the true hazard ratio (0.5 to 1), the number of published trials (N=10 to 100), the degree of censoring within trials (0% to 90%), and the mechanism leading to participant dropout (noninformative versus informative). Results demonstrate that previous well‐known tests for detecting funnel plot asymmetry suffer from low power or excessive type‐I error rates in meta‐analysis of survival data, particularly when trials are affected by participant dropout. Because our novel test (adopting estimates of the asymptotic precision as study weights) yields reasonable power and maintains appropriate type‐I error rates, we recommend its use to evaluate funnel plot asymmetry in meta‐analysis of survival data. The use of funnel plot asymmetry tests should, however, be avoided when there are few trials available for any meta‐analysis.

MiR-342-3p suppresses cell proliferation and migration by targeting AGR2 in non-small cell lung cancer

AGR2 is a well-studied secreted protein that is involved in multiple biological processes including cell proliferation and migration. The mechanism by which AGR2 increases the growth and migration of non-small cell lung cancer cells (NSCLC) is still unknown. In this study, we report that AGR2 is directly targeted by miR-342-3p. Functional studies suggest that overexpression of miR-342-3p inhibits the proliferation and migration of non-small cell lung cancer cells. Overexpression of AGR2 counteracts the phenotypes induced by miR-342-3p. Moreover, AGR2 expression is up-regulated and negatively correlated with miR-342-3p levels in NSCLC cells and tissues. A meta-analysis of survival data indicates that NSCLC patients with high levels of AGR2 in their tumors have a worse prognosis. Collectively, the identification of miR-342-3p and AGR2 might facilitate the development of biomarkers and therapeutic targets for this devastating disease.

Review of the Reporting of Survival Analyses within Randomised Controlled Trials and the Implications for Meta-Analysis.

BackgroundMeta-analysis is a growing approach to evidence synthesis and network meta-analysis in particular represents an important and developing method within Health Technology Assessment (HTA). Meta-analysis of survival data is usually performed using the individual summary statistic—the hazard ratio (HR) from each randomised controlled trial (RCT).ObjectivesThe objectives of this study are to: (i) review the methods and reporting of survival analyses in oncology RCTs; and (ii) assess the suitability and relevance of survival data reported in RCTs for inclusion into meta-analysis.MethodsFive oncology journals were searched to identify Phase III RCTs published between April and July 2015. Eligible studies included those that analysed a survival outcome.ResultsThirty-two RCTs reporting survival outcomes in cancer populations were identified. None of the publications reported details relating to a strategy for statistical model building, the goodness of fit of the final model, or final model validation for the analysis of survival outcomes. The majority of studies (88%) reported the use of Cox proportional hazards (PH) regression to analyse survival endpoints. However, most publications failed to report the validation of the statistical models in terms of the PH assumption.ConclusionsThis review highlights deficiencies in terms of reporting the methods and validity of survival analyses within oncology RCTs. We support previous recommendations to encourage authors to improve the reporting of survival analyses in journal publications. We also recommend that the final choice of a statistical model for survival should be informed by goodness of model fit to a given dataset, and that model assumptions are validated. The failure of trial investigators and statisticians to investigate the PH for RCT survival data is likely to result in clinical decisions based on inappropriate methods. The development of alternative approaches for the meta-analysis of survival outcomes when the PH assumption is implausible is required if valid clinical decisions are to be made.

Quantitative Secretomic Analysis Identifies Extracellular Protein Factors That Modulate the Metastatic Phenotype of Non-Small Cell Lung Cancer

Lung cancer is the leading cause of cancer-related deaths for men and women in the United States, with non-small cell lung cancer (NSCLC) representing 85% of all diagnoses. Late stage detection, metastatic disease and lack of actionable biomarkers contribute to the high mortality rate. Proteins in the extracellular space are known to be critically involved in regulating every stage of the pathogenesis of lung cancer. To investigate the mechanism by which secreted proteins contribute to the pathogenesis of NSCLC, we performed quantitative secretomic analysis of two isogenic NSCLC cell lines (NCI-H1993 and NCI-H2073) and an immortalized human bronchial epithelial cell line (HBEC3-KT) as control. H1993 was derived from a chemo-naïve metastatic tumor, while H2073 was derived from the primary tumor after etoposide/cisplatin therapy. From the conditioned media of these three cell lines, we identified and quantified 2713 proteins, including a series of proteins involved in regulating inflammatory response, programmed cell death and cell motion. Gene Ontology (GO) analysis indicates that a number of proteins overexpressed in H1993 media are involved in biological processes related to cancer metastasis, including cell motion, cell-cell adhesion and cell migration. RNA interference (RNAi)-mediated knock down of a number of these proteins, including SULT2B1, CEACAM5, SPRR3, AGR2, S100P, and S100A14, leads to dramatically reduced migration of these cells. In addition, meta-analysis of survival data indicates NSCLC patients whose tumors express higher levels of several of these secreted proteins, including SULT2B1, CEACAM5, SPRR3, S100P, and S100A14, have a worse prognosis. Collectively, our results provide a potential molecular link between deregulated secretome and NSCLC cell migration/metastasis. In addition, the identification of these aberrantly secreted proteins might facilitate the development of biomarkers for early detection of this devastating disease.

Progression-Free Survival with Fulvestrant 500 mg and Alternative Endocrine Therapies as Second-Line Treatment for Advanced Breast Cancer: A Network Meta-Analysis with Parametric Survival Models

BackgroundOuwens et al. and Jansen have presented methods for (network) meta-analysis of survival data by using a multidimensional treatment effect as an alternative to the synthesis of constant hazards ratios, which allow for a better fit to the data and the expected survival of competing interventions for cost-effectiveness analysis. However, results may be sensitive to the assumed underlying survival function. ObjectiveTo estimate the expected progression-free survival (PFS) for fulvestrant 500 mg versus alternative hormonal therapies for postmenopausal women with advanced breast cancer who relapsed previously by means of a network meta-analysis of currently available randomized controlled trials using alternative underlying survival functions. MethodsEleven randomized controlled trials were included that evaluated fulvestrant 500 mg (n = 3), fulvestrant 250 mg (n = 5), fulvestrant 250 mg loading dose (n = 3), anastrozole 1 mg (n = 3), megestrol acetate (n = 4), letrozole 2.5 mg (n = 3), letrozole 0.5 mg (n = 3), and exemestane (n = 2). PFS percentages and numbers at risk were derived from Kaplan-Meier curves and combined by means of Bayesian network meta-analysis on the basis of the difference in the shape and scale parameters of the Weibull, log-normal, and log-logistic parametric survival functions. ResultsThe log-normal distribution provided the best fit, suggesting that the proportional hazard assumption was not valid. Based on the difference in expected PFS, it was found that fulvestrant 500 mg is more efficacious than fulvestrant 250 mg, megestrol acetate, and anastrozole (−5.73 months; 95% credible interval [CrI]−10.67,−1.67). Expected PFS for fulvestrant 500 mg ranged from 10.87 (95% CrI 9.21, 13.07) to 17.02 (95% CrI 13.33, 22.02) months for the Weibull versus log-logistic distribution. ConclusionsFulvestrant 500 mg is expected to be more efficacious than fulvestrant 250 mg, megestrol acetate, and anastrozole 1 mg and at least as efficacious as exemestane and letrozole 2.5 mg in terms of PFS among postmenopausal women with advanced breast cancer after failure on endocrine therapy. The findings were not sensitive to the distribution, although the expected PFS varied substantially, emphasizing the importance of performing sensitivity analyses.

Time lag to benefit after screening for breast and colorectal cancer: meta-analysis of survival data from the United States, Sweden, United Kingdom, and Denmark

Objectives To determine a pooled, quantitative estimate of the length of time needed after breast or colorectal cancer screening before a survival benefit is observed.Design Meta-analysis of survival data from...

Combination of vinorelbine alternating i.v. and oral in combination with docetaxel as 1st line chemotherapy of metastatic breast cancer

Ouwens et al. and Jansen have presented methods for (network) meta-analysis of survival data by using a multidimensional treatment effect as an alternative to the synthesis of constant hazards ratios, which allow for a better fit to the data and the expected survival of competing interventions for cost-effectiveness analysis. However, results may be sensitive to the assumed underlying survival function.To estimate the expected progression-free survival (PFS) for fulvestrant 500 mg versus alternative hormonal therapies for postmenopausal women with advanced breast cancer who relapsed previously by means of a network meta-analysis of currently available randomized controlled trials using alternative underlying survival functions.Eleven randomized controlled trials were included that evaluated fulvestrant 500 mg (n = 3), fulvestrant 250 mg (n = 5), fulvestrant 250 mg loading dose (n = 3), anastrozole 1 mg (n = 3), megestrol acetate (n = 4), letrozole 2.5 mg (n = 3), letrozole 0.5 mg (n = 3), and exemestane (n = 2). PFS percentages and numbers at risk were derived from Kaplan-Meier curves and combined by means of Bayesian network meta-analysis on the basis of the difference in the shape and scale parameters of the Weibull, log-normal, and log-logistic parametric survival functions.The log-normal distribution provided the best fit, suggesting that the proportional hazard assumption was not valid. Based on the difference in expected PFS, it was found that fulvestrant 500 mg is more efficacious than fulvestrant 250 mg, megestrol acetate, and anastrozole (−5.73 months; 95% credible interval [CrI]−10.67,−1.67). Expected PFS for fulvestrant 500 mg ranged from 10.87 (95% CrI 9.21, 13.07) to 17.02 (95% CrI 13.33, 22.02) months for the Weibull versus log-logistic distribution.Fulvestrant 500 mg is expected to be more efficacious than fulvestrant 250 mg, megestrol acetate, and anastrozole 1 mg and at least as efficacious as exemestane and letrozole 2.5 mg in terms of PFS among postmenopausal women with advanced breast cancer after failure on endocrine therapy. The findings were not sensitive to the distribution, although the expected PFS varied substantially, emphasizing the importance of performing sensitivity analyses.