It remains controversial whether primary tumor resection (PTR) before chemotherapy improves survival in patients with colorectal cancer (CRC) with asymptomatic primary tumor and synchronous ...unresectable metastases.
This randomized phase III study investigated the superiority of PTR followed by chemotherapy versus chemotherapy alone in relation to overall survival (OS) in patients with unresectable stage IV asymptomatic CRC and three or fewer unresectable metastatic diseases confined to the liver, lungs, distant lymph nodes, or peritoneum. Chemotherapy regimens of either mFOLFOX6 plus bevacizumab or CapeOX plus bevacizumab were decided before study entry. The primary end point was OS, which was analyzed by intention-to-treat.
Between June 2012 and September 2019, a total of 165 patients were randomly assigned to either chemotherapy alone (84 patients) or PTR plus chemotherapy (81 patients). When the first interim analysis was performed in September 2019 with 50% (114/227) of the expected events observed among 160 patients at the data cutoff date of June 5, 2019, the Data and Safety Monitoring Committee recommended early termination of the trial because of futility. With a median follow-up of 22.0 months, median OS was 25.9 months (95% CI, 19.9 to 31.5) in the PTR plus chemotherapy arm and 26.7 (95% CI, 21.9 to 32.5) in the chemotherapy-alone arm (hazard ratio, 1.10; 95% CI, 0.76 to 1.59; one-sided
= .69). Three postoperative deaths occurred in the PTR plus chemotherapy arm.
Given that PTR followed by chemotherapy showed no survival benefit over chemotherapy alone, PTR should no longer be considered a standard of care for patients with CRC with asymptomatic primary tumors and synchronous unresectable metastases.
Rigorous, informative meta-analyses rely on availability of appropriate summary statistics or individual participant data. For continuous outcomes, especially those with naturally skewed ...distributions, summary information on the mean or variability often goes unreported. While full reporting of original trial data is the ideal, we sought to identify methods for handling unreported mean or variability summary statistics in meta-analysis.
We undertook two systematic literature reviews to identify methodological approaches used to deal with missing mean or variability summary statistics. Five electronic databases were searched, in addition to the Cochrane Colloquium abstract books and the Cochrane Statistics Methods Group mailing list archive. We also conducted cited reference searching and emailed topic experts to identify recent methodological developments. Details recorded included the description of the method, the information required to implement the method, any underlying assumptions and whether the method could be readily applied in standard statistical software. We provided a summary description of the methods identified, illustrating selected methods in example meta-analysis scenarios.
For missing standard deviations (SDs), following screening of 503 articles, fifteen methods were identified in addition to those reported in a previous review. These included Bayesian hierarchical modelling at the meta-analysis level; summary statistic level imputation based on observed SD values from other trials in the meta-analysis; a practical approximation based on the range; and algebraic estimation of the SD based on other summary statistics. Following screening of 1124 articles for methods estimating the mean, one approximate Bayesian computation approach and three papers based on alternative summary statistics were identified. Illustrative meta-analyses showed that when replacing a missing SD the approximation using the range minimised loss of precision and generally performed better than omitting trials. When estimating missing means, a formula using the median, lower quartile and upper quartile performed best in preserving the precision of the meta-analysis findings, although in some scenarios, omitting trials gave superior results.
Methods based on summary statistics (minimum, maximum, lower quartile, upper quartile, median) reported in the literature facilitate more comprehensive inclusion of randomised controlled trials with missing mean or variability summary statistics within meta-analyses.
AbstractObjectivesTo study the impact of blinding on estimated treatment effects, and their variation between trials; differentiating between blinding of patients, healthcare providers, and ...observers; detection bias and performance bias; and types of outcome (the MetaBLIND study).DesignMeta-epidemiological study.Data sourceCochrane Database of Systematic Reviews (2013-14).Eligibility criteria for selecting studiesMeta-analyses with both blinded and non-blinded trials on any topic.Review methodsBlinding status was retrieved from trial publications and authors, and results retrieved automatically from the Cochrane Database of Systematic Reviews. Bayesian hierarchical models estimated the average ratio of odds ratios (ROR), and estimated the increases in heterogeneity between trials, for non-blinded trials (or of unclear status) versus blinded trials. Secondary analyses adjusted for adequacy of concealment of allocation, attrition, and trial size, and explored the association between outcome subjectivity (high, moderate, low) and average bias. An ROR lower than 1 indicated exaggerated effect estimates in trials without blinding.ResultsThe study included 142 meta-analyses (1153 trials). The ROR for lack of blinding of patients was 0.91 (95% credible interval 0.61 to 1.34) in 18 meta-analyses with patient reported outcomes, and 0.98 (0.69 to 1.39) in 14 meta-analyses with outcomes reported by blinded observers. The ROR for lack of blinding of healthcare providers was 1.01 (0.84 to 1.19) in 29 meta-analyses with healthcare provider decision outcomes (eg, readmissions), and 0.97 (0.64 to 1.45) in 13 meta-analyses with outcomes reported by blinded patients or observers. The ROR for lack of blinding of observers was 1.01 (0.86 to 1.18) in 46 meta-analyses with subjective observer reported outcomes, with no clear impact of degree of subjectivity. Information was insufficient to determine whether lack of blinding was associated with increased heterogeneity between trials. The ROR for trials not reported as double blind versus those that were double blind was 1.02 (0.90 to 1.13) in 74 meta-analyses.ConclusionNo evidence was found for an average difference in estimated treatment effect between trials with and without blinded patients, healthcare providers, or outcome assessors. These results could reflect that blinding is less important than often believed or meta-epidemiological study limitations, such as residual confounding or imprecision. At this stage, replication of this study is suggested and blinding should remain a methodological safeguard in trials.
Highly diverse bacterial populations inhabit the gastrointestinal tract and modulate host inflammation and promote immune tolerance. In allogeneic hematopoietic stem cell transplantation (allo-HSCT), ...the gastrointestinal mucosa is damaged, and colonizing bacteria are impacted, leading to an impaired intestinal microbiota with reduced diversity. We examined the impact of intestinal diversity on subsequent mortality outcomes following transplantation. Fecal specimens were collected from 80 recipients of allo-HSCT at the time of stem cell engraftment. Bacterial 16S rRNA gene sequences were characterized, and microbial diversity was estimated using the inverse Simpson index. Subjects were classified into high, intermediate, and low diversity groups and assessed for differences in outcomes. Mortality outcomes were significantly worse in patients with lower intestinal diversity; overall survival at 3 years was 36%, 60%, and 67% for low, intermediate, and high diversity groups, respectively (P = .019, log-rank test). Low diversity showed a strong effect on mortality after multivariate adjustment for other clinical predictors (transplant related mortality: adjusted hazard ratio, 5.25; P = .014). In conclusion, the diversity of the intestinal microbiota at engraftment is an independent predictor of mortality in allo-HSCT recipients. These results indicate that the intestinal microbiota may be an important factor in the success or failure in allo-HSCT.
•Intestinal diversity is predictive of mortality in allo-HSCT.
This article reviews the benefits, obstacles, and challenges that can hinder (and have hindered) implementation of routine outcome monitoring in clinical practice. Recommendations for future routine ...outcome assessment efforts are also provided. Spanning three generations, as well as multiple developed tools and approaches, the four authors of this article have spent much of their careers working to address these issues and attempt to consolidate this learning and experience briefly here. Potential "elephants in the room" are brought into the discussion wherever relevant, rather than leaving them to obstruct silently the field's efforts. Some of these topics have been largely ignored, yet must be addressed if we are to fulfill our promise of integrating science and practice. This article is an attempt to identify these important issues and start an honest and open dialogue.
Purpose To compare overall survival between patients who received neoadjuvant therapy (NAT) followed by resection and those who received upfront resection (UR)-as well as a subgroup of UR patients ...who also received adjuvant therapy-for early-stage resectable pancreatic adenocarcinoma. Patients and Methods Adult patients with resected, clinical stage I or II adenocarcinoma of the head of the pancreas were identified in the National Cancer Database from 2006 to 2012. Patients who underwent NAT followed by curative-intent resection were matched by propensity score with patients whose tumors were resected upfront. Overall survival was compared by using a Cox proportional hazards regression model. Early postoperative and oncologic outcomes were evaluated. Results We identified 15,237 patients with clinical stage I or II resected pancreatic head adenocarcinoma. From the NAT group, 2,005 patients (95%) were matched with 6,015 patients who underwent UR. The NAT group was associated with improved survival compared with UR (median survival, 26 months v 21 months, respectively; stratified log-rank P < .01; hazard ratio, 0.72; 95% CI, 0.68 to 0.78). Patients in the UR group had higher pathologic T stage (pT3 and T4: 86% v 73%; P < .01), higher positive lymph nodes (73% v 48%; P < .01), and higher positive resection margin (24% v 17%; P < .01). Compared with a subset of UR patients who received adjuvant therapy, NAT patients had a better survival (adjusted hazard ratio, 0.83; 95% CI, 0.73 to 0.89). Conclusion NAT followed by resection has a significant survival benefit compared with UR in early-stage, resected pancreatic head adenocarcinoma. These findings support the use of NAT, particularly as a patient selection tool, in the management of resectable pancreatic adenocarcinoma.
There is increasing recognition that insufficient attention has been paid to the choice of outcomes measured in clinical trials. The lack of a standardized outcome classification system results in ...inconsistencies due to ambiguity and variation in how outcomes are described across different studies. Being able to classify by outcome would increase efficiency in searching sources such as clinical trial registries, patient registries, the Cochrane Database of Systematic Reviews, and the Core Outcome Measures in Effectiveness Trials (COMET) database of core outcome sets (COS), thus aiding knowledge discovery.
A literature review was carried out to determine existing outcome classification systems, none of which were sufficiently comprehensive or granular for classification of all potential outcomes from clinical trials. A new taxonomy for outcome classification was developed, and as proof of principle, outcomes extracted from all published COS in the COMET database, selected Cochrane reviews, and clinical trial registry entries were classified using this new system.
Application of this new taxonomy to COS in the COMET database revealed that 274/299 (92%) COS include at least one physiological outcome, whereas only 177 (59%) include at least one measure of impact (global quality of life or some measure of functioning) and only 105 (35%) made reference to adverse events.
This outcome taxonomy will be used to annotate outcomes included in COS within the COMET database and is currently being piloted for use in Cochrane Reviews within the Cochrane Linked Data Project. Wider implementation of this standard taxonomy in trial and systematic review databases and registries will further promote efficient searching, reporting, and classification of trial outcomes.
Implementation outcome measures are essential for monitoring and evaluating the success of implementation efforts. Yet, currently available measures lack conceptual clarity and have largely unknown ...reliability and validity. This study developed and psychometrically assessed three new measures: the Acceptability of Intervention Measure (AIM), Intervention Appropriateness Measure (IAM), and Feasibility of Intervention Measure (FIM).
Thirty-six implementation scientists and 27 mental health professionals assigned 31 items to the constructs and rated their confidence in their assignments. The Wilcoxon one-sample signed rank test was used to assess substantive and discriminant content validity. Exploratory and confirmatory factor analysis (EFA and CFA) and Cronbach alphas were used to assess the validity of the conceptual model. Three hundred twenty-six mental health counselors read one of six randomly assigned vignettes depicting a therapist contemplating adopting an evidence-based practice (EBP). Participants used 15 items to rate the therapist's perceptions of the acceptability, appropriateness, and feasibility of adopting the EBP. CFA and Cronbach alphas were used to refine the scales, assess structural validity, and assess reliability. Analysis of variance (ANOVA) was used to assess known-groups validity. Finally, half of the counselors were randomly assigned to receive the same vignette and the other half the opposite vignette; and all were asked to re-rate acceptability, appropriateness, and feasibility. Pearson correlation coefficients were used to assess test-retest reliability and linear regression to assess sensitivity to change.
All but five items exhibited substantive and discriminant content validity. A trimmed CFA with five items per construct exhibited acceptable model fit (CFI = 0.98, RMSEA = 0.08) and high factor loadings (0.79 to 0.94). The alphas for 5-item scales were between 0.87 and 0.89. Scale refinement based on measure-specific CFAs and Cronbach alphas using vignette data produced 4-item scales (α's from 0.85 to 0.91). A three-factor CFA exhibited acceptable fit (CFI = 0.96, RMSEA = 0.08) and high factor loadings (0.75 to 0.89), indicating structural validity. ANOVA showed significant main effects, indicating known-groups validity. Test-retest reliability coefficients ranged from 0.73 to 0.88. Regression analysis indicated each measure was sensitive to change in both directions.
The AIM, IAM, and FIM demonstrate promising psychometric properties. Predictive validity assessment is planned.
Core outcome sets (COSs) are consensus-derived minimum sets of outcomes to be assessed in a specific situation. COSs are being increasingly developed to limit outcome-reporting bias, allow ...comparisons across trials, and strengthen clinical decision making. Despite the increasing interest in outcomes research, methods to develop COSs have not yet been standardized. The aim of this paper is to present the Harmonizing Outcomes Measures for Eczema (HOME) roadmap for the development and implementation of COSs, which was developed on the basis of our experience in the standardization of outcome measurements for atopic eczema. Following the establishment of a panel representing all relevant stakeholders and a research team experienced in outcomes research, the scope and setting of the core set should be defined. The next steps are the definition of a core set of outcome domains such as symptoms or quality of life, followed by the identification or development and validation of appropriate outcome measurement instruments to measure these core domains. Finally, the consented COS needs to be disseminated, implemented, and reviewed. We believe that the HOME roadmap is a useful methodological framework to develop COSs in dermatology, with the ultimate goal of better decision making and promoting patient-centered health care.
Purpose Patients with squamous non-small-cell lung cancer (NSCLC) have poor prognosis and limited treatment options. This randomized, double-blind, phase III study investigated the efficacy and ...safety of first-line ipilimumab or placebo plus paclitaxel and carboplatin in advanced squamous NSCLC. Patients and Methods Patients with stage IV or recurrent chemotherapy-naïve squamous NSCLC were randomly assigned (1:1) to receive paclitaxel and carboplatin plus blinded ipilimumab 10 mg/kg or placebo every 3 weeks on a phased induction schedule comprising six chemotherapy cycles, with ipilimumab or placebo from cycles 3 to 6 and then, after induction treatment, ipilimumab or placebo maintenance every 12 weeks for patients with stable disease or better. The primary end point was overall survival (OS) in patients receiving at least one dose of blinded study therapy. Results Of 956 randomly assigned patients, 749 received at least one dose of blinded study therapy (chemotherapy plus ipilimumab, n = 388; chemotherapy plus placebo, n = 361). Median OS was 13.4 months for chemotherapy plus ipilimumab and 12.4 months for chemotherapy plus placebo (hazard ratio, 0.91; 95% CI, 0.77 to 1.07; P = .25). Median progression-free survival was 5.6 months for both groups (hazard ratio, 0.87; 95% CI, 0.75 to 1.01). Rates of grade 3 or 4 treatment-related adverse events (TRAEs), any-grade serious TRAEs, and TRAEs leading to discontinuation were numerically higher with chemotherapy plus ipilimumab (51%, 33%, and 28%, respectively) than with chemotherapy plus placebo (35%, 10%, and 7%, respectively). Seven treatment-related deaths occurred with chemotherapy plus ipilimumab, and one occurred with chemotherapy plus placebo. Conclusion The addition of ipilimumab to first-line chemotherapy did not prolong OS compared with chemotherapy alone in patients with advanced squamous NSCLC. The safety profile of chemotherapy plus ipilimumab was consistent with that observed in previous lung and melanoma studies. Ongoing studies are evaluating ipilimumab in combination with nivolumab in this population.
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