Ciclesonide versus other inhaled corticosteroids for chronic asthma in children

Background Inhaled corticosteroids (ICS) are the cornerstone of asthma maintenance treatment in children. Particularly among parents, there is concern about the safety of ICS as studies in children have shown reduced growth. Small-particle-size ICS targeting the smaller airways have improved lung deposition and effective asthma control might be achieved at lower daily doses. Ciclesonide is a relatively new ICS. This small-particle ICS is a pro-drug that is converted in the airways to an active metabolite and therefore with potentially less local (throat infection) and systemic (reduced growth) side effects. It can be inhaled once daily, thereby possibly improving adherence. Objectives To assess the efficacy and adverse effects of ciclesonide compared to other ICS in the management of chronic asthma in children. Search methods We searched the Cochrane Airways Group Register of trials with pre-defined terms. Additional searches of MEDLINE (via PubMed), EMBASE and Clinicalstudyresults. org were undertaken. Searches are up to date to 7 November 2012. Selection criteria Randomised controlled parallel or cross-over studies were eligible for the review. We included studies comparing ciclesonide with other corticosteroids both at nominally equivalent doses or lower doses of ciclesonide. Data collection and analysis Two review authors independently assessed trial quality and extracted data. Study authors were contacted for additional information. Adverse effects information was collected from the trials. Main results Six studies were included in this review (3256 children, 4 to 17 years of age). Two studies were published as conference abstracts only. Ciclesonide was compared to budesonide and fluticasone. Ciclesonide compared to budesonide (dose ratio 1: 2): asthma symptoms and adverse effect were similar in both groups. Pooled results showed no significant difference in children who experience an exacerbation (risk ratio (RR) 2.20, 95% confidence interval (CI) 0.75 to 6.43). Both studies reported that 24-hour urine cortisol levels showed a statistically significant decrease in the budesonide group compared to the ciclesonide group. Ciclesonide compared to fluticasone (dose ratio 1: 1): no significant differences were found for the outcome asthma symptoms. Pooled results showed no significant differences in number of patients with exacerbations (RR 1.37, 95% CI 0.58 to 3.21) and data from a study that could not be pooled in the meta-analysis reported similar numbers of patients with exacerbations in both groups. None of the studies found a difference in adverse effects. No significant difference was found for 24-hour urine cortisol levels between the groups (mean difference 0.54 nmol/mmol, 95% CI -5.92 to 7.00). Ciclesonide versus fluticasone (dose ratio 1: 2) was assessed in one study and showed similar results between the two corticosteroids for asthma symptoms. The number of children with exacerbations was significantly higher in the ciclesonide group (RR 3.57, 95% CI 1.35 to 9.47). No significant differences were found in adverse effects (RR 0.98, 95% CI 0.81 to 1.14) and 24-hour urine cortisol levels (mean difference 1.15 nmol/mmol, 95% CI 0.07 to 2.23). The quality of evidence was judged 'low' for the outcomes asthma symptoms and adverse events and 'very low' for the outcome exacerbations for ciclesonide versus budesonide (dose ratio 1: 1). The quality of evidence was graded 'moderate' for the outcome asthma symptoms, 'very low' for the outcome exacerbations and 'low' for the outcome adverse events for ciclesonide versus fluticasone (dose ratio 1: 1). For ciclesonide versus fluticasone (dose ratio 1: 2) the quality was rated 'low' for the outcome asthma symptoms and 'very low' for exacerbations and adverse events (dose ratio 1: 2). Authors' conclusions An improvement in asthma symptoms, exacerbations and side effects of ciclesonide versus budesonide and fluticasone could be neither demonstrated nor refuted and the trade-off between benefits and harms of using ciclesonide instead of budesonide or fluticasone is unclear. The resource use or costs of different ICS should therefore also be considered in final decision making. Longer-term superiority trials are needed to identify the usefulness and safety of ciclesonide compared to other ICS. Additionally these studies should be powered for patient relevant outcomes (exacerbations, asthma symptoms, quality of life and side effects). There is a need for studies comparing ciclesonide once daily with other ICS twice daily to assess the advantages of ciclesonide being a pro-drug that can be administered once daily with possibly increased adherence leading to increased control of asthma and fewer side effects

A decision tool for updating Cochrane reviews

This report describes the development and validation of an updating tool to help assess the need and likely benefits of updating a Cochrane review. The report is presented in five sections. Section 1 describes the background and rationale for the updating tool, including information about when and how to update. Section 2 describes the development of the updating tool and the resulting decision tree and checklist. Section 3 presents the results of the in-house and ongoing formal pilot of the tool, while Sections 4 and 5 provide information about the dissemination of the tool and our key conclusions. This project was funded by the Cochrane Opportunities Fund in 2007

Search filters to identify geriatric medicine in Medline

Objectives To create user-friendly search filters with high sensitivity, specificity, and precision to identify articles on geriatric medicine in Medline. Design A diagnostic test assessment framework was used. A reference set of 2255 articles was created by hand-searching 22 biomedical journals in Medline, and each article was labeled as 'relevant', 'not relevant', or 'possibly relevant' for geriatric medicine. From the relevant articles, search terms were identified to compile different search strategies. The articles retrieved by the various search strategies were compared with articles from the reference set as the index test to create the search filters. Measures Sensitivity, specificity, precision, accuracy, and number-needed-to-read (NNR) were calculated by comparing the results retrieved by the different search strategies with the reference set. Results The most sensitive search filter had a sensitivity of 94.8%, a specificity of 88.7%, a precision of 73.0%, and an accuracy of 90.2%. It had an NNR of 1.37. The most specific search filter had a specificity of 96.6%, a sensitivity of 69.1%, a precision of 86.6%, and an accuracy of 89.9%. It had an NNR of 1.15. Conclusion These geriatric search filters simplify searching for relevant literature and therefore contribute to better evidence-based practice. The filters are useful to both the clinician who wants to find a quick answer to a clinical question and the researcher who wants to find as many relevant articles as possible without retrieving too many irrelevant article

Chemotherapy and radiotherapy for advanced pancreatic cancer

Background: Pancreatic cancer (PC) is a highly lethal disease with few effective treatment options. Over the past few decades, many anti-cancer therapies have been tested in the locally advanced and metastatic setting, with mixed results. This review attempts to synthesise all the randomised data available to help better inform patient and clinician decision-making when dealing with this difficult disease. Objectives: To assess the effect of chemotherapy, radiotherapy or both for first-line treatment of advanced pancreatic cancer. Our primary outcome was overall survival, while secondary outcomes include progression-free survival, grade 3/4 adverse events, therapy response and quality of life. Search methods: We searched for published and unpublished studies in CENTRAL (searched 14 June 2017), Embase (1980 to 14 June 2017), MEDLINE (1946 to 14 June 2017) and CANCERLIT (1999 to 2002) databases. We also handsearched all relevant conference abstracts published up until 14 June 2017. Selection criteria: All randomised studies assessing overall survival outcomes in patients with advanced pancreatic ductal adenocarcinoma. Chemotherapy and radiotherapy, alone or in combination, were the eligible treatments. Data collection and analysis: Two review authors independently analysed studies, and a third settled any disputes. We extracted data on overall survival (OS), progression-free survival (PFS), response rates, adverse events (AEs) and quality of life (QoL), and we assessed risk of bias for each study. Main results: We included 42 studies addressing chemotherapy in 9463 patients with advanced pancreatic cancer. We did not identify any eligible studies on radiotherapy. We did not find any benefit for chemotherapy over best supportive care. However, two identified studies did not have sufficient data to be included in the analysis, and many of the chemotherapy regimens studied were outdated. Compared to gemcitabine alone, participants receiving 5FU had worse OS (HR 1.69, 95% CI 1.26 to 2.27, moderate-quality evidence), PFS (HR 1.47, 95% CI 1.12 to 1.92) and QoL. On the other hand, two studies showed FOLFIRINOX was better than gemcitabine for OS (HR 0.51 95% CI 0.43 to 0.60, moderate-quality evidence), PFS (HR 0.46, 95% CI 0.38 to 0.57) and response rates (RR 3.38, 95% CI 2.01 to 5.65), but it increased the rate of side effects. The studies evaluating CO-101, ZD9331 and exatecan did not show benefit or harm when compared with gemcitabine alone. Giving gemcitabine at a fixed dose rate improved OS (HR 0.79, 95% CI 0.66 to 0.94, high-quality evidence) but increased the rate of side effects when compared with bolus dosing. When comparing gemcitabine combinations to gemcitabine alone, gemcitabine plus platinum improved PFS (HR 0.80, 95% CI 0.68 to 0.95) and response rates (RR 1.48, 95% CI 1.11 to 1.98) but not OS (HR 0.94, 95% CI 0.81 to 1.08, low-quality evidence). The rate of side effects increased. Gemcitabine plus fluoropyrimidine improved OS (HR 0.88, 95% CI 0.81 to 0.95), PFS (HR 0.79, 95% CI 0.72 to 0.87) and response rates (RR 1.78, 95% CI 1.29 to 2.47, high-quality evidence), but it also increased side effects. Gemcitabine plus topoisomerase inhibitor did not improve survival outcomes but did increase toxicity. One study demonstrated that gemcitabine plus nab-paclitaxel improved OS (HR 0.72, 95% CI 0.62 to 0.84, high-quality evidence), PFS (HR 0.69, 95% CI 0.58 to 0.82) and response rates (RR 3.29, 95% CI 2.24 to 4.84) but increased side effects. Gemcitabine-containing multi-drug combinations (GEMOXEL or cisplatin/epirubicin/5FU/gemcitabine) improved OS (HR 0.55, 95% CI 0.39 to 0.79, low-quality evidence), PFS (HR 0.43, 95% CI 0.30 to 0.62) and QOL. We did not find any survival advantages when comparing 5FU combinations to 5FU alone. Authors' conclusions: Combination chemotherapy has recently overtaken the long-standing gemcitabine as the standard of care. FOLFIRINOX and gemcitabine plus nab-paclitaxel are highly efficacious, but our analysis shows that other combination regimens also offer a benefit. Selection of the most appropriate chemotherapy for individual patients still remains difficult, with clinicopathological stratification remaining elusive. Biomarker development is essential to help rationalise treatment selection for patients

Clinical trial registration was associated with lower risk of bias compared with non-registered trials among trials included in systematic reviews

Objective: To examine the association between clinical trial registration and risk of bias in clinical trials that have been included in systematic reviews. As a secondary objective, we evaluated the risk of bias among trials registered prospectively vs. retrospectively. Method: Clinical trials published in 2005 or after included in a sample of 100 Cochrane systematic reviews published from 2014-2019. Results: Of 1,177 clinical trials identified, we verified 368 (31%) had been registered, of which 135 (36.7%) were registered prospectively (i.e., before or up to 1 month after enrollment of the first participant). Across the bias domains (one bias assessment for each domain per trial), the percentage of trials at low risk ranged from 29% to 58%; unclear risk ranged from to 26% to 61% and high risk ranged from 2% to 38%. Trials that had been registered had less high or unclear risk of bias in five domains: random sequence generation (univariate risk ratio [RR] 0.69, 95% confidence interval [95% CI] 0.58-0.81), allocation concealment (RR 0.64, 95% CI 0.57-0.72), performance bias (RR 0.65, 95% CI 0.58-0.72), detection bias (RR 0.70, 95% CI 0.62-0.78), and reporting bias (RR 0.62, 95% CI 0.53-0.73). An association between clinical trial registration and high or unclear risk of attrition bias could not be demonstrated nor refuted (RR 1.02, 95% CI 0.89-1.17). It also was observed in terms of overall risk of bias, that registered trials had less high or unclear overall risk of bias than trials that had not been registered (univariate RR 0.29, 95% CI 0.19-0.46). Prospective clinical trial registration was associated with low risks of selection bias due to inadequate allocation concealment, performance bias, and detection bias compared with retrospective clinical trial registration. Conclusion: In a large sample of clinical trials included in recently published systematic reviews of interventions, clinical trial registration was associated with low risk of bias for five of the six domains examined

Poor compliance of clinical trial registration among trials included in systematic reviews: a cohort study

OBJECTIVES: The objective of the study was to examine whether clinical trials that have been included in systematic reviews have been registered in clinical trial registers and, when they have, whether results of the trials were included in the clinical trial register. STUDY DESIGN AND SETTING: This study used a sample of 100 systematic reviews published by the Cochrane Musculoskeletal, Oral, Skin and Sensory Network between 2014 and 2019. RESULTS: We identified 2,000 trials (369,778 participants) from a sample of 100 systematic reviews. The median year of trial publication was 2007. Of 1,177 trials published in 2005 or later, a clinical trial registration record was identified for 368 (31%). Of these registered trials, 135 (37%) were registered prospectively and results were posted for 114 (31%); most registered trials evaluated pharmaceutical interventions (62%). Of trials published in the last 10 years, the proportion of registered trials increased to 38% (261 of 682). CONCLUSION: Although some improvement in clinical trial registration has been observed in recent years, the proportion of registered clinical trials included in recently published systematic reviews remains less than desirable. Prospective clinical trial registration provides an essential role in assessing the risk of bias and judging the quality of evidence in systematic reviews of intervention safety and effectiveness

Data sources and methods used to determine pretest probabilities in a cohort of Cochrane diagnostic test accuracy reviews

BACKGROUND: A pretest probability must be selected to calculate data to help clinicians, guideline boards and policy makers interpret diagnostic accuracy parameters. When multiple analyses for the same target condition are compared, identical pretest probabilities might be selected to facilitate the comparison. Some pretest probabilities may lead to exaggerations of the patient harms or benefits, and guidance on how and why to select a specific pretest probability is minimally described. Therefore, the aim of this study was to assess the data sources and methods used in Cochrane diagnostic test accuracy (DTA) reviews for determining pretest probabilities to facilitate the interpretation of DTA parameters. A secondary aim was to assess the use of identical pretest probabilities to compare multiple meta-analyses within the same target condition. METHODS: Cochrane DTA reviews presenting at least one meta-analytic estimate of the sensitivity and/or specificity as a primary analysis published between 2008 and January 2018 were included. Study selection and data extraction were performed by one author and checked by other authors. Observed data sources (e.g. studies in the review, or external sources) and methods to select pretest probabilities (e.g. median) were categorized. RESULTS: Fifty-nine DTA reviews were included, comprising of 308 meta-analyses. A pretest probability was used in 148 analyses. Authors used included studies in the DTA review, external sources, and author consensus as data sources for the pretest probability. Measures of central tendency with or without a measure of dispersion were used to determine the pretest probabilities, with the median most commonly used. Thirty-two target conditions had at least one identical pretest probability for all of the meta-analyses within their target condition. About half of the used identical pretest probabilities were inside the prevalence ranges from all analyses within a target condition. CONCLUSIONS: Multiple sources and methods were used to determine (identical) pretest probabilities in Cochrane DTA reviews. Indirectness and severity of downstream consequences may influence the acceptability of the certainty in calculated data with pretest probabilities. Consider: whether to present normalized frequencies, the influence of pretest probabilities on normalized frequencies, and whether to use identical pretest probabilities for meta-analyses in a target condition

Using self-regulation assessment to explore associations between self-regulation, participation and health-related quality of life in a rehabilitation population

Objective: Self-regulation, participation and health-related quality of life are important rehabilitation outcomes. The aim of this study was to explore associations between these outcomes in a multi-diagnostic and heterogenic group of former rehabilitation patients.Methods: This cross-sectional survey used the Self-Regulation Assessment (SeRA), Utrecht Scale for Evaluation of Rehabilitation-Participation (USER-Participation) and the Patient-Reported-Outcome-Measurement-System (PROMIS) ability and PROMIS satisfaction with participation in social roles, and the EuroQol-5L-5D and PROMIS-10 Global Health. Regression analyses, controlling for demographic and condition-related factors, were performed.Results: Respondents (n=563) had a mean age of 56.5 (standard deviation (SD) 12.7) years. The largest diagnostic groups were chronic pain disorder and brain injury. In addition to demographic and condition-related factors, self-regulation subscales explained 0–15% of the variance in participation outcome scores, and 0–22% of the variance in HRQoL outcome scores. Self-regulation subscales explained up to 22% of the variance in satisfaction subscales of participation (USER-Participation and PROMIS) and the mental health subscale of the PROMIS-10. Self-regulation subscales explained up to 11% of the restriction and frequency subscales of participation (USER-Participation) and the physical health subscale of the PROMIS-10.Conclusion: Self-regulation is more strongly associated with outcomes such as satisfaction with participation and mental health compared with outcomes such as restrictions in participation and physical health.</p

Chemotherapy and radiotherapy for advanced pancreatic cancer

Background: Pancreatic cancer (PC) is a highly lethal disease with few effective treatment options. Over the past few decades, many anti-cancer therapies have been tested in the locally advanced and metastatic setting, with mixed results. This review attempts to synthesise all the randomised data available to help better inform patient and clinician decision-making when dealing with this difficult disease. Objectives: To assess the effect of chemotherapy, radiotherapy or both for first-line treatment of advanced pancreatic cancer. Our primary outcome was overall survival, while secondary outcomes include progression-free survival, grade 3/4 adverse events, therapy response and quality of life. Search methods: We searched for published and unpublished studies in CENTRAL (searched 14 June 2017), Embase (1980 to 14 June 2017), MEDLINE (1946 to 14 June 2017) and CANCERLIT (1999 to 2002) databases. We also handsearched all relevant conference abstracts published up until 14 June 2017. Selection criteria: All randomised studies assessing overall survival outcomes in patients with advanced pancreatic ductal adenocarcinoma. Chemotherapy and radiotherapy, alone or in combination, were the eligible treatments. Data collection and analysis: Two review authors independently analysed studies, and a third settled any disputes. We extracted data on overall survival (OS), progression-free survival (PFS), response rates, adverse events (AEs) and quality of life (QoL), and we assessed risk of bias for each study. Main results: We included 42 studies addressing chemotherapy in 9463 patients with advanced pancreatic cancer. We did not identify any eligible studies on radiotherapy. We did not find any benefit for chemotherapy over best supportive care. However, two identified studies did not have sufficient data to be included in the analysis, and many of the chemotherapy regimens studied were outdated. Compared to gemcitabine alone, participants receiving 5FU had worse OS (HR 1.69, 95% CI 1.26 to 2.27, moderate-quality evidence), PFS (HR 1.47, 95% CI 1.12 to 1.92) and QoL. On the other hand, two studies showed FOLFIRINOX was better than gemcitabine for OS (HR 0.51 95% CI 0.43 to 0.60, moderate-quality evidence), PFS (HR 0.46, 95% CI 0.38 to 0.57) and response rates (RR 3.38, 95% CI 2.01 to 5.65), but it increased the rate of side effects. The studies evaluating CO-101, ZD9331 and exatecan did not show benefit or harm when compared with gemcitabine alone. Giving gemcitabine at a fixed dose rate improved OS (HR 0.79, 95% CI 0.66 to 0.94, high-quality evidence) but increased the rate of side effects when compared with bolus dosing. When comparing gemcitabine combinations to gemcitabine alone, gemcitabine plus platinum improved PFS (HR 0.80, 95% CI 0.68 to 0.95) and response rates (RR 1.48, 95% CI 1.11 to 1.98) but not OS (HR 0.94, 95% CI 0.81 to 1.08, low-quality evidence). The rate of side effects increased. Gemcitabine plus fluoropyrimidine improved OS (HR 0.88, 95% CI 0.81 to 0.95), PFS (HR 0.79, 95% CI 0.72 to 0.87) and response rates (RR 1.78, 95% CI 1.29 to 2.47, high-quality evidence), but it also increased side effects. Gemcitabine plus topoisomerase inhibitor did not improve survival outcomes but did increase toxicity. One study demonstrated that gemcitabine plus nab-paclitaxel improved OS (HR 0.72, 95% CI 0.62 to 0.84, high-quality evidence), PFS (HR 0.69, 95% CI 0.58 to 0.82) and response rates (RR 3.29, 95% CI 2.24 to 4.84) but increased side effects. Gemcitabine-containing multi-drug combinations (GEMOXEL or cisplatin/epirubicin/5FU/gemcitabine) improved OS (HR 0.55, 95% CI 0.39 to 0.79, low-quality evidence), PFS (HR 0.43, 95% CI 0.30 to 0.62) and QOL. We did not find any survival advantages when comparing 5FU combinations to 5FU alone. Authors' conclusions: Combination chemotherapy has recently overtaken the long-standing gemcitabine as the standard of care. FOLFIRINOX and gemcitabine plus nab-paclitaxel are highly efficacious, but our analysis shows that other combination regimens also offer a benefit. Selection of the most appropriate chemotherapy for individual patients still remains difficult, with clinicopathological stratification remaining elusive. Biomarker development is essential to help rationalise treatment selection for patient