Summary In response to limitations in the understanding and use of published evidence, evidence-based medicine (EBM) began as a movement in the early 1990s. EBM's initial focus was on educating ...clinicians in the understanding and use of published literature to optimise clinical care, including the science of systematic reviews. EBM progressed to recognise limitations of evidence alone, and has increasingly stressed the need to combine critical appraisal of the evidence with patient's values and preferences through shared decision making. In another progress, EBM incorporated and further developed the science of producing trustworthy clinical practice guidelines pioneered by investigators in the 1980s. EBM's enduring contributions to clinical medicine include placing the practice of medicine on a solid scientific basis, the development of more sophisticated hierarchies of evidence, the recognition of the crucial role of patient values and preferences in clinical decision making, and the development of the methodology for generating trustworthy recommendations.
Usually the researchers performing meta-analysis of continuous outcomes from clinical trials need their mean value and the variance (or standard deviation) in order to pool data. However, sometimes ...the published reports of clinical trials only report the median, range and the size of the trial.
In this article we use simple and elementary inequalities and approximations in order to estimate the mean and the variance for such trials. Our estimation is distribution-free, i.e., it makes no assumption on the distribution of the underlying data.
We found two simple formulas that estimate the mean using the values of the median (m), low and high end of the range (a and b, respectively), and n (the sample size). Using simulations, we show that median can be used to estimate mean when the sample size is larger than 25. For smaller samples our new formula, devised in this paper, should be used. We also estimated the variance of an unknown sample using the median, low and high end of the range, and the sample size. Our estimate is performing as the best estimate in our simulations for very small samples (n < or = 15). For moderately sized samples (15 < n < or = 70), our simulations show that the formula range/4 is the best estimator for the standard deviation (variance). For large samples (n > 70), the formula range/6 gives the best estimator for the standard deviation (variance). We also include an illustrative example of the potential value of our method using reports from the Cochrane review on the role of erythropoietin in anemia due to malignancy.
Using these formulas, we hope to help meta-analysts use clinical trials in their analysis even when not all of the information is available and/or reported.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A woman receives a diagnosis of diffuse large B-cell lymphoma; a standard chemotherapy regimen is recommended. Use of prophylactic granulocyte CSF is considered. G-CSF stimulates proliferation of ...neutrophil progenitors and release of mature neutrophils from bone marrow.
Foreword
This
Journal
feature begins with a case vignette that includes a therapeutic recommendation. A discussion of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies, the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines, if they exist, are presented. The article ends with the authors' clinical recommendations.
Stage
A 55-year-old, previously healthy woman received a diagnosis of diffuse large-B-cell lymphoma after the evaluation of an enlarged left axillary lymph node obtained on biopsy. She had been asymptomatic except for the presence of enlarged axillary lymph nodes, which she had found while bathing. She was referred to an oncologist, who performed a staging evaluation. A complete blood count and test results for liver and renal function and serum lactate dehydrogenase were normal. Positron-emission tomography and computed tomography (PET–CT) identified enlarged lymph nodes with abnormal uptake in the left axilla, mediastinum, and retroperitoneum. Results on bone marrow biopsy were . . .
Cancer is a disease of aging and, as the world's population ages, the number of older persons with cancer is increasing and will make up a growing share of the oncology population in virtually every ...country. Despite this, older patients remain vastly underrepresented in research that sets the standards for cancer treatments. Consequently, most of what we know about cancer therapeutics is based on clinical trials conducted in younger, healthier patients, and effective strategies to improve clinical trial participation of older adults with cancer remain sparse. For this systematic review, the authors evaluated published studies regarding barriers to participation and interventions to improve participation of older adults in cancer trials. The quality of the available evidence was low and, despite a literature describing multifaceted barriers, only one intervention study aimed to increase enrollment of older adults in trials. The findings starkly amplify the paucity of evidence‐based, effective strategies to improve participation of this underrepresented population in cancer trials. Within these limitations, the authors provide their opinion on how the current cancer research infrastructure must be modified to accommodate the needs of older patients. Several underused solutions are offered to expand clinical trials to include older adults with cancer. However, as currently constructed, these recommendations alone will not solve the evidence gap in geriatric oncology, and efforts are needed to meet older and frail adults where they are by expanding clinical trials designed specifically for this population and leveraging real‐world data.
Background
Bisphosphonates are specific inhibitors of osteoclastic activity and are used in the treatment of patients with multiple myeloma (MM). While bisphosphonates are shown to be effective in ...reducing vertebral fractures and pain, their role in improving overall survival (OS) remains unclear. This is an update of a Cochrane review first published in 2002 and previously updated in 2010 and 2012.
Objectives
To assess the evidence related to benefits and harms associated with use of various types of bisphosphonates (aminobisphosphonates versus non‐aminobisphosphonates) in the management of patients with MM. Our primary objective was to determine whether adding bisphosphonates to standard therapy in MM improves OS and progression‐free survival (PFS), and decreases skeletal‐related morbidity. Our secondary objectives were to determine the effects of bisphosphonates on pain, quality of life, incidence of hypercalcemia, incidence of bisphosphonate‐related gastrointestinal toxicities, osteonecrosis of jaw (ONJ) and hypocalcemia.
Search methods
We searched MEDLINE, Embase (September 2011 to July 2017) and the CENTRAL (2017, Issue 7) to identify all randomized controlled trial (RCT) in MM up to July 2017 using a combination of text and MeSH terms.
Selection criteria
Any randomized controlled trial (RCT) comparing bisphosphonates versus placebo/no treatment/bisphosphonates and observational studies or case reports examining bisphosphonate‐related ONJ in patients with MM were eligible for inclusion.
Data collection and analysis
Two review authors extracted the data. Data were pooled and reported as hazard ratio (HR) or risk ratio (RR) using a random‐effects model. We used meta‐regression to explore statistical heterogeneity. Network meta‐analysis using Bayesian approach was conducted.
Main results
In this update, we included four new studies (601 participants), resulting in a total of 24 included studies.
Twenty RCTs compared bisphosphonates with either placebo or no treatment and four RCTs involved another bisphosphonate as a comparator. The 24 included RCTs enrolled 7293 participants. Pooled results showed that there was moderate‐quality evidence of a reduction in mortality with on OS from 41% to 31%, but the confidence interval is consistent with a larger reduction and small increase in mortality compared with placebo or no treatment (HR 0.90, 95% CI 0.76 to 1.07; 14 studies; 2706 participants). There was substantial heterogeneity among the included RCTs (I2 = 65%) for OS. To explain this heterogeneity we performed a meta‐regression assessing the relationship between bisphosphonate potency and improvement in OS, which found an OS benefit with zoledronate but limited evidence of an effect on PFS. This provided a further rationale for performing a network meta‐analyses of the various types of bisphosphonates that were not compared head‐to‐head in RCTs. Results from network meta‐analyses showed evidence of a benefit for OS with zoledronate compared with etidronate (HR 0.56, 95% CI 0.29 to 0.87) and placebo (HR 0.67, 95% CI 0.46 to 0.91). However, there was no evidence for a difference between zoledronate and other bisphosphonates.
The effect of bisphosphonates on disease progression (PFS) is uncertain. Based on the HR of 0.75 (95% CI 0.57 to 1.00; seven studies; 908 participants), 47% participants would experience disease progression without treatment compared with between 30% and 47% with bisphosphonates (low‐quality evidence). There is probably a similar risk of non‐vertebral fractures between treatment groups (RR 1.03, 95% CI 0.68 to 1.56; six studies; 1389 participants; moderate‐quality evidence). Pooled analysis demonstrated evidence for a difference favoring bisphosphonates compared with placebo or no treatment on prevention of pathological vertebral fractures (RR 0.74, 95% CI 0.62 to 0.89; seven studies; 1116 participants; moderate‐quality evidence) and skeletal‐related events (SREs) (RR 0.74, 95% CI 0.63 to 0.88; 10 studies; 2141 participants; moderate‐quality evidence). The evidence for less pain with bisphosphonates was of very low quality (RR 0.75, 95% CI 0.60 to 0.95; eight studies; 1281 participants).
Bisphosphonates may increase ONJ compared with placebo but the confidence interval is very wide (RR 4.61, 95% CI 0.99 to 21.35; P = 0.05; six studies; 1284 participants; low‐quality evidence). The results from the network meta‐analysis did not show any evidence for a difference in the incidence of ONJ (eight RCTs, 3746 participants) between bisphosphonates. Data from nine observational studies (1400 participants) reported an incidence of 5% to 51% with combination of pamidronate and zoledronate, 3% to 11% with zoledronate alone, and 0% to 18% with pamidronate alone.
The pooled results showed no evidence for a difference in increase in frequency of gastrointestinal symptoms with the use of bisphosphonates compared with placebo or no treatment (RR 1.23, 95% CI 0.95 to 1.59; seven studies; 1829 participants; low‐quality evidence).The pooled results showed no evidence for a difference in increase in frequency of hypocalcemia with the use of bisphosphonates compared with placebo or no treatment (RR 2.19, 95% CI 0.49 to 9.74; three studies; 1090 participants; low‐quality evidence). The results from network meta‐analysis did not show any evidence for differences in the incidence of hypocalcemia, renal dysfunction and gastrointestinal toxicity between the bisphosphonates used.
Authors' conclusions
Use of bisphosphonates in participants with MM reduces pathological vertebral fractures, SREs and pain. Bisphosphonates were associated with an increased risk of developing ONJ. For every 1000 participants treated with bisphosphonates, about one patient will suffer from the ONJ. We found no evidence of superiority of any specific aminobisphosphonate (zoledronate, pamidronate or ibandronate) or non‐aminobisphosphonate (etidronate or clodronate) for any outcome. However, zoledronate was found to be better than placebo and first‐generation bisposphonate (etidronate) in pooled direct and indirect analyses for improving OS and other outcomes such as vertebral fractures. Direct head‐to‐head trials of the second‐generation bisphosphonates are needed to settle the issue if zoledronate is truly the most efficacious bisphosphonate currently used in practice.
CONTEXT The optimal treatment of acute myeloid leukemia (AML) in first complete remission (CR1) is uncertain. Current consensus, based on cytogenetic risk, recommends myeloablative allogeneic stem ...cell transplantation (SCT) for poor-risk but not for good-risk AML. Allogeneic SCT, autologous transplantation, and consolidation chemotherapy are considered of equivalent benefit for intermediate-risk AML. OBJECTIVE To quantify relapse-free survival (RFS) and overall survival benefit of allogeneic SCT for AML in CR1 overall and also for good-, intermediate-, and poor-risk AML. METHODS Systematic review and meta-analysis of prospective trials evaluating allogeneic SCT vs nonallogeneic SCT therapies for AML in CR1. The search used the combined search terms allogeneic; acut* and leukem*/leukaem*/leucem*/leucaem*/aml; myelo* or nonlympho* in the PubMed, Embase, and Cochrane Registry of Controlled Trials databases in March 2009. The search identified 1712 articles. STUDY SELECTION Prospective trials assigning adult patients with AML in CR1 to undergo allogeneic SCT vs nonallogeneic SCT treatment(s) based on donor availability and trials reporting RFS and/or overall survival outcomes on an intention-to-treat, donor vs no-donor basis were identified. DATA EXTRACTION Two reviewers independently extracted study characteristics, interventions, and outcomes. Hazard ratios (HRs) with 95% confidence intervals (CIs) were determined. DATA SYNTHESIS Overall, 24 trials and 6007 patients were analyzed (5951 patients in RFS analyses and 5606 patients in overall survival analyses); 3638 patients were analyzed by cytogenetic risk (547, 2499, and 592 with good-, intermediate-, and poor-risk AML, respectively). Interstudy heterogeneity was not significant. Fixed-effects meta-analysis was performed. Compared with nonallogeneic SCT, the HR of relapse or death with allogeneic SCT for AML in CR1 was 0.80 (95% CI, 0.74-0.86). Significant RFS benefit of allogeneic SCT was documented for poor-risk (HR, 0.69; 95% CI, 0.57-0.84) and intermediate-risk AML (HR, 0.76; 95% CI, 0.68-0.85) but not for good-risk AML (HR, 1.06; 95% CI, 0.80-1.42). The HR of death with allogeneic SCT for AML in CR1 was 0.90 (95% CI, 0.82-0.97). Significant overall survival benefit with allogeneic SCT was documented for poor-risk (HR, 0.73; 95% CI, 0.59-0.90) and intermediate-risk AML (HR, 0.83; 95% CI, 0.74-0.93) but not for good-risk AML (HR, 1.07; 95% CI, 0.83-1.38). CONCLUSION Compared with nonallogeneic SCT therapies, allogeneic SCT has significant RFS and overall survival benefit for intermediate- and poor-risk AML but not for good-risk AML in first complete remission.
Decision-making relies on both analytical and emotional thinking. Cognitive reasoning styles (e.g. maximizing and satisficing tendencies) heavily influence analytical processes, while affective ...processes are often dependent on regret. The relationship between regret and cognitive reasoning styles has not been well studied in physicians, and is the focus of this paper.
A regret questionnaire and 6 scales measuring individual differences in cognitive styles (maximizing-satisficing tendencies; analytical vs. intuitive reasoning; need for cognition; intolerance toward ambiguity; objectivism; and cognitive reflection) were administered through a web-based survey to physicians of the University of South Florida. Bonferroni's adjustment was applied to the overall correlation analysis. The correlation analysis was also performed without Bonferroni's correction, given the strong theoretical rationale indicating the need for a separate hypothesis. We also conducted a multivariate regression analysis to identify the unique influence of predictors on regret.
165 trainees and 56 attending physicians (age range 25 to 69) participated in the survey. After bivariate analysis we found that maximizing tendency positively correlated with regret with respect to both decision difficulty (r=0.673; p<0.001) and alternate search strategy (r=0.239; p=0.002). When Bonferroni's correction was not applied, we also found a negative relationship between satisficing tendency and regret (r=-0.156; p=0.021). In trainees, but not faculty, regret negatively correlated with rational-analytical thinking (r=-0.422; p<0.001), need for cognition (r=-0.340; p<0.001), and objectivism (r=-0.309; p=0.003) and positively correlated with ambiguity intolerance (r=0.285; p=0.012). However, after conducting a multivariate regression analysis, we found that regret was positively associated with maximizing only with respect to decision difficulty (r=0.791; p<0.001), while it was negatively associated with satisficing (r=-0.257; p=0.020) and objectivism (r=-0.267; p=0.034). We found no statistically significant relationship between regret and overall accuracy on conditional inferential tasks.
Regret in physicians is strongly associated with their tendency to maximize; i.e. the tendency to consider more choices among abundant options leads to more regret. However, physicians who exhibit satisficing tendency - the inclination to accept a "good enough" solution - feel less regret. Our observation that objectivism is a negative predictor of regret indicates that the tendency to seek and use empirical data in decision-making leads to less regret. Therefore, promotion of evidence-based reasoning may lead to lower regret.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Platelet (PLT) transfusion is indicated either prophylactically or therapeutically to reduce the risk of bleeding or to control active bleeding. Significant uncertainty exists regarding ...the appropriate use of PLT transfusion and the optimal threshold for transfusion in various settings. We formulated 12 key questions to assess the role of PLT transfusion.
Study Design and Methods
We performed a systematic review (SR) of randomized controlled trials (RCTs) and observational studies. A comprehensive search of PubMed, Web of Science, and Cochrane registry of controlled trials was performed. Methodologic quality of included studies was assessed and a meta‐analysis was performed if more than two studies with similar designs were identified for a specific question.
Results
Seventeen RCTs and 55 observational studies were included in the final SR. Results from RCTs showed a beneficial effect of prophylactic compared with therapeutic transfusion for the prevention of significant bleeding in patients with hematologic disorders undergoing chemotherapy or stem cell transplantation. We found no difference in significant bleeding events related to the PLT count threshold for transfusion or the dose of PLTs transfused. Overall methodologic quality of RCTs was moderate. Results from observational studies showed no evidence that PLT transfusion prevented significant bleeding in patients undergoing central venous catheter insertions, lumbar puncture, or other surgical procedures. The methodologic quality of observational studies was very low.
Conclusion
We provide a comprehensive assessment of evidence on the use of PLT transfusions in a variety of clinical settings. Our report summarizes current knowledge and identifies gaps to be addressed in future research.
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