Comparative survival benefit of currently licensed second or third line treatments for epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) negative advanced or metastatic non-small cell lung cancer: a systematic review and secondary analysis of trials.

BACKGROUND: A review of therapies for advanced cancers licenced by the EMA between 2009 and 2013 concluded that for more than half of these drugs there was little evidence of overall survival or quality of life benefit. Recent years have witnessed a growing number of licensed second-line pharmacotherapies for advanced/metastatic non-small cell lung cancer (NSCLC). With the aim of gauging patient survival benefit, we conducted a systematic review of randomised controlled trials (RCT) and compared survival outcomes from available licensed treatments for patients with advanced/metastatic NSCLC. METHODS: RCTs of second/third line treatments in participants with advanced/metastatic NSCLC and negative/low expression of Anaplastic Lymphoma Kinase (ALK) and of Epidermal Growth Factor Receptor (EGFR) were included. We searched electronic databases (MEDLINE; EMBASE; Web of Science) from January, 2000 up to July, 2017. Two or more independent reviewers screened bibliographic records, extracted data, and assessed risk of bias of studies. Published Kaplan Meier plots for OS and PFS along with restricted-mean-survival methods and parametric modelling were used to estimate the survival outcomes as mean number of months of survival. Network meta-analysis was undertaken to rank interventions and to make indirect comparisons. RESULTS: We included 11 RCTs with data for 7581 participants that compared nine different drugs. In studies of patients regardless of histology groups, targeted drugs (ramucirumab and nintedanib) yielded small overall survival gains of < 2.5 months over docetaxel, erlotinib provided no benefit, while immunotherapies (atezolizumab and pembrolizumab) delivered 5 to 6 months gain. Studies with patients stratified by histology confirmed the apparent superiority of immunotherapy (nivolumab and atezolizumab) over targeted treatments (ramucirumab, nintedanib, afatinib) providing between about 4 to 8 months OS gain over docetaxel. In network analysis immunotherapies consistently ranked higher than alternatives irrespective of population histology and outcome measure. CONCLUSION: Our review indicates that nivolumab, pembrolizumab and atezolizumab provide superior survival benefits compared to other licensed drugs for late stage NSCLC. Patient gains from these immunotherapies are substantial compared to the expected average survival with chemotherapy (docetaxel) of < 1 year for people with squamous histology and about 1.25 year for those with non-squamous histology.

Comparing interferon-gamma release assays with tuberculin skin test for identifying latent tuberculosis infection that progresses to active tuberculosis: systematic review and meta-analysis.

BACKGROUND: Timely and accurate identification of people with latent tuberculosis infection (LTBI) is important for controlling Mycobacterium tuberculosis (TB). There is no gold standard for diagnosis of LTBI. Screening tests such as interferon gamma release assays (IGRAs) and tuberculin skin test (TST) provide indirect and imperfect information. This systematic review compared two types of IGRAs QuantiFERON®-TB Gold In-Tube test (QFT-GIT) and T-SPOT.TB with TST for identification of LTBI by predicting progression to a diagnosis of active TB in three subgroups: children, immunocompromised people, and those recently arrived from countries with high TB burden. METHODS: Cohort studies were eligible for inclusion. We searched MEDLINE, EMBASE, the Cochrane Library and other databases from December 2009 to June 2015. One reviewer screened studies, extracted data, and assessed risk of bias with cross checking by a second reviewer. Strength of association between test results and incidence of TB was summarised using cumulative incidence ratios (CIRs with 95% CIs). Summary effect measures: the ratio of CIRs (R-CIR) with 95% CIs. R-CIRs, were pooled using a random-effects model. Heterogeneity was assessed using Chi-squared and I2 statistics. RESULTS: Seventeen studies, mostly of moderate or high risk of bias (five in children, 10 in immunocompromised people, and two in those recently arrived) were included. In children, while in two studies, there was no significant difference between QFT-GIT and TST (≥5 mm) (pooled R-CIR = 1.11, 95% CI: 0.71, 1.74), two other studies showed QFT-GIT to outperform TST (≥10 mm) in identifying LTBI. In immunocompromised people, IGRA (T-SPOT.TB) was not significant different from TST (≥10 mm) for identifying LTBI, (pooled R-CIR = 1.01, 95% CI: 0.65, 1.58). The forest plot of two studies in recently arrived people from countries with high TB burden demonstrated inconsistent findings (high heterogeneity; I2 = 92%). CONCLUSIONS: Prospective studies comparing IGRA testing against TST on the progression from LTBI to TB were sparse, and these results should be interpreted with caution due to uncertainty, risk of bias, and unexplained heterogeneity. Population-based studies with adequate sample size and follow-up are required to adequately compare the performance of IGRA with TST in people at high risk of TB.

Cost-effectiveness of manual therapy for the management of musculoskeletal conditions: a systematic review and narrative synthesis of evidence from randomized controlled trials.

OBJECTIVES: The purpose of this study was to systematically review trial-based economic evaluations of manual therapy relative to other alternative interventions used for the management of musculoskeletal conditions. METHODS: A comprehensive literature search was undertaken in major medical, health-related, science and health economic electronic databases. RESULTS: Twenty-five publications were included (11 trial-based economic evaluations). The studies compared cost-effectiveness and/or cost-utility of manual therapy interventions to other treatment alternatives in reducing pain (spinal, shoulder, ankle). Manual therapy techniques (e.g., osteopathic spinal manipulation, physiotherapy manipulation and mobilization techniques, and chiropractic manipulation with or without other treatments) were more cost-effective than usual general practitioner (GP) care alone or with exercise, spinal stabilization, GP advice, advice to remain active, or brief pain management for improving low back and shoulder pain/disability. Chiropractic manipulation was found to be less costly and more effective than alternative treatment compared with either physiotherapy or GP care in improving neck pain. CONCLUSIONS: Preliminary evidence from this review shows some economic advantage of manual therapy relative to other interventions used for the management of musculoskeletal conditions, indicating that some manual therapy techniques may be more cost-effective than usual GP care, spinal stabilization, GP advice, advice to remain active, or brief pain management for improving low back and shoulder pain/disability. However, at present, there is a paucity of evidence on the cost-effectiveness and/or cost-utility evaluations for manual therapy interventions. Further improvements in the methodological conduct and reporting quality of economic evaluations of manual therapy are warranted in order to facilitate adequate evidence-based decisions among policy makers, health care practitioners, and patients.

A systematic review and meta-analysis of efficacy, cost-effectiveness, and safety of selected complementary and alternative medicine for neck and low-back pain.

Background. Back pain is a common problem and a major cause of disability and health care utilization. Purpose. To evaluate the efficacy, harms, and costs of the most common CAM treatments (acupuncture, massage, spinal manipulation, and mobilization) for neck/low-back pain. Data Sources. Records without language restriction from various databases up to February 2010. Data Extraction. The efficacy outcomes of interest were pain intensity and disability. Data Synthesis. Reports of 147 randomized trials and 5 nonrandomized studies were included. CAM treatments were more effective in reducing pain and disability compared to no treatment, physical therapy (exercise and/or electrotherapy) or usual care immediately or at short-term follow-up. Trials that applied sham-acupuncture tended towards statistically nonsignificant results. In several studies, acupuncture caused bleeding on the site of application, and manipulation and massage caused pain episodes of mild and transient nature. Conclusions. CAM treatments were significantly more efficacious than no treatment, placebo, physical therapy, or usual care in reducing pain immediately or at short-term after treatment. CAM therapies did not significantly reduce disability compared to sham. None of the CAM treatments was shown systematically as superior to one another. More efforts are needed to improve the conduct and reporting of studies of CAM treatments.

Universal school-based prevention programs for alcohol misuse in young people.

BACKGROUND: Alcohol misuse in young people is cause of concern for health services, policy makers, prevention workers, criminal justice system, youth workers, teachers, parents. This is one of three reviews examining the effectiveness of (1) school-based, (2) family-based, and (3) multi-component prevention programs. OBJECTIVES: To review evidence on the effectiveness of universal school-based prevention programs in preventing alcohol misuse in school-aged children up to 18 years of age. SEARCH STRATEGY: Relevant evidence (up to 2002) was selected from the previous Cochrane review. Later studies, to July 2010, were identified from MEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, Project CORK, and PsycINFO. SELECTION CRITERIA: Randomized trials evaluating universal school-based prevention programs and reporting outcomes for alcohol use in students 18 years of age or younger were included. Two reviewers screened titles/abstracts and full text of identified records. DATA COLLECTION AND ANALYSIS: Two reviewers extracted relevant data independently using an a priori defined extraction form. Risk of bias was assessed. MAIN RESULTS: 53 trials were included, most of which were cluster-randomised. The reporting quality of trials was poor, only 3.8% of them reporting adequate method of randomisation and program allocation concealment. Incomplete data was adequately addressed in 23% of the trials. Due to extensive heterogeneity across interventions, populations, and outcomes, the results were summarized only qualitatively.Six of the 11 trials evaluating alcohol-specific interventions showed some evidence of effectiveness compared to a standard curriculum. In 14 of the 39 trials evaluating generic interventions, the program interventions demonstrated significantly greater reductions in alcohol use either through a main or subgroup effect. Gender, baseline alcohol use, and ethnicity modified the effects of interventions. Results from the remaining 3 trials with interventions targeting cannabis, alcohol, and/or tobacco were inconsistent. AUTHORS' CONCLUSIONS: This review identified studies that showed no effects of preventive interventions, as well as studies that demonstrated statistically significant effects. There was no easily discernible pattern in characteristics that would distinguish trials with positive results from those with no effects. Most commonly observed positive effects across programs were for drunkenness and binge drinking. Current evidence suggests that certain generic psychosocial and developmental prevention programs can be effective and could be considered as policy and practice options. These include the Life Skills Training Program, the Unplugged program, and the Good Behaviour Game. A stronger focus of future research on intervention program content and delivery context is warranted. 

Universal multi-component prevention programs for alcohol misuse in young people.

BACKGROUND: Alcohol misuse in young people is a cause of concern for health services, policy makers, prevention workers, and criminal justice system, youth workers, teachers, and parents. OBJECTIVES: To systematically review evidence on the effectiveness of universal multi-component prevention programs in preventing alcohol misuse in school-aged children up to 18 years of age. To update a part of a previously published Cochrane systematic review. SEARCH STRATEGY: Relevant evidence (up to 2002) was selected from the previous Cochrane review. Later studies, to July 2010, were identified from MEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, Project CORK, and PsycINFO. SELECTION CRITERIA: Randomized trials evaluating universal multi-component prevention programs (intervention delivered in more than one setting) and reporting outcomes for alcohol use in students 18 years of age or younger were included. Two reviewers screened titles/abstracts and full text of identified records. DATA COLLECTION AND ANALYSIS: Two reviewers extracted relevant data independently using an a priori defined extraction form. Risk of bias was assessed. MAIN RESULTS: 20 parallel-group trials were included. The reporting quality of trials was poor, only 25% and 5% of them reporting adequate method of randomisation and program allocation concealment, respectively. Incomplete data was adequately addressed in about half of the trials and this information was unclear for about 20% of the trials. Due to extensive heterogeneity across interventions, populations, and outcomes, the results were summarized only qualitatively.12 of the 20 trials showed some evidence of effectiveness compared to a control or other intervention group, with persistence of effects ranging from 3 months to 3 years. Of the remaining 8 trials, one trial reported significant effects using one-tailed tests and 7 trials reported no significant effects of the multi-component interventions for reducing alcohol misuse.Assessment of the additional benefit of multiple versus single component interventions was possible in 7 trials with multiple arms. Only one of the 7 trials clearly showed a benefit of components delivered in more than one setting. AUTHORS' CONCLUSIONS: There is some evidence that multi-component interventions for alcohol misuse prevention in young people can be effective. However, there is little evidence that interventions with multiple components are more effective than interventions with single components.

Universal family-based prevention programs for alcohol misuse in young people.

BACKGROUND: Alcohol misuse in young people is a cause of concern for health services, policy makers, prevention workers, and criminal justice system, youth workers, teachers, and parents. OBJECTIVES: To systematically review evidence on the effectiveness of universal family-based prevention programs in preventing alcohol misuse in school-aged children up to 18 years of age. To update a part of a previously published Cochrane systematic review. SEARCH STRATEGY: Relevant evidence (up to 2002) was selected from the previous Cochrane review. Later studies, to July 2010, were identified from MEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, Project CORK, and PsycINFO. SELECTION CRITERIA: Randomized trials evaluating universal family-based prevention programs and reporting outcomes for alcohol use in students 18 years of age or younger were included. Two reviewers screened titles/abstracts and full text of identified records. DATA COLLECTION AND ANALYSIS: Two reviewers extracted relevant data independently using an a priori defined extraction form. Risk of bias was assessed. MAIN RESULTS: 12 parallel-group trials were included. The reporting quality of trials was poor, only 20% of them reporting adequate method of randomisation and program allocation concealment. Incomplete data was adequately addressed in about half of the trials and this information was unclear for about 30% of the trials. Due to extensive heterogeneity across interventions, populations, and outcomes, the results were summarized only qualitatively.9 of the 12 trials showed some evidence of effectiveness compared to a control or other intervention group, with persistence of effects over the medium and longer-term. Four of these effective interventions were gender-specific, focusing on young females. One study with a small sample size showed positive effects that were not statistically significant, and two studies with larger sample sizes reported no significant effects of the family-based intervention for reducing alcohol misuse. AUTHORS' CONCLUSIONS: In conclusion, in this Cochrane systematic review we found that that the effects of family-based prevention interventions are small but generally consistent and also persistent into the medium- to longer-term.

An evaluation of the completeness of safety reporting in reports of complementary and alternative medicine trials.

BACKGROUND: Adequate reporting of safety in publications of randomized controlled trials (RCTs) is a pre-requisite for accurate and comprehensive profile evaluation of conventional as well as complementary and alternative medicine (CAM) treatments. Clear and concise information on the definition, frequency, and severity of adverse events (AEs) is necessary for assessing the benefit-harm ratio of any intervention. The objectives of this study are to assess the quality of safety reporting in CAM RCTs; to explore the influence of different trial characteristics on the quality of safety reporting. METHODS: Survey of safety reporting in RCTs published in 2009 across 15 widely used CAM interventions identified from the Cochrane Collaboration's CAM Field specialized register of trials. Primary outcome measures, the adequacy of reporting of AEs; was defined and categorized according to the CONSORT for harms extension; the percentage of words devoted to the reporting of safety in the entire report and in the results section. RESULTS: Two-hundred and five trials were included in the review. Of these, 15% (31/205) reported that no harms were observed during the trial period. Of the remaining 174 trials reporting any safety information, only 21% (36/174) had adequate safety reporting.For all trials, the median percentage of words devoted to the reporting of safety in the results section was 2.6. Moreover, 69% (n = 141) of all trials devoted a lesser or equal percentage of words to safety compared to author affiliations. Of the predictor variables used in regression analysis, multicenter trials had more words devoted to safety in the results section than single centre trials (P = 0.045). CONCLUSIONS: An evaluation of safety reporting in the reports of CAM RCTs across 15 different CAM interventions demonstrated that the reporting of harms was largely inadequate. The quality of reporting safety information in primary reports of CAM randomized trials requires improvement.

Conduit vessel blood flow during the trek to Mount Everest base camp.

OBJECTIVE: Hemodynamic changes in response to the hypoxic environment of high altitude are vascular bed-specific. The aim of the present study was to investigate diameter and blood flow changes in conduit vessels in response to hypobaric hypoxia. METHODS: Eleven healthy subjects ascending Mount Everest to base camp participated in this study. Vessel diameter and blood velocity for brachial, carotid, common femoral, superficial femoral, and deep femoral arteries were measured by portable Doppler ultrasound. Blood flow was calculated from these values. Measurements were taken at sea level, at increasing altitudes on ascent to base camp (1310 m, 3470 m, 5330 m), and repeated on descent to lower altitude (1310 m). RESULTS: For all vessels except carotids, both vessel diameter and blood flow decreased between sea level and initial ascent to altitude, with subsequent persistence of these decreased values; there was no further significant change with continued ascent to higher altitude. Blood flow for all arteries (except carotids) increased significantly on descent to lower altitude, with an associated nonsignificant increase in velocity and decrease in diameter. CONCLUSIONS: This study showed that there is vasoconstriction of limb conduit vessels at altitude, which persists upon descent to lower altitude. Blood flow in these vessels also decreases with initial exposure to high altitude, yet increases when returning to lower altitude, reflecting variations in blood velocity. Carotid arteries responded differently to the stimulus of hypobaria than limb conduit vessels; there was no change in diameter seen on ascent or descent, but there was a progressive decrease in blood flow on ascent, with no change on subsequent descent.

Factors associated with attendance at screening for breast cancer: a systematic review and meta-analysis.

OBJECTIVE: Attendance at population-based breast cancer (mammographic) screening varies. This comprehensive systematic review and meta-analysis assesses all identified patient-level factors associated with routine population breast screening attendance. DESIGN: CINAHL, Cochrane Library, Embase, Medline, OVID, PsycINFO and Web of Science were searched for studies of any design, published January 1987-June 2019, and reporting attendance in relation to at least one patient-level factor. DATA SYNTHESIS: Independent reviewers performed screening, data extraction and quality appraisal. OR and 95% CIs were calculated for attendance for each factor and random-effects meta-analysis was undertaken where possible. RESULTS: Of 19 776 studies, 335 were assessed at full text and 66 studies (n=22 150 922) were included. Risk of bias was generally low. In meta-analysis, increased attendance was associated with higher socioeconomic status (SES) (n=11 studies; OR 1.45, 95% CI: 1.20 to 1.75); higher income (n=5 studies; OR 1.96, 95% CI: 1.68 to 2.29); home ownership (n=3 studies; OR 2.16, 95% CI: 2.08 to 2.23); being non-immigrant (n=7 studies; OR 2.23, 95% CI: 2.00 to 2.48); being married/cohabiting (n=7 studies; OR 1.86, 95% CI: 1.58 to 2.19) and medium (vs low) level of education (n=6 studies; OR 1.24, 95% CI: 1.09 to 1.41). Women with previous false-positive results were less likely to reattend (n=6 studies; OR 0.77, 95% CI: 0.68 to 0.88). There were no differences by age group or by rural versus urban residence. CONCLUSIONS: Attendance was lower in women with lower SES, those who were immigrants, non-homeowners and those with previous false-positive results. Variations in service delivery, screening programmes and study populations may influence findings. Our findings are of univariable associations. Underlying causes of lower uptake such as practical, physical, psychological or financial barriers should be investigated. TRIAL REGISTRATION NUMBER: CRD42016051597.

Systematic review: comparative effectiveness and harms of combination therapy and monotherapy for dyslipidemia.

BACKGROUND: Statin therapy effectively prevents vascular disease, but treatment targets are often not achieved. PURPOSE: To compare the benefits and harms of high-dose statin monotherapy with those of combination therapy in adults at high risk for coronary disease. DATA SOURCES: English-language records from MEDLINE (1966 to 2009), EMBASE (1980 to 2009), and the Cochrane Library (third quarter of 2008). STUDY SELECTION: A reviewer screened records, and a second reviewer verified selection of randomized, controlled trials in adult patients that compared combinations of statins and bile-acid sequestrants, fibrates, ezetimibe, niacin, or omega-3 fatty acids with statin monotherapy, as well as nonrandomized comparative studies that were longer than 24 weeks and reported clinical and harms outcomes. DATA EXTRACTION: Data were abstracted for studies by using standardized forms, and study quality was rated with a standardized scale and strength of evidence by using the Grading of Recommendations Assessment, Development, and Evaluation approach. DATA SYNTHESIS: 102 studies met eligibility criteria. The main analysis compared combination therapy with high-dose statin monotherapy in high-risk patients. Very-low-strength evidence showed that statin-ezetimibe (2 trials; n = 439) and statin-fibrate (1 trial; n = 166) combinations did not reduce mortality more than high-dose statin monotherapy. No trials compared the effect of combination therapy versus high-dose statin monotherapy on the incidence of myocardial infarction, stroke, or revascularization procedures. Two statin-ezetimibe trials (n = 295) demonstrated higher low-density lipoprotein cholesterol goal attainment with combination therapy (odds ratio, 7.21 [95% CI, 4.30 to 12.08]). Trials in lower-risk patients did not show a difference in mortality. LIMITATIONS: Studies were generally short, focused on surrogate outcomes, and were heterogeneous in the sample's risk for coronary disease. Few studies examined treatment combinations other than statin-ezetimibe. CONCLUSION: Limited evidence suggests that combinations of lipid-lowering agents do not improve clinical outcomes more than high-dose statin monotherapy. Very-low-quality evidence favors statin-ezetimibe treatment for attainment of low-density lipoprotein cholesterol goals. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

Oral phosphodiesterase-5 inhibitors and hormonal treatments for erectile dysfunction: a systematic review and meta-analysis.

BACKGROUND: Erectile dysfunction (ED) is a common male sexual disorder. The relative benefits and harms of pharmacologic therapies for ED, as well as the value of hormonal testing in men with ED, are uncertain. PURPOSE: To evaluate the efficacy and harms of oral phosphodiesterase-5 (PDE-5) inhibitors and hormonal treatments for ED and assess the effect of measuring serum hormone levels on treatment outcomes for ED. DATA SOURCES: English-language studies from MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, PsycINFO, AMED, and SCOPUS through April 2009. Trial reference lists also were scanned. STUDY SELECTION: Randomized, controlled trials (RCTs) of oral PDE-5 inhibitors and hormonal treatment for ED, and observational studies reporting measurement of serum hormone levels, prevalence of hormonal abnormalities, or both in men with ED. DATA EXTRACTION: Two independent reviewers abstracted data on study, participant, and treatment characteristics; efficacy and harms outcomes; and prevalence of hormonal abnormalities. DATA SYNTHESIS: Data, primarily from short-term trials (

Systematic review with meta-analysis of over 90 000 patients. Does fast-track review diagnose colorectal cancer earlier?

BACKGROUND: National UK data on colorectal cancer (CRC) stage at diagnosis is incomplete. Site-specific fast-track (2-week wait) cancer data are not collected directly by NHS England. Policy making based on these data alone can lead to inaccuracy. AIMS: To review available data on key outcomes (cancer conversion rate and stage at diagnosis) for the UK's lower gastrointestinal 2-week wait pathway. METHODS: A comprehensive literature search was conducted between 2000 and 2017. Primary outcomes were cancer conversion rate and cancer stage at diagnosis. Results were expressed as proportions with 95% CIs. A random effects model was used for meta-analysis; heterogeneity was assessed by I2 . RESULTS: Of 95 papers reviewed, 49 were included in analysis with a total study population of 93,655. Cancer conversion rate was 7.7% (95% CI: 6.9-8.5). The proportion presenting at Dukes A = 11.2% (95% CI 7.4-15.6), B = 36.7% (95% CI 30.8-42.8), C = 35.7% (95% CI: 30.8-40.8) and D = 11.1% (95% CI 7.3-15.5). No colonic pathology was diagnosed in 54.6% (95% CI: 46.2-62.8). CONCLUSIONS: Only 7.7% of patients referred by the 2-week wait pathway were found to have CRC. No beneficial effect on stage at diagnosis was found compared to non-2-week wait referral pathways. Over half of patients had no colonic pathology and detection of adenomas was very low. These results should prompt a reconsideration of the benefits of the 2-week wait pathway in CRC diagnosis and outcomes, with more focus on strategies to improve patient selection.

The use of aspirin for primary prevention of colorectal cancer: a systematic review prepared for the U.S. Preventive Services Task Force.

BACKGROUND: Aspirin for prevention of colorectal cancer is controversial. PURPOSE: To examine the benefits and harms of aspirin chemoprevention. DATA SOURCES: MEDLINE, 1966 to December 2006; EMBASE, 1980 to April 2005; CENTRAL, Cochrane Collaboration's registry of clinical trials; Cochrane Database of Systematic Reviews. STUDY SELECTION: Two independent reviewers conducted multilevel screening to identify randomized, controlled trials (RCTs), case-control studies, and cohort studies of aspirin chemoprophylaxis. For harms, systematic reviews were sought. DATA EXTRACTION: In duplicate, data were abstracted and checked and quality was assessed. DATA SYNTHESIS: Regular use of aspirin reduced the incidence of colonic adenomas in RCTs (relative risk [RR], 0.82 [95% CI, 0.7 to 0.95]), case-control studies (RR, 0.87 [CI, 0.77 to 0.98]), and cohort studies (RR, 0.72 [CI, 0.61 to 0.85]). In cohort studies, regular use of aspirin was associated with RR reductions of 22% for incidence of colorectal cancer. Two RCTs of low-dose aspirin failed to show a protective effect. Data for colorectal cancer mortality were limited. Benefits from chemoprevention were more evident when aspirin was used at a high dose and for periods longer than 10 years. Aspirin use was associated with a dose-related increase in incidence of gastrointestinal complications. LIMITATIONS: Important clinical and methodological heterogeneity in the definitions of regular use, dose, and duration of use of aspirin necessitated careful grouping for analysis. CONCLUSIONS: Aspirin appears to be effective at reducing the incidence of colonic adenoma and colorectal cancer, especially if used in high doses for more than 10 years. However, the possible harms of such a practice require careful consideration. Further evaluation of the cost-effectiveness of chemoprevention compared with, and in combination with, a screening strategy is required.

Nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors for primary prevention of colorectal cancer: a systematic review prepared for the U.S. Preventive Services Task Force.

PURPOSE: To examine the benefits and harms of nonaspirin (non-ASA) nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase (COX-2) inhibitors for the prevention of colorectal cancer (CRC) and adenoma. DATA SOURCES: MEDLINE (1966 to 2006), EMBASE (1980 to 2006), Cochrane Central Register of Controlled Trials, Cochrane Collaboration's registry of clinical trials, Cochrane Database of Systematic Reviews. STUDY SELECTION: Randomized, controlled trials and case-control and cohort studies of the effectiveness of NSAIDs for the prevention of CRC and colorectal adenoma were identified by multilevel screening by 2 independent reviewers. Systematic reviews of harms were sought. DATA EXTRACTION: Data abstraction, checking, and quality assessment were completed in duplicate. DATA SYNTHESIS: A single cohort study showed no effect of non-ASA NSAIDs on death due to CRC. Colorectal cancer incidence was reduced with non-ASA NSAIDs in cohort studies (relative risk, 0.61 [95% CI, 0.48 to 0.77]) and case-control studies (relative risk, 0.70 [CI, 0.63 to 0.78]). Colorectal adenoma incidence was also reduced with non-ASA NSAID use in cohort studies (relative risk, 0.64 [CI, 0.48 to 0.85]) and case-control studies (relative risk, 0.54 [CI, 0.4 to 0.74]) and by COX-2 inhibitors in randomized, controlled trials (relative risk, 0.72 [CI, 0.68 to 0.77]). The ulcer complication rate associated with non-ASA NSAIDs is 1.5% per year. Compared with non-ASA NSAIDs, COX-2 inhibitors reduce this risk but, in multiyear use, have a higher ulcer complication rate than placebo. Cyclooxygenase-2 inhibitors and nonnaproxen NSAIDs increase the risk for serious cardiovascular events (relative risk, 1.86 [CI, 1.33 to 2.59] for COX-2 inhibitors vs. placebo). LIMITATIONS: Heterogeneity in the dose, duration and frequency of use necessitated careful grouping for analysis. CONCLUSIONS: Cyclooxygenase-2 inhibitors and NSAIDs reduce the incidence of colonic adenomas. Nonsteroidal anti-inflammatory drugs also reduce the incidence of CRC. However, these agents are associated with important cardiovascular events and gastrointestinal harms. The balance of benefits to risk does not favor chemoprevention in average-risk individuals.

Comparative efficacy and safety of licensed treatments for previously treated non-small cell lung cancer: A systematic review and network meta-analysis.

PURPOSE: This systematic review with network meta-analysis compared the efficacy and safety of currently licensed second-line treatments in patients with late stage non-small cell lung cancer (NSCLC). METHODS: Randomised controlled trials (RCTs) of participants with advanced/metastatic NSCLC receiving second/third line treatments were screened. We searched electronic databases (MEDLINE; EMBASE; Web of Science) from January, 2000 to July, 2017. Two reviewers screened bibliographic records, extracted data, and assessed risk of bias of included studies. The outcomes were overall survival (OS), progression-free survival (PFS), and drug-related grade 3-5 adverse-events (AEs). We pooled study-specific hazard ratios (HR; for OS and PFS) and risk ratios (RR; for AEs) using conventional and network-meta-analyses, and ranked interventions by the surface under the cumulative ranking curve. FINDINGS: We included 11 RCTs (7,581 participants) comparing nine drugs. All drugs except for erlotinib significantly improved OS compared to docetaxel. Nivolumab was the highest ranking drug followed by atezolizumab and pembrolizumab. There was no significant difference in OS across these three drugs (HR = 0.98, 95% CI 0.79, 1.21 for nivolumab vs atezolizumab; HR = 0.98, 95% CI 0.77, 1.25 for nivolumab vs pembrolizumab). For PFS, ramucirumab + docetaxel and nivolumab were the drugs with the highest ranking. All interventions except ramucirumab + docetaxel had a reduced risk for severe drug-related AEs vs. docetaxel. Of the drugs with the highest ranking on AEs, nivolumab was significantly safer compared to atezolizumab (RR = 0.55, 95% CI 0.38, 0.79) or pembrolizumab (RR = 0.52, 95% CI 0.34, 0.81). IMPLICATIONS: Nivolumab, pembrolizumab and atezolizumab exhibited superior benefit/risk balance compared to other licensed drugs used late stage NSCLC. Our results indicate that the use of immunotherapies in people diagnosed with non-specific late stage NSCLC should be promoted. The use of docetaxel may now be judged irrelevant as a comparator intervention for approval of new drugs for second line treatment of NSCLC. STUDY REGISTRATION NUMBER: PROSPERO CRD42017065928.

Ixazomib for Relapsed or Refractory Multiple Myeloma: Review from an Evidence Review Group on a NICE Single Technology Appraisal.

Ixazomib is an oral proteasome inhibitor used in combination with lenalidomide plus dexamethasone (IXA-LEN-DEX) and licensed for relapsed or refractory multiple myeloma. As part of a single technology appraisal (ID807) undertaken by the National Institute of Health and Care Excellence, the Evidence Review Group, Warwick Evidence was invited to independently review the evidence submitted by the manufacturer of ixazomib, Takeda UK Ltd. The main source of clinical effectiveness data about IXA-LEN-DEX came from the Tourmaline-MM1 randomized controlled trial in which 771 patients with relapsed or refractory multiple myeloma received either IXA-LEN-DEX or placebo-LEN-DEX as their second-, third-, or fourth-line treatment. Takeda estimated the cost effectiveness of IXA-LEN-DEX using a de-novo partitioned-survival model with three health states (pre-progression, post-progression, and dead). In their first submission, this model was used to estimate the cost effectiveness of IXA-LEN-DEX vs. bortezomib plus dexamethasone (BORT-DEX) in second-line treatment, and of IXA-LEN-DEX vs. LEN-DEX in third-line treatment. To estimate the relative clinical performance of IXA-LEN-DEX vs. BORT-DEX, Takeda conducted network meta-analyses for important outcomes. The network meta-analysis for overall survival was found to be flawed in several respects, but mainly because a hazard ratio input for one of the studies in the network had been inverted, resulting in a large inflation of the claimed superiority of IXA-LEN-DEX over BORT-DEX and a considerable overestimation of its cost effectiveness. In subsequent submissions, Takeda withdrew second-line treatment as an option for IXA-LEN-DEX. The manufacturer's first submission comparing IXA-LEN-DEX with LEN-DEX for third-line therapy employed Tourmaline-MM1 data from third- and fourth-line patients as proxy for a third-line population. The appraisal committee did not consider this reasonable because randomization in Tourmaline-MM1 was stratified according to one previous treatment and two or more previous treatments. A further deficiency was considered to be the manufacturer's use of interim survival data rather than the most mature data available. A second submission from the company focussed on IXA-LEN-DEX vs. LEN-DEX as third- or fourth-line treatment (the two or more previous lines population) and a new patient access scheme was introduced. Covariate modeling of survival outcomes was proposed using the most mature survival data. The Evidence Review Group's main criticisms of the new evidence included: the utility associated with the pre-progression health state was overestimated, treatment costs of ixazomib were underestimated, survival models were still associated with great uncertainty, leading to clinically implausible anomalies and highly variable incremental cost-effectiveness ratio estimates, and the company had not explored a strong assumption that the survival benefit of IXA-LEN-DEX over LEN-DEX would be fully maintained for a further 22 years beyond the observed data, which encompassed only approximately 2.5 years of observation. The appraisal committee remained unconvinced that ixazomib represented a cost-effective use of National Health Service resources. Takeda's third submission offered new base-case parametric models for survival outcomes, a new analysis of utilities, and proposed a commercial access agreement. In a brief critique of the third submission, the Evidence Review Group agreed that the selection of appropriate survival models was problematic and at the request of the National Institute for Health Care and Excellence investigated external sources of evidence regarding survival outcomes. The Evidence Review Group considered that some cost and utility estimates in the submission may have remained biased in favor of ixazomib. As a result of their third appraisal meeting, the committee judged that for the two to three prior therapies population, and at the price agreed in a commercial access agreement, ixazomib had the potential to be cost effective. It was referred to the Cancer Drugs Fund so that further data could accrue with the aim of diminishing the clinical uncertainties.

A systematic review identified few methods and strategies describing when and how to update systematic reviews.

OBJECTIVE: Systematic reviews (SRs) are convenient summaries of evidence for health care practitioners. They form a basis for clinical practice guidelines and suggest directions for new research. SRs are most helpful if they are current; however, most of them are not being updated. This SR summarizes strategies and methods describing when and how to update SRs. STUDY DESIGN AND SETTING: We searched MEDLINE (1966 to December 2005), PsycINFO, the Cochrane Methodology Register, and the 2005 Cochrane Colloquium proceedings to identify records describing when and how to update SRs in health care. RESULTS: Four updating strategies, one technique, and two statistical methods were identified. Three strategies addressed steps for updating, and one strategy presented a model for assessing the need to update. One technique discussed the use of the "entry date" field in bibliographic searching. The statistical methods were cumulative meta-analysis and a test for detecting outdated meta-analyses with statistically nonsignificant results. CONCLUSION: Little research has been conducted on when and how to update SRs in contrast to other methodological areas of conducting SRs (e.g., publication bias, variance imputation). The feasibility and efficiency of the identified approaches is uncertain. More research is needed to develop pragmatic and efficient methodologies for updating SRs.

Indirect effects of childhood pneumococcal conjugate vaccination on invasive pneumococcal disease: a systematic review and meta-analysis.

BACKGROUND: The full extent to which childhood pneumococcal conjugate vaccines (PCV) can indirectly reduce illness in unvaccinated populations is not known. We aimed to estimate the magnitude and timing of indirect effects of PCVs on invasive pneumococcal disease. METHODS: In this systematic review and meta-analysis, we searched bibliographic databases for non-randomised quasi-experimental or observational studies reporting invasive pneumococcal disease changes following PCV introduction in unvaccinated populations (studies published Sept 1, 2010, to Jan 6, 2016), updating the previous systematic review of the same topic (studies published Jan 1, 1994, to Sept 30, 2010). Two reviewers extracted summary data by consensus. We used a Bayesian mixed-effects model to account for between-study heterogeneity to estimate temporal indirect effects by pooling of invasive pneumococcal disease changes by serotype and serogroup. FINDINGS: Data were extracted from 70 studies included in the previous review and 172 additional studies, covering 27 high-income and seven middle-income countries. The predicted mean times to attaining a 90% reduction in invasive pneumococcal disease were 8·9 years (95% credible interval [CrI] 7·8-10·3) for grouped serotypes contained in the seven-valent PCV (PCV7), and 9·5 years (6·1-16·6) for the grouped six additional serotypes contained in the 13-valent PCV (PCV13) but not in PCV7. Disease due to grouped serotypes contained in the 23-valent pneumococcal polysaccharide vaccine (PPV23) decreased at similar rates per year in adults aged 19-64 years (relative risk [RR] 0·85, 95% CrI 0·75-0·95) and 65 years and older (0·87, 0·84-0·90). However, we noted no changes in either group in invasive pneumococcal disease caused by the additional 11 serotypes covered by PPV23 but not PCV13. INTERPRETATION: Population childhood PCV programmes will lead, on average, to substantial protection across the whole population within a decade. This large indirect protection should be considered when assessing vaccination of older age groups. FUNDING: Policy Research Programme of the Department of Health, England.

Multiplex tests to identify gastrointestinal bacteria, viruses and parasites in people with suspected infectious gastroenteritis: a systematic review and economic analysis.

BACKGROUND: Gastroenteritis is a common, transient disorder usually caused by infection and characterised by the acute onset of diarrhoea. Multiplex gastrointestinal pathogen panel (GPP) tests simultaneously identify common bacterial, viral and parasitic pathogens using molecular testing. By providing test results more rapidly than conventional testing methods, GPP tests might positively influence the treatment and management of patients presenting in hospital or in the community. OBJECTIVE: To systematically review the evidence for GPP tests [xTAG® (Luminex, Toronto, ON, Canada), FilmArray (BioFire Diagnostics, Salt Lake City, UT, USA) and Faecal Pathogens B (AusDiagnostics, Beaconsfield, NSW, Australia)] and to develop a de novo economic model to compare the cost-effectiveness of GPP tests with conventional testing in England and Wales. DATA SOURCES: Multiple electronic databases including MEDLINE, EMBASE, Web of Science and the Cochrane Database were searched from inception to January 2016 (with supplementary searches of other online resources). REVIEW METHODS: Eligible studies included patients with acute diarrhoea; comparing GPP tests with standard microbiology techniques; and patient, management, test accuracy or cost-effectiveness outcomes. Quality assessment of eligible studies used tailored Quality Assessment of Diagnostic Accuracy Studies-2, Consolidated Health Economic Evaluation Reporting Standards and Philips checklists. The meta-analysis included positive and negative agreement estimated for each pathogen. A de novo decision tree model compared patients managed with GPP testing or comparable coverage with patients managed using conventional tests, within the Public Health England pathway. Economic models included hospital and community management of patients with suspected gastroenteritis. The model estimated costs (in 2014/15 prices) and quality-adjusted life-year losses from a NHS and Personal Social Services perspective. RESULTS: Twenty-three studies informed the review of clinical evidence (17 xTAG, four FilmArray, two xTAG and FilmArray, 0 Faecal Pathogens B). No study provided an adequate reference standard with which to compare the test accuracy of GPP with conventional tests. A meta-analysis (of 10 studies) found considerable heterogeneity; however, GPP testing produces a greater number of pathogen-positive findings than conventional testing. It is unclear whether or not these additional 'positives' are clinically important. The review identified no robust evidence to inform consequent clinical management of patients. There is considerable uncertainty about the cost-effectiveness of GPP panels used to test for suspected infectious gastroenteritis in hospital and community settings. Uncertainties in the model include length of stay, assumptions about false-positive findings and the costs of tests. Although there is potential for cost-effectiveness in both settings, key modelling assumptions need to be verified and model findings remain tentative. LIMITATIONS: No test-treat trials were retrieved. The economic model reflects one pattern of care, which will vary across the NHS. CONCLUSIONS: The systematic review and cost-effectiveness model identify uncertainties about the adoption of GPP tests within the NHS. GPP testing will generally correctly identify pathogens identified by conventional testing; however, these tests also generate considerable additional positive results of uncertain clinical importance. FUTURE WORK: An independent reference standard may not exist to evaluate alternative approaches to testing. A test-treat trial might ascertain whether or not additional GPP 'positives' are clinically important or result in overdiagnoses, whether or not earlier diagnosis leads to earlier discharge in patients and what the health consequences of earlier intervention are. Future work might also consider the public health impact of different testing treatments, as test results form the basis for public health surveillance. STUDY REGISTRATION: This study is registered as PROSPERO CRD2016033320. FUNDING: The National Institute for Health Research Health Technology Assessment programme.