Jessica Griffin

Risk Factors for Breast Cancer for Women Aged 40 to 49 Years: A Systematic Review and Meta-analysis

BACKGROUND Identifying risk factors for breast cancer specific to women in their 40s could inform screening decisions. PURPOSE To determine what factors increase risk for breast cancer in women aged 40 to 49 years and the magnitude of risk for each factor. DATA SOURCES MEDLINE (January 1996 to the second week of November 2011), Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (fourth quarter of 2011), Scopus, reference lists of published studies, and the Breast Cancer Surveillance Consortium. STUDY SELECTION English-language studies and systematic reviews of risk factors for breast cancer in women aged 40 to 49 years. Additional inclusion criteria were applied for each risk factor. DATA EXTRACTION Data on participants, study design, analysis, follow-up, and outcomes were abstracted. Study quality was rated by using established criteria, and only studies rated as good or fair were included. Results were summarized by using meta-analysis when sufficient studies were available or from the best evidence based on study quality, size, and applicability when meta-analysis was not possible. Data from the Breast Cancer Surveillance Consortium were analyzed with proportional hazards models by using partly conditional Cox regression. Reference groups for comparisons were set at U.S. population means. DATA SYNTHESIS Sixty-six studies provided data for estimates. Extremely dense breasts on mammography or first-degree relatives with breast cancer were associated with at least a 2-fold increase in risk for breast cancer. Prior breast biopsy, second-degree relatives with breast cancer, or heterogeneously dense breasts were associated with a 1.5- to 2.0-fold increased risk; current use of oral contraceptives, nulliparity, and age 30 years or older at first birth were associated with a 1.0- to 1.5-fold increased risk. LIMITATIONS Studies varied by measures, reference groups, and adjustment for confounders, which could bias combined estimates. Effects of multiple risk factors were not considered. CONCLUSION Extremely dense breasts and first-degree relatives with breast cancer were each associated with at least a 2-fold increase in risk for breast cancer in women aged 40 to 49 years. Identification of these risk factors may be useful for personalized mammography screening. PRIMARY FUNDING SOURCE National Cancer Institute.

Use of Medications to Reduce Risk for Primary Breast Cancer: A Systematic Review for the U.S. Preventive Services Task Force

BACKGROUND Medications to reduce risk for primary breast cancer are recommended for women at increased risk; however, use is low. PURPOSE To update evidence about the effectiveness and adverse effects of medications to reduce breast cancer risk, patient use of such medications, and methods for identifying women at increased risk for breast cancer. DATA SOURCES MEDLINE and Cochrane databases (through 5 December 2012), Scopus, Web of Science, clinical trial registries, and reference lists. STUDY SELECTION English-language randomized trials of medication effectiveness and adverse effects, observational studies of adverse effects and patient use, and diagnostic accuracy studies of risk assessment. DATA EXTRACTION Investigators independently extracted data on participants, study design, analysis, follow-up, and results, and a second investigator confirmed key data. Investigators independently dual-rated study quality and applicability using established criteria. DATA SYNTHESIS Seven good- and fair-quality trials indicated that tamoxifen and raloxifene reduced incidence of invasive breast cancer by 7 to 9 cases in 1000 women over 5 years compared with placebo. New results from STAR (Study of Tamoxifen and Raloxifene) showed that tamoxifen reduced breast cancer incidence more than raloxifene by 5 cases in 1000 women. Neither reduced breast cancer-specific or all-cause mortality rates. Both reduced the incidence of fractures, but tamoxifen increased the incidence of thromboembolic events more than raloxifene by 4 cases in 1000 women. Tamoxifen increased the incidence of endometrial cancer and cataracts compared with placebo and raloxifene. Trials provided limited and heterogeneous data on medication adherence and persistence. Many women do not take tamoxifen because of associated harms. Thirteen risk-stratification models were modest predictors of breast cancer. LIMITATION Data on mortality and adherence measures and for women who are nonwhite, are premenopausal, or have comorbid conditions were lacking. CONCLUSION Medications reduced the incidence of invasive breast cancer and fractures and increased the incidence of thromboembolic events. Tamoxifen was more effective than raloxifene but also increased the incidence of endometrial cancer and cataracts. Use is limited by adverse effects and inaccurate methods to identify candidates. PRIMARY FUNDING SOURCE Agency for Healthcare Research and Quality.

Harms of Breast Cancer Screening: Systematic Review to Update the 2009 U.S. Preventive Services Task Force Recommendation.

In 2009, the U.S. Preventive Services Task Force (USPSTF) recommended biennial mammography screening for women aged 50 to 74 years (1) on the basis of evidence of benefits and harms (2, 3). The USPSTF concluded that screening decisions for women aged 40 to 49 years should be based on individual considerations and that evidence was insufficient to assess benefits and harms for those aged 75 years or older (1). Although there is general consensus that mammography screening is beneficial for many women, benefits must be weighed against potential harms to determine the net effect of screening on individual women. Determining the balance between benefits and harms is complicated by several important considerations that are unresolved, including defining and quantifying potential harms; the optimal ages at which to begin and end routine screening; the optimal screening intervals; appropriate use of various imaging modalities, including supplemental technologies; values and preferences of women in regards to screening; and how all of these considerations vary depending on a womans risk for breast cancer. This systematic review updates evidence for the USPSTF on the harms of breast cancer screening, including false-positive mammography results, overdiagnosis, anxiety, pain during procedures, and radiation exposure, and how these adverse effects vary by age, risk factor, screening interval, and screening modality. Systematic reviews of the effectiveness of screening (4), performance characteristics of screening methods (5), and the accuracy of breast density determination and use of supplemental screening technologies (6) are provided in additional reports. Methods Scope, Key Questions, and Analytic Framework The USPSTF determined the scope and key questions for this review by using established methods (7, 8). A standard protocol was developed and publicly posted on the USPSTF Web site. A technical report further describes the methods and includes search strategies and additional information (4). Investigators created an analytic framework outlining the key questions, patient populations, interventions, and outcomes reviewed (Appendix Figure 1). Key questions include the harms of routine breast cancer screening and how they differ by age, risk factor, screening interval, and screening modality (mammography [film, digital, or tomosynthesis], magnetic resonance imaging [MRI], and ultrasonography). Harms include false-positive and false-negative mammography results, overdiagnosis, anxiety and other psychological responses, pain during procedures, and radiation exposure. Overdiagnosis refers to women receiving a diagnosis of ductal carcinoma in situ (DCIS) or invasive breast cancer when they have abnormal lesions that are unlikely to become clinically evident during their lifetime in the absence of screening. Overdiagnosed women may be harmed by unnecessary procedures and treatments as well as by the burden of receiving a cancer diagnosis. Appendix Figure 1. Analytic framework and key questions. KQ = key question. * Excludes women with preexisting breast cancer; clinically significant BRCA1 or BRCA2 mutations, Li-Fraumeni syndrome, Cowden syndrome, hereditary diffuse gastric cancer, or other familial breast cancer syndrome; high-risk lesions (ductal carcinoma in situ, lobular carcinoma in situ, atypical ductal hyperplasia, or atypical lobular hyperplasia); or previous large doses of chest radiation (20 Gy) before age 30 y. False-positive and false-negative mammography results, biopsy recommendations due to false-positive mammography results, overdiagnosis and resulting overtreatment, anxiety, pain, and radiation exposure. Family history; breast density; race/ethnicity; menopausal status; current use of menopausal hormone therapy or oral contraceptives; prior benign breast biopsy; and, for women aged >50 y, body mass index. Mammography (film, digital, or tomosynthesis), magnetic resonance imaging, ultrasonography, and clinical breast examination (alone or in combination). The target population for the USPSTF recommendation includes women aged 40 years or older and excludes women with known physical signs or symptoms of breast abnormalities and those at high risk for breast cancer whose surveillance and management are beyond the scope of the USPSTF recommendations for preventive services (preexisting breast cancer or high-risk breast lesions, hereditary genetic syndromes associated with breast cancer, and previous large doses of chest radiation before age 30 years). Risk factors considered in this review are common among women who are not at high risk for breast cancer (9) (described in Appendix Figure 1). Data Sources and Searches A research librarian conducted electronic searches of the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and Ovid MEDLINE through December 2014 for relevant studies and systematic reviews. Searches were supplemented by references identified from additional sources, including reference lists and experts. Studies of harms included in the previous systematic review for the USPSTF (2, 3) were also included. Study Selection Two investigators independently evaluated each study to determine eligibility based on prespecified inclusion criteria. Discrepancies were resolved through consensus. We included recently published systematic reviews; randomized, controlled trials (RCTs); and observational studies of prespecified harms. When available, studies providing outcomes specific to age, risk factors, screening intervals, and screening modalities were preferred over studies providing general outcomes. Studies that were most clinically relevant to practice in the United States were selected; relevance was determined by practice setting, population, date of publication, and use of technologies and therapies in current practice. Studies meeting criteria for high quality and with designs ranked higher in the study designbased hierarchy of evidence were emphasized because they are less susceptible to bias (for example, RCTs were chosen over observational studies). Data Extraction and Quality Assessment Details of the study design, patient population, setting, screening method, interventions, analysis, follow-up, and results were abstracted by one investigator and confirmed by another. Two investigators independently applied criteria developed by the USPSTF (7, 8) to rate the quality of each RCT, cohort study, casecontrol study, and systematic review as good, fair, or poor; criteria to rate studies with other designs included in this review are not available. Discrepancies were resolved through consensus. Data Synthesis Studies meeting inclusion criteria were qualitatively synthesized. Most studies in this review had designs for which quality rating criteria are not available, which limited data synthesis. When possible, we assessed the aggregate internal validity (quality) of the body of evidence for each key question (good, fair, or poor) by using methods developed by the USPSTF based on the number, quality, and size of studies; consistency of results between studies; and directness of evidence (7, 8). Role of the Funding Source This research was funded by the Agency for Healthcare Research and Quality (AHRQ) under a contract to support the work of the USPSTF. The investigators worked with USPSTF members and AHRQ staff to develop and refine the scope, analytic frameworks, and key questions; resolve issues during the project; and finalize the report. The AHRQ had no role in study selection, quality assessment, synthesis, or development of conclusions. The AHRQ provided project oversight; reviewed the draft report; and distributed the draft for peer review, including to representatives of professional societies and federal agencies. The AHRQ performed a final review of the manuscript to ensure that the analysis met methodological standards. The investigators are solely responsible for the content and the decision to submit the manuscript for publication. Results Of the 12004 abstracts identified by searches and other sources, 59 studies met inclusion criteria for key questions in this report, including 10 systematic reviews of 134 studies and 49 additional studies (Appendix Figure 2). Appendix Figure 2. Summary of evidence search and selection. RCT = randomized, controlled trial. * Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews. False-Positive Mammography Results Two new observational studies estimated the cumulative probability of false-positive results after 10 years of screening with film and digital mammography, based on data from the Breast Cancer Surveillance Consortium, a large population-based database in the United States (Appendix Table 1) (10, 11). When screening began at age 40 years, the cumulative probability of receiving at least 1 false-positive mammography result after 10 years was 61% (95% CI, 59% to 63%) with annual screening and 42% (CI, 41% to 43%) with biennial screening (10). Estimates were similar when screening began at age 50 years. The cumulative probability of receiving a biopsy recommendation due to a false-positive mammography result after 10 years of screening was 7% (CI, 6% to 8%) with annual screening versus 5% (CI, 4% to 5%) with biennial screening for women who initiated screening at age 40 years and 9% (CI, 7% to 12%) with annual screening versus 6% (CI, 6% to 7%) with biennial screening for those who began at age 50 years. Appendix Table 1. U.S. Studies of Cumulative False-Positive Mammography and Biopsy Results In a separate analysis, rates of false-positive mammography results were highest among women receiving annual mammography who had extremely dense breasts and either were aged 40 to 49 years (65.5%) or used combination hormone therapy (65.8%) (11). The highest rates of biopsy due to false-positive mammography results were related to similar characteristics and ranged from 12% to 1

Systemic Pharmacologic Therapies for Low Back Pain: A Systematic Review for an American College of Physicians Clinical Practice Guideline.

Low back pain is one of the most frequently encountered conditions in clinical practice (1, 2). The most commonly prescribed medications for low back pain are nonsteroidal anti-inflammatory drugs (NSAIDs), skeletal muscle relaxants, antidepressants, and opioids (35); benzodiazepines, systemic corticosteroids, and antiseizure medications are also prescribed (3). Patients often use over-the-counter acetaminophen and NSAIDs. A 2007 guideline (6) and associated systematic review (7) from the American College of Physicians (ACP) and American Pain Society (APS) found evidence to support the use of acetaminophen and NSAIDs as first-line pharmacologic options for low back pain; secondary options were skeletal muscle relaxants, benzodiazepines, and antidepressants. New evidence and medications are now available. Here, we review the current evidence on benefits and harms of medications for low back pain. This article has been used by ACP to update a clinical practice guideline, also in this issue. Methods Detailed methods and data for our review, including the analytic framework, additional medications (topical capsaicin and lidocaine), nonpharmacologic therapies (addressed in a separate article) (8), search strategies, inclusion criteria, data extraction and quality-rating methods, and additional outcomes (for example, quality of life, global improvement, and patient satisfaction), are available in the full report (9). The protocol was developed by using a standardized process (10) with input from experts and the public and is registered in the PROSPERO database (11). This article addresses the key question, what are the comparative benefits and harms of different systemic pharmacologic therapies for acute or chronic nonradicular low back pain, radicular low back pain, or spinal stenosis? Data Sources and Searches A research librarian searched Ovid MEDLINE (January 2007 through April 2015), the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews (through April 2015). We used the prior ACP/APS review (12) to identify earlier studies. Updated searches were performed through November 2016. We also reviewed reference lists and searched ClinicalTrials.gov. Study Selection Two investigators independently reviewed abstracts and full-text articles against prespecified eligibility criteria. The population was adults with nonradicular or radicular low back pain of any duration (categorized as acute [<4 weeks], subacute [4 to 12 weeks], and chronic [12 weeks]). Excluded conditions were low back pain due to cancer, infection, inflammatory arthropathy, high-velocity trauma, or fracture; low back pain during pregnancy; and presence of severe or progressive neurologic deficits. We evaluated acetaminophen, NSAIDs, opioids, tramadol and tapentadol, antidepressants, skeletal muscle relaxants, benzodiazepines, corticosteroids, and antiseizure medications versus placebo, no treatment, or other therapies. We also evaluated the combination of 2 medications versus 1 medication alone. Outcomes were long-term (1 year) or short-term (6 months) pain or function, mood (for antidepressants), risk for surgery (for corticosteroids), and harms. Given the large number of medications addressed, we included systematic reviews of randomized trials (13, 14). For each medication, we selected the most recent, most relevant, and highest-quality comprehensive systematic review based on a validated assessment tool (14, 15). If more than 1 good-quality systematic review was available, we preferentially selected updates of those used in the ACP/APS review. We supplemented systematic reviews with additional trials. Although we did not include systematic reviews identified in update searches, we checked reference lists for additional studies. We excluded nonEnglish-language articles and abstract-only publications. Data Extraction and Quality Assessment One investigator extracted study data, and a second verified accuracy. For systematic reviews, we abstracted details about inclusion criteria, search strategy, databases searched, search dates, number and characteristics of included studies, quality assessment methods and ratings, synthesis methods, and results. For randomized trials, we abstracted details about the setting, sample size, eligibility criteria, population characteristics, treatment characteristics, results, and funding source. Two investigators independently assessed the quality of each study as good, fair, or poor using criteria developed by the U.S. Preventive Services Task Force (for randomized trials) (16) and AMSTAR (A Measurement Tool to Assess Systematic Reviews) (14). For primary studies included in systematic reviews, we used both the quality ratings and the overall grade (for example, good, fair, or poor, or high or low) as determined in the reviews. We classified the magnitude of effects as small/slight, moderate, or large/substantial based on the definitions in the ACP/APS review (Table 1) (6, 17). We also reported risk estimates based on the proportion of patients achieving successful pain or function outcomes (for example, >30% or >50% improvement). Table 1. Definitions for Magnitude of Effects, Based on Mean Between-Group Differences Data Synthesis and Analysis We synthesized data qualitatively for each medication, stratified according to the duration of symptoms (acute, subacute, or chronic) and presence or absence of radicular symptoms. We reported meta-analysis results from systematic reviews. When statistical heterogeneity was present, we examined the degree of inconsistency and evaluated subgroup and sensitivity analyses. We did not conduct an updated meta-analysis; rather, we qualitatively examined whether results of new studies were consistent with pooled or qualitative findings from prior systematic reviews. Qualitative assessments were based on whether the findings from the new studies were in the same direction as the prior systematic reviews and whether the magnitude of effects was similar; when prior meta-analyses were available, we analyzed whether the estimates and CIs from new studies were encompassed in the CIs from pooled estimates. We assessed the strength of evidence (SOE) for each body of evidence as high, moderate, low, or insufficient based on aggregate study quality, precision, consistency, and directness (18). Role of the Funding Source The Agency for Healthcare Research and Quality (AHRQ) of the U.S. Department of Health and Human Services funded this review. AHRQ staff assisted in developing the scope and key questions. The AHRQ had no role in study selection, quality assessment, or synthesis. Results Literature Search The search and selection of articles are summarized in the Figure. Database searches found 2847 potentially relevant articles. After dual review of abstracts and titles, we selected 746 articles for full-text dual review; 46 publications met inclusion criteria. Quality ratings are summarized in Supplement Tables 1 and 2. Supplement. Data Supplement. Figure. Summary of evidence search and selection. ACP = American College of Physicians; AHRQ = Agency for Healthcare Research and Quality; APS = American Pain Society; NSAID = nonsteroidal anti-inflammatory drug; RCT = randomized, controlled trial; SR = systematic review. * Cochrane databases include the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews. Other sources include prior reports, reference lists of relevant articles, and systematic reviews. Publications may be included or excluded for multiple reasons. Acetaminophen Ten trials evaluated acetaminophen; 9 of these (sample sizes, 39 to 456) were included in the ACP/APS review (19). We identified 1 additional large (n= 1643), good-quality, placebo-controlled trial (20). Six trials compared acetaminophen with NSAIDs and were included in a systematic review of NSAIDs (Supplement Table 3) (21, 22). Along with the new trial, 3 others (2325) were rated good- or high-quality. For acute low back pain, 1 new trial found no differences between 4 weeks or less of scheduled or as-needed acetaminophen (about 4 g/d) and placebo in pain (differences, 0.20 point on a 0- to 10-point scale), function (differences, 0.60 point on the 0- to 24-point RolandMorris Disability Questionnaire [RDQ]), or risk for serious adverse events (about 1% in each group) after 12 weeks (Supplement Table 4) (20). One trial of acetaminophen versus no treatment included in the ACP/APS review (26) also found no differences. We found no difference between acetaminophen and NSAIDs in pain intensity (standardized mean difference [SMD], 0.21 [95% CI, 0.02 to 0.43]) at 3 weeks or less based on 3 low-quality trials, although estimates favored NSAIDs (22). Acetaminophen had a lower risk for adverse events than NSAIDs (relative risk [RR], 0.57 [CI, 0.36 to 0.89]). Evidence was insufficient to determine the effects of acetaminophen versus various nonpharmacologic therapies (24, 27, 28) or amitriptyline (25); each comparison was evaluated in 1 trial with methodological shortcomings. No study evaluated acetaminophen for chronic or radicular low back pain. NSAIDs Seventy trials evaluated NSAIDs; 57 were in the ACP/APS review. Sixty-five trials (total n= 11237; sample sizes, 20 to 690), 28 of which were high-quality, were included in a systematic review (Supplement Table 3) (22). We identified 5 additional trials (n= 54 to 525) (Supplement Table 5) (2933). One trial was rated good-quality (31), and 4 were rated fair-quality (29, 30). For acute back pain, 1 systematic review (22) found that NSAIDs were associated with greater mean improvements in pain intensity than placebo (4 trials: weighted mean difference, 8.39 points on a 0- to 100-point scale [CI, 12.68 to 4.10 points]; chi-square test, 3.47 points; P> 0.10) (3437). One additional trial (n= 171) reported consistent findings (29). Three trials in this review found no differences between an NSAID and placeb

Systematic Review: Comparative Effectiveness of Medications to Reduce Risk for Primary Breast Cancer

Nelson and colleagues reviewed trials and observational studies to summarize the benefits and harms of tamoxifen citrate, raloxifene, and tibolone in reducing the risk for primary breast cancer in ...

Urinary biomarkers for diagnosis of bladder cancer: A systematic review and meta-analysis

Bladder cancer is the fourth most commonly diagnosed cancer in U.S. men and the 10th most commonly diagnosed cancer in U.S. women (1). Standard methods for diagnosis of bladder cancer involve cytologic evaluation of urine, imaging tests, and cystoscopy (2, 3). Because cystoscopy is uncomfortable and costly, alternative diagnostic methods have been sought. Urine-based biomarkers have been developed as potential alternatives or adjuncts to standard tests for the initial diagnosis of bladder cancer or identification of recurrent disease (4). Six urinary biomarkers have been approved by the U.S. Food and Drug Administration (FDA) for diagnosis or surveillance of bladder cancer: quantitative nuclear matrix protein 22 (NMP22) (Alere NMP22 [Alere]), qualitative NMP22 (BladderChek [Alere]), qualitative bladder tumor antigen (BTA) (BTA stat [Polymedco]), quantitative BTA (BTA TRAK [Polymedco]), fluorescence in situ hybridization (FISH) (UroVysion [Abbott Molecular]), and fluorescent immunohistochemistry (ImmunoCyt [Scimedx]). The qualitative NMP22 and BTA tests can be performed as point-of-care tests, and the others are performed in a laboratory. One additional test, Cxbladder (Pacific Edge Diagnostics USA), is a laboratory-developed test that does not require FDA approval. Other biomarkers have been developed but are not FDA-approved. The purpose of this study was to systematically review the evidence on the comparative accuracy of urinary biomarkers for diagnosis of bladder cancer. It was done as part of a larger review (5) on the evaluation and treatment of nonmuscle-invasive bladder cancer that was nominated to the Agency for Healthcare Research and Quality (AHRQ) by the American Urological Association for use in updating its guidelines. Methods Detailed methods and data for this review, including the analytic framework, key questions, search strategies, inclusion criteria, study data extraction, and quality ratings, are available in the full report (5). The protocol was developed using a standardized process (6) with input from experts and the public and is registered in the PROSPERO database (7). This article focuses on the accuracy of urinary biomarkers for initial diagnosis of bladder cancer or for diagnosis of recurrent disease, including any variance in diagnostic accuracy based on tumor characteristics, patient characteristics, or the nature of presenting signs or symptoms. Data Sources and Searches A research librarian searched multiple electronic databases, including Ovid MEDLINE (January 1990 through June 2015), the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews (through June 2015). We also reviewed reference lists and searched ClinicalTrials.gov. Study Selection Two investigators independently reviewed abstracts and full-text articles against prespecified eligibility criteria. We included cross-sectional and cohort studies on the diagnostic accuracy of urinary biomarkers in adults who had signs or symptoms of bladder cancer or were undergoing surveillance for recurrent disease after treatment. We focused on urinary biomarkers approved by the FDA for the diagnosis of bladder cancer (quantitative or qualitative NMP22, qualitative or quantitative BTA, FISH, and ImmunoCyt) or classified by the FDA as a laboratory-developed test (Cxbladder). We excluded studies that used a casecontrol design; studies that did not evaluate the diagnostic accuracy of biomarkers against standard diagnostic methods (cystoscopy and histopathology); and studies on the accuracy of biomarkers for screening in assessing prognosis, guiding therapy, or monitoring response to treatment. Data Extraction and Quality Assessment One investigator extracted details about the setting, tests evaluated, definition of a positive test result, study design, reference standard, inclusion criteria, population characteristics, proportion found to have bladder cancer, bladder cancer stage and grade, results, and funding sources. We constructed 22 tables with the number of true-positive, false-positive, true-negative, and false-negative results from published sample sizes, prevalence, sensitivity, and specificity. A second investigator verified extractions for accuracy. Two investigators independently assessed the risk of bias for each study as low, moderate, or high using criteria adapted from QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2) (8). Discrepancies were resolved through discussion and consensus. Data Synthesis and Analysis We performed meta-analyses for sensitivity and specificity using a bivariate logistic mixed-effects model (9) with SAS, version 10.0 (SAS Institute) (10). We assumed random effects with a bivariate normal distribution and measured statistical heterogeneity with the random-effects variance (2). When few studies were available for an analysis, we used the moment estimates of correlation between sensitivity and specificity in the bivariate model. We calculated positive and negative likelihood ratios (LRs) using the summarized sensitivity and specificity (11, 12). Because studies of a particular biomarker generally used the same definition for a positive test result, we did not plot summary receiver-operating characteristic curves (13). For head-to-head comparisons, we used the same bivariate logistic mixed-effects model, with an added indicator variable for the tests. We conducted analyses for each biomarker by using data from all patients and data stratified according to whether testing was performed for initial diagnosis (evaluation of symptoms) or diagnosis of recurrence (surveillance). We also performed analyses stratified by study design features (such as retrospective or prospective or use of a prespecified threshold to define a positive test result), risk of bias (overall and whether the study performed blinding to the results of the index test), the country in which the study was conducted, and tumor grade and stage (14). We assessed the strength of evidence (SOE) for each body of evidence as high, moderate, low, or insufficient based on aggregate study quality, precision, consistency, and directness. Role of the Funding Source This project was funded under contract HHSA290201200014I from the AHRQ, U.S. Department of Health and Human Services. AHRQ staff assisted in developing the scope and key questions. The AHRQ had no role in study selection, quality assessment, or synthesis. Results The literature flow diagram (Figure 1) summarizes the search and selection of articles. Database searches resulted in 4358 potentially relevant articles. After dual review of abstracts and titles, we selected 262 articles for full-text dual review and determined that 57 studies (in 60 publications) met our inclusion criteria (Appendix Table 1) (15-74). Nineteen studies evaluated quantitative NMP22, 4 evaluated qualitative NMP22, 23 evaluated qualitative BTA, 4 evaluated quantitative BTA, 10 evaluated FISH, 13 evaluated ImmunoCyt, and 1 evaluated Cxbladder. Sample sizes ranged from 26 to 3916, mean age ranged from 54 to 77 years, the proportion of male patients ranged from 57% to 88%, and the proportion diagnosed with bladder cancer ranged from 3% to 81%. Eight studies focused on diagnostic testing for signs and symptoms suggestive of bladder cancer, 16 focused on surveillance of previously treated bladder cancer, and 19 evaluated mixed populations. Forty-three studies were conducted in the United States or Europe. We rated 2 studies as having low risk of bias (20, 21), 3 as having high risk of bias (25, 62, 68), and the remainder as having medium risk of bias. Frequent methodological shortcomings were failure to report blinded interpretation of the reference standard, failure to report enrollment of a random or consecutive sample of patients, or failure to report predefined criteria for a positive test result. Figure 1. Summary of evidence search and selection. * Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews. Includes prior reports, reference lists of relevant articles, and systematic reviews. Appendix Table 1. Biomarker Study Characteristics Appendix Table 1 Continued Appendix Table 1 Continued Appendix Table 1 Continued Quantitative NMP22 Sensitivity of quantitative NMP22 was 0.69 (95% CI, 0.62 to 0.75), and specificity was 0.77 (CI, 0.70 to 0.83) (19 studies), for a positive LR of 3.05 (CI, 2.28 to 4.10) and a negative LR of 0.40 (CI, 0.32 to 0.50) (Appendix Figure 1). Exclusion of 2 studies that used a cutoff other than >10 U/mL for a positive test result (18, 37) resulted in similar sensitivity and specificity. Diagnostic accuracy was similar for evaluation of symptoms and for surveillance. Excluding 1 study with high risk of bias (68) and restricting the analysis to prospective studies, those conducted in the United States or Europe, or those that used a prespecified threshold for a positive test result had little effect on pooled estimates. Restricting the analysis to 3 studies with blinded reference standard interpretation resulted in higher specificity (0.89 [CI, 0.78 to 0.95]) (15, 42, 58). Appendix Figure 1. Sensitivity and specificity of quantitative NMP22. NMP22 = nuclear matrix protein 22; TN = true-negative; TP = true-positive. Qualitative NMP22 Sensitivity of qualitative NMP22 was 0.58 (CI, 0.39 to 0.75), and specificity was 0.88 (CI, 0.78 to 0.94) (4 studies), for a positive LR of 4.89 (CI, 3.23 to 7.40) and a negative LR of 0.48 (CI, 0.33 to 0.71) (Appendix Figure 2) (20, 21, 23, 37). Restricting the analysis to 2 studies with low risk of bias resulted in similar estimates (sensitivity, 0.53 [CI, 0.29 to 0.75]; specificity, 0.87 [CI, 0.74 to 0.94]) (20, 21). Subgroup and sensitivity analyses were limited by small numbers of studies. Appendix Figure 2. Sensitivity and specificity of qualitative NMP22. NMP22 = nuclear matrix protein 22; TN = true-negative; TP = true-positive. Qualitative BTA Sensitivity of qualit

Intravesical Therapy for the Treatment of Nonmuscle Invasive Bladder Cancer: A Systematic Review and Meta-Analysis

Purpose: We systematically review the benefits and harms of intravesical therapies for nonmuscle invasive bladder cancer. Materials and Methods: Systematic literature searches were performed of Ovid MEDLINE (January 1990 through February 2016), the Cochrane databases and reference lists. Randomized and quasi‐randomized trials of intravesical bacillus Calmette‐Guérin, mitomycin C, gemcitabine, thiotepa, valrubicin, doxorubicin, epirubicin and interferon vs transurethral bladder tumor resection alone, and head‐to‐head trials of intravesical therapies were selected. Data were pooled using a random effects model. Results: Overall 39 trials evaluated adjuvant intravesical therapy vs transurethral bladder tumor resection alone. Bacillus Calmette‐Guérin was associated with a decreased risk of bladder cancer recurrence (3 trials, RR 0.56, 95% CI 0.43–0.71) and progression (4 trials, RR 0.39, 95% CI 0.24–0.64) (strength of evidence low). Mitomycin C, doxorubicin, epirubicin and thiotepa were also associated with a decreased risk of recurrence, with no difference in risk of progression (strength of evidence low). There were 55 trials that compared one intravesical therapy agent against another. There were no differences between bacillus Calmette‐Guérin vs mitomycin C in recurrence risk (RR 0.95, 95% CI 0.81–1.11), but bacillus Calmette‐Guérin was associated with a decreased risk of recurrence in the subgroup of trials of maintenance regimens (RR 0.79, 95% CI 0.71–0.87, strength of evidence low). Bacillus Calmette‐Guérin was associated with a lower recurrence risk vs doxorubicin, epirubicin, interferon alpha‐2a, bacillus Calmette‐Guérin plus interferon alpha‐2b, and thiotepa (strength of evidence low to moderate). Bacillus Calmette‐Guérin was associated with higher rates of local and systemic adverse events than other intravesical agents (strength of evidence low). Head‐to‐head trials showed no clear differences between standard and lower doses of bacillus Calmette‐Guérin in recurrence, progression or mortality risk (strength of evidence low). Limited evidence suggested that bacillus Calmette‐Guérin maintenance regimens are associated with reduced recurrence risk vs no further intravesical therapy in responders to induction therapy (strength of evidence low). Conclusions: For nonmuscle invasive bladder cancer several intravesical therapies are associated with a decreased risk of recurrence vs transurethral bladder tumor resection alone. Bacillus Calmette‐Guérin is the only agent associated with a decreased progression risk vs transurethral bladder tumor resection alone, but may be associated with a higher risk of adverse events than other intravesical therapies, indicating trade‐offs between potential benefits and harms.

Treatment of muscle‐invasive bladder cancer: A systematic review

There is uncertainty regarding the use of bladder‐sparing alternatives to standard radical cystectomy, optimal lymph node dissection techniques, and optimal chemotherapeutic regimens. This study was conducted to systematically review the benefits and harms of bladder‐sparing therapies, lymph node dissection, and systemic chemotherapy for patients with clinically localized muscle‐invasive bladder cancer. Systematic literature searches of MEDLINE (from 1990 through October 2014), the Cochrane databases, reference lists, and the ClinicalTrials.gov Web site were performed. A total of 41 articles were selected for review. Bladder‐sparing therapies were found to be associated with worse survival compared with radical cystectomy, although the studies had serious methodological shortcomings, findings were inconsistent, and only a few studies evaluated currently recommended techniques. More extensive lymph node dissection might be more effective than less extensive dissection at improving survival and decreasing local disease recurrence, but there were methodological shortcomings and some inconsistency. Six randomized trials found cisplatin‐based combination neoadjuvant chemotherapy to be associated with a decreased mortality risk versus cystectomy alone. Four randomized trials found adjuvant chemotherapy to be associated with decreased mortality versus cystectomy alone, but none of these trials reported a statistically significant effect. There was insufficient evidence to determine optimal chemotherapeutic regimens. Cancer 2016;122:842–51.

Comparative Effectiveness of Fluorescent Versus White Light Cystoscopy for Initial Diagnosis or Surveillance of Bladder Cancer on Clinical Outcomes: Systematic Review and Meta-Analysis

Purpose: We systematically reviewed the comparative effectiveness of fluorescent vs white light cystoscopy on bladder cancer clinical outcomes. Materials and Methods: Systematic literature searches of Ovid MEDLINE® (January 1990 through September 2015), Cochrane databases and reference lists were performed. A total of 14 randomized trials of fluorescent cystoscopy using 5‐aminolevulinic acid or hexaminolevulinic acid vs white light cystoscopy for the diagnosis of initial or recurrent bladder cancer that reported bladder cancer recurrence, progression, mortality and harms were selected for review. Results: Fluorescent cystoscopy was associated with a decreased risk of bladder cancer recurrence vs white light cystoscopy at short‐term (less than 3 months, 10 trials, RR 0.59, 95% CI 0.40 to 0.88, I2=69%), intermediate‐term (3 months to less than 1 year, 6 trials, RR 0.70, 95% CI 0.56 to 0.88, I2=19%) and long‐term followup (1 year or more, 12 trials, RR 0.81, 95% CI 0.70 to 0.93, I2=49%). However, the findings were inconsistent, and potentially susceptible to performance and publication bias (strength of evidence low). There were no differences between cystoscopic methods in risk of mortality (3 trials, RR 1.28, 95% CI 0.55 to 2.95, I2=41%) (strength of evidence low) or progression (9 trials, RR 0.74, 95% CI 0.52 to 1.03, I2=0%) (strength of evidence moderate). Estimates for short‐term recurrence (6 trials, RR 0.62, 95% CI 0.38 to 1.00), long‐term recurrence (7 trials, RR 0.75, 95% CI 0.62 to 0.92) and progression (4 trials, RR 0.51, 95% CI 0.28 to 0.96) were statistically significant in the subgroup of trials that used hexaminolevulinic acid, but there were no statistically significant interactions based on the photosensitizer used. Fluorescent cystoscopy was not associated with a decreased risk of long‐term recurrence in 3 trials that used methods to reduce performance bias with initial cystoscopy (RR 0.96, 95% CI 0.79 to 1.18, I2=36%). Data on harms were sparse. Conclusions: Fluorescent cystoscopy was associated with a reduced risk of bladder cancer recurrence vs white light cystoscopy. However, additional trials that adequately guard against performance bias are needed to confirm these findings. Fluorescent cystoscopy with hexaminolevulinic acid may be associated with a decreased risk of progression, but more studies with long‐term followup are needed to better understand the effects of the photosensitizer used on progression.

Management of Suspected Opioid Overdose With Naloxone in Out-of-Hospital Settings: A Systematic Review

Since 2000, the rate of drug overdose deaths involving opioids has increased 4-fold (1, 2). Overdose is now the leading cause of injury-related death in the United States (3). In 2015, the number of overdose deaths involving prescription or illicit opioids exceeded 33000, the highest number on record (2). Opioid overdose is frequently treated with naloxone in out-of-hospital settings by emergency medical services (EMS) personnel and laypersons. Although recommendations, guidelines, and protocols are available to inform use of naloxone in out-of-hospital settings, uncertainties exist with regard to the optimal dosing and route of administration and management after successful reversal of opioid overdose (46). A recent concern is whether current dosing guidelines are sufficient for reversing overdose involving highly potent synthetic opioids, such as fentanyl and fentanyl analogues (2, 711). The purpose of this systematic review was to synthesize the evidence on 1) the effects of route of administration and dosing of naloxone in persons with suspected opioid overdose in out-of-hospital settings on mortality, reversal of overdose symptoms, and harms, and 2) the need for transport to a health care facility after naloxone reversal. This review was conducted as part of a systematic review that was nominated to the Agency for Healthcare Research and Quality (AHRQ) by the National Highway Traffic Safety Administration. Methods Detailed methods and data for this review, including the analytic framework, key questions, search strategies, inclusion criteria, study data extraction, and quality ratings, are available in the full report (12). The protocol was developed using a standardized process (13) with input from experts and the public and is registered in the PROSPERO database (14). The analytic framework used to guide this review is shown in Figure 1. Figure 1. Analytic framework. * Patients with confirmed or suspected opioid overdose who exhibit altered mental status, miosis, or respiratory distress and are treated in out-of-hospital settings by emergency medical services personnel. Administration of naloxone hydrochloride via intranasal, intravenous, intramuscular, or subcutaneous injection (including naloxone autoinjector). Question 1 addresses comparisons involving route of administration and dose. Question 2 addresses comparisons involving dose titration to varying degrees of return of consciousness (intermediate outcome). We addressed the following key questions: 1. For patients with confirmed or suspected opioid overdose, what are the comparative benefits and harms of out-of-hospital administration of naloxone using intravenous, intramuscular, subcutaneous, and intranasal routes of administration? 1a. For patients with confirmed or suspected opioid overdose who receive naloxone in out-of-hospital settings, what are the comparative benefits and harms of different intravenous, intramuscular, subcutaneous, or intranasal doses of naloxone? 2. For patients with confirmed or suspected opioid overdose in out-of-hospital settings, what are the comparative benefits and harms of titration of naloxone until the patient resumes sufficient spontaneous respiratory effort versus until the patient regains consciousness? 3. For patients with confirmed or suspected opioid overdose in out-of-hospital settings treated with multiple doses of naloxone (including those who do not improve after an initial dose of intranasal naloxone), what are the effects on benefits and harms of differences in the timing of repeated dosing? 4. For patients with confirmed or suspected opioid overdose in out-of-hospital settings who regain sufficient spontaneous respiratory effort and are alert and oriented after naloxone administration, what are the benefits and harms of transport to a health care facility versus nontransport? Data Sources and Searches A research librarian searched multiple electronic databases, including Ovid MEDLINE (1946 through September 2017), PsycINFO, the Cochrane Central Register of Controlled Trials, and CINAHL. We also reviewed reference lists, searched ClinicalTrials.gov (through September 2017), contacted representatives of federal agencies involved in naloxone or opioid overdose research, reviewed medical and statistical reviews on the U.S. Food and Drug Administrations (FDA) Center for Drug Evaluation and Research Web site, and reviewed materials presented at a recent FDA meeting (15) on naloxone dosing (1621). Study Selection Two investigators independently reviewed abstracts and full-text articles against prespecified eligibility criteria. We included randomized controlled trials (RCTs) and cohort studies comparing different routes of administration, doses, or dosing strategies for naloxone and studies on the effects of transport or nontransport after successful reversal of opioid overdose with naloxone in out-of-hospital settings. Naloxone could be administered by EMS personnel, other health care providers, or laypersons. We also included studies on dosing and routes of administration in emergency department (ED) settings. We included uncontrolled longitudinal studies of patients who were successfully treated for opioid overdose with naloxone in the field and were not transported to a health care facility; this was a protocol modification due to no controlled studies of transport versus nontransport. Outcomes were mortality, reversal of overdose symptoms (based on adequate spontaneous respiratory effort or level of consciousness), time to reversal of symptoms, recurrence of symptoms, cardiac or respiratory arrest, other clinical sequelae of overdose (such as noncardiogenic pulmonary edema), function, quality of life, health care use, and harms (such as drug withdrawal, combativeness, or injury to the person administering naloxone). For key question 4, additional outcomes were rates of linkage to treatment for opioid use disorder and subsequent opioid overdoses. Data Extraction and Quality Assessment One investigator extracted details about the design, year, setting, country, sample size, eligibility criteria, population and clinical characteristics, intervention characteristics (route of administration, dose or concentration, time to initial and repeated dosing, and training and background of personnel administering the drug), funding source, and results. A second investigator verified extractions for accuracy. Two investigators independently assessed risk of bias for each study as low, moderate, or high using criteria adapted from the Methods Guide for Effectiveness and Comparative Effectiveness Reviews (13) and the U.S. Preventive Services Task Force (22). Discrepancies were resolved through discussion and consensus. Data Synthesis and Analysis We constructed evidence tables with study characteristics, results, and risk-of-bias ratings for all included studies and summary tables to highlight the main findings. Given the small number of studies for each key question and clinical and methodological heterogeneity of the studies, we determined that meta-analysis was not indicated and synthesized studies qualitatively. We graded the strength of evidence (SOE) for each key question and comparison for prioritized clinical outcomes (mortality, time to reversal of symptoms, recurrence of symptoms, respiratory or cardiac arrest, rates and severity of drug withdrawal, and combativeness) using the approach described in the Methods Guide for Effectiveness and Comparative Effectiveness Reviews (13). One investigator performed initial SOE assessments, and final ratings were determined by consensus among the entire team. Role of the Funding Source This project was funded under contract no. HHSA290-2015-00009-I from the AHRQ, U.S. Department of Health and Human Services. Staff from the AHRQ assisted in developing the scope and key questions. A representative from the AHRQ served as a Contracting Officers Technical Representative and provided technical assistance during the conduct of the full evidence report and comments on draft versions of the report. The AHRQ did not directly participate in the literature search, determination of study eligibility criteria, data analysis, or interpretation. Results Literature Searches The literature flow diagram (Figure 2) summarizes the search and selection of articles. Database searches resulted in 1934 potentially relevant articles. After dual review of abstracts and titles, we selected 200 articles for full-text dual review and determined that 13 studies met inclusion criteria (Appendix Tables 1, 2, and 3) (2335). No study reported funding from manufacturers of naloxone. Figure 2. Evidence search and selection. * Other sources include prior reports, reference lists, referrals from experts, and gray literature. Appendix Table 1. Characteristics and Results of RCTs Comparing Routes of Naloxone Administration Appendix Table 2. Characteristics and Results of Observational Studies Comparing Routes of Naloxone Administration Appendix Table 3. Deaths and Serious Adverse Events After Nontransport to Health Care Facility After Successful Reversal of Suspected Opioid Overdose With Naloxone Routes of Naloxone Administration Three RCTs (n= 100 to 182) (2325) and 4 cohort studies (n= 93 to 609) (2629) compared different routes of naloxone administration (Appendix Tables 1 and 2). All studies had methodological shortcomings, including unblinded design and baseline between-group differences; the cohort studies also did not adjust for potential confounders or report attrition (risk-of-bias ratings are shown in Appendix Tables 4 and 5). Appendix Table 4. Risk-of-Bias Ratings of RCTs Appendix Table 5. Risk-of-Bias Ratings of Observational Studies Two Australian trials compared out-of-hospital intranasal versus intramuscular naloxone administration but evaluated intranasal formulations not used in the United States (23, 24). One trial compared intranasal naloxone (2 mg/mL) versus intramuscular naloxone (2 m