Jennifer Priest Mitchell

Screening for Lung Cancer With Low-Dose Computed Tomography: A Systematic Review to Update the U.S. Preventive Services Task Force Recommendation

BACKGROUND Lung cancer is the leading cause of cancer-related death in the United States. Because early-stage lung cancer is associated with lower mortality than late-stage disease, early detection and treatment may be beneficial. PURPOSE To update the 2004 review of screening for lung cancer for the U.S. Preventive Services Task Force, focusing on screening with low-dose computed tomography (LDCT). DATA SOURCES MEDLINE (2000 to 31 May 2013), the Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (through the fourth quarter of 2012), Scopus, and reference lists. STUDY SELECTION English-language randomized, controlled trials or cohort studies that evaluated LDCT screening for lung cancer. DATA EXTRACTION One reviewer extracted study data about participants, design, analysis, follow-up, and results, and a second reviewer checked extractions. Two reviewers rated study quality using established criteria. DATA SYNTHESIS Four trials reported results of LDCT screening among patients with smoking exposure. One large good-quality trial reported that screening was associated with significant reductions in lung cancer (20%) and all-cause (6.7%) mortality. Three small European trials showed no benefit of screening. Harms included radiation exposure, overdiagnosis, and a high rate of false-positive findings that typically were resolved with further imaging. Smoking cessation was not affected. Incidental findings were common. LIMITATIONS Three trials were underpowered and of insufficient duration to evaluate screening effectiveness. Overdiagnosis, an important harm of screening, is of uncertain magnitude. No studies reported results in women or minority populations. CONCLUSION Strong evidence shows that LDCT screening can reduce lung cancer and all-cause mortality. The harms associated with screening must be balanced with the benefits. PRIMARY FUNDING SOURCE Agency for Healthcare Research and Quality.

Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer in Women: A Systematic Review to Update the U.S. Preventive Services Task Force Recommendation

The U.S. Preventive Services Task Force (USPSTF) recommended in 2005 that women whose family histories are associated with increased risks for clinically significant, or deleterious, mutations in the BRCA1 or BRCA2 gene be referred for genetic counseling and evaluation for mutation testing (1). This recommendation was intended for primary prevention of cancer and applies to women without previous diagnoses of breast or ovarian cancer. Deleterious mutations in the BRCA1 and BRCA2 genes are associated with increased risks for breast, ovarian, fallopian tube, and peritoneal cancer in women and breast cancer in men (2). They are also, to a lesser degree, associated with pancreatic and early-onset prostate cancer, and BRCA2 mutations are associated with melanoma. Mutations in BRCA genes cluster in families exhibiting an autosomal dominant pattern of transmission and account for 5% to 10% of cases of breast cancer overall (3, 4). Specific BRCA mutations, known as founder mutations, occur among certain ethnic groups, including Ashkenazi Jewish (57), black (8), and Hispanic persons (9, 10), and in identified families (1115). Other genes are associated with hereditary susceptibility to breast and ovarian cancer but are not commonly tested, such as PTEN (the Cowden syndrome) and TP53 (the LiFraumeni syndrome) (2, 16). Genetic risk assessment and testing involve determining individual risk for BRCA mutations, followed by selective testing of high-risk persons. Characteristics associated with an increased likelihood ofBRCA mutations (1720) include breast and ovarian cancer in relatives and young age at onset. These and other individual and family characteristics can be used to assess personal mutation risk and the need for referral for additional evaluation. Genetic counseling is the process of identifying and counseling persons at risk for familial or inherited cancer and is recommended before testing (21, 22). Guidelines recommend testing for mutations only when an individual has a personal or family history of cancer suggestive of inherited cancer susceptibility and the results can be adequately interpreted and will aid in management (23). The type of mutation analysis that is required depends on family history. Persons without links to families or groups with known mutations (510, 1214) generally have direct DNA sequencing. For appropriate candidates, interventions to reduce cancer risk include earlier, more frequent, or intensive cancer screening; risk-reducing medications; and risk-reducing surgery, including bilateral mastectomy and salpingo-oophorectomy. This systematic review is an update of a prior review (1, 24, 25) for the USPSTF on the effectiveness and adverse effects of risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women. Its purpose is to evaluate and summarize research addressing specific key questions important to the USPSTF as it considers new recommendations for primary care practice. Methods This research is part of a comprehensive systematic review that includes an additional analysis of studies of the prevalence and penetrance of BRCA mutations that is not included in this manuscript (26). We followed a standard protocol consistent with the Agency for Healthcare Research and Quality (AHRQ) methods for systematic reviews (27). On the basis of evidence gaps identified from a prior review (24, 25), the USPSTF and AHRQ determined the key questions for this update by using the methods of the USPSTF (28). Investigators created an analytic framework incorporating the key questions and outlining the patient populations, interventions, outcomes, and potential adverse effects (Appendix Figure 1). A work plan was externally reviewed and modified. Appendix Figure 1. Analytic framework and key questions. KQ = key question; MRI = magnetic resonance imaging. * Clinically significant mutations of the BRCA1 or BRCA2 gene or related syndromes. Testing may be done on the unaffected woman, the relative with cancer, or the relative with the highest risk, as appropriate. No known mutation in relatives and none detected in the patient. Known mutation in relatives but none detected in the patient. Interventions include increased early detection through intensive screening (e.g., earlier and more frequent mammography and breast MRI), risk-reducing medications (tamoxifen and raloxifene), and risk-reducing surgery (mastectomy and salpingo-oophorectomy). The target population includes women without cancer or known BRCA mutations who are seen in clinical settings applicable to U.S. primary care practice, although the ideal candidate for mutation testing could be a male or female relative withcancer. The conditions of interest are mutation carrier status and BRCA-related cancer (predominantly breast, ovarian, fallopian tube, and peritoneal). Although other types of cancer are also considered during familial risk assessment, studies with these cancer outcomes are outside the scope of this review. Data Sources We searched MEDLINE from 2004 to 30 July 2013, the Cochrane Central Register of Controlled Trials and Cochrane Databaseof Systematic Reviews from 2004 through the second quarter of 2013, and Health Technology Assessment during the fourth quarter of 2012 for relevant English-language studies, systematic reviews, and meta-analyses. We manually reviewed reference lists of articles and reviewed citations of key studies by using Scopus. Study Selection Research published in 2004 or later and done in the United States or in populations that receive services and interventions applicable to medical practice in the United States was reviewed. Randomized, controlled trials (RCTs); systematic reviews; prospective and retrospective cohort studies; casecontrol studies; and diagnostic accuracy evaluations were included if they addressed the accuracy of risk assessment methods, outcomes of genetic counseling and testing, and the effectiveness of interventions to reduce BRCA-related cancer and mortality among mutation carriers. Risk assessment methods were included if they were designed to guide referrals to genetic counselors or other genetic specialists and could be used by nonspecialists in genetics in clinical settings (that is, methods that were brief and nontechnical and did not require special training to administer or interpret). Evaluation of comprehensive models used in the practice of genetic counseling was outside the scope of this review, which focuses on primary care practice. Interventions included intensive screening, risk-reducing medications, and risk-reducing surgery. Only risk-reducing medications approved by the U.S. Food and Drug Administration (that is, tamoxifen and raloxifene) were considered, consistent with the scope of the USPSTF. Studies of any design were included if they described potential adverse effects, including inaccurate risk assessment; inappropriate testing; false-positive and false-negative results; false reassurance; incomplete testing; misinterpretation of results; anxiety; cancer-related worry; immediate and long-term harms associated with interventions; and ethical, legal, and social implications. For adverse effects of interventions, studies were included that enrolled women at high risk for BRCA-related cancer regardless of their mutation status. After an initial review of abstracts, we reviewed full-text articles by using additional inclusion criteria. Studies from the prior review that met inclusion criteria for the update were included to build on previous relevant research. Appendix Figure 2 shows the results of the search and selection process. Appendix Figure 2. Summary of evidence search and selection. * Identified from reference lists, hand-searching, suggestions from experts, and other methods. Results are provided in an additional publication (26). Studies that provided data and contributed to the body of evidence were considered to be included. Studies may contribute data to >1 key question. This number includes studies from the prior review as well as studies published since 2004. Data Abstraction and Quality Assessment An investigator abstracted data about the study design and setting; participant characteristics; procedures for data collection; number of participants enrolled and lost to follow-up; methods of exposure and outcome ascertainment; analytic methods, including adjustment for confounders; and outcomes. A second investigator confirmed the accuracy of key data. Two investigators used predefined criteria for RCTs; systematic reviews; and cohort, casecontrol, and diagnostic accuracy studies developed by the USPSTF (28, 29) to rate the quality of studies (good, fair, or poor) and resolved discrepancies by consensus. Quality could not be assessed for many studies with designs that did not have predefined criteria, such as descriptive, cross-sectional, and prepost studies and case series. The applicability of studies was determined using the population, intervention, comparator, outcomes, timing of outcomes measurement, and setting format adapted to this topic (30). Data Synthesis and Analysis Because of heterogeneity across studies, results were not combined in a quantitative meta-analysis. We assessed the aggregate quality of the body of evidence (good, fair, or poor) by using methods that the USPSTF developed on the basis of the number, quality, and size of studies and consistency of results between studies (28). Studies were considered consistent if outcomes were generally in the same direction of effect and ranges of effect sizes were narrow. Role of the Funding Source This research was funded by the AHRQ. Investigators worked with AHRQ staff and USPSTF members to define the scope, analytic framework, and key questions; resolve issues arising during the project; and review the final report to ensure that it met basic methodological standards for systematic reviews. The draft report was reviewed by content experts, USPSTF members, AHR

Preventing Dental Caries in Children <5 Years: Systematic Review Updating USPSTF Recommendation

BACKGROUND AND OBJECTIVE: Screening and preventive interventions by primary care providers could improve outcomes related to early childhood caries. The objective of this study was to update the 2004 US Preventive Services Task Force systematic review on prevention of caries in children younger than 5 years of age. METHODS: Searching Medline and the Cochrane Library (through March 2013) and reference lists, we included trials and controlled observational studies on the effectiveness and harms of screening and treatments. One author extracted study characteristics and results, which were checked for accuracy by a second author. Two authors independently assessed study quality. RESULTS: No study evaluated effects of screening by primary care providers on clinical outcomes. One good-quality cohort study found pediatrician examination associated with a sensitivity of 0.76 for identifying a child with cavities. No new trials evaluated oral fluoride supplementation. Three new randomized trials were consistent with previous studies in finding fluoride varnish more effective than no varnish (reduction in caries increment 18% to 59%). Three trials of xylitol were inconclusive regarding effects on caries. New observational studies were consistent with previous evidence showing an association between early childhood fluoride use and enamel fluorosis. Evidence on the accuracy of risk prediction instruments in primary care settings is not available. CONCLUSIONS: There is no direct evidence that screening by primary care clinicians reduces early childhood caries. Evidence previously reviewed by the US Preventive Services Task Force found oral fluoride supplementation effective at reducing caries incidence, and new evidence supports the effectiveness of fluoride varnish in higher-risk children.