Interventions to Improve Follow-up of Positive Results on Fecal Blood Tests

Colorectal cancer (CRC), the second leading cause of cancer death in the United States (1), is largely preventable with screening (2). Annual or biennial testing for fecal occult blood with high-sensitivity guaiac or fecal immunochemical tests (fecal tests) has proven effectiveness based on randomized controlled trials (RCTs) (3) and is recommended for CRC screening in adults aged 50 to 75 years (4, 5). Fecal immunochemical testing has become the most commonly used method for CRC screening worldwide (5). It is also increasingly used in the United States to maximize population-level screening rates (6). However, the effectiveness of fecal screening tests depends on timely follow-up diagnostic colonoscopy of patients with positive test results; guidelines generally recommend colonoscopy within 1 to 3 months (5, 7, 8). A long interval between a positive test result and colonoscopy can have important implications for CRC prognosis (911). The proportion of test-positive patients having a timely colonoscopy (for example, within 6 months) varies widely and can be lower than 50% (12, 13), compared with 80% to 90% in landmark RCTs (14, 15). Colonoscopy follow-up is complex because it involves the interaction of several levels of care and evaluating the appropriateness of an invasive diagnostic test (16, 17). Several patient-, provider-, and system-level factors have been evaluated to improve follow-up of test-positive patients (13, 1821), but lack of comparative data impedes implementation of potentially effective interventions. Previous reviews of interventions to improve follow-up of fecal tests either have not used a systematic search strategy, have not determined levels of evidence for intervention types, or are outdated (22, 23). Our aims were therefore to identify interventions that have been evaluated for improving rates of follow-up colonoscopy after positive fecal test results and to assess whether evidence supports these interventions. Methods Our protocol is registered in PROSPERO (CRD42016048286). In contrast to the analysis plan stated there, meta-analyses were not done because of study heterogeneity. Reporting conformed to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines (24). Data Sources and Searches We searched the Cochrane Central Register of Controlled Trials, PubMed, and Embase without language restrictions from inception through 30 June 2017 (Appendix Table 1). Conference proceedings were included, and pertinent reference lists were manually searched. Both ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry were searched for unpublished studies, returning 2 relevant trials. We contacted the study investigators: 1 trial was never completed (25), and the investigator of the other trial did not respond (26). Appendix Table 1. Search Strategies Study Selection Two investigators (K.S. and C.B.) independently screened titles and abstracts. We included both randomized and nonrandomized studies that examined asymptomatic adults aged 41 years or older with a positive result on a fecal immunochemical test or fecal occult blood test (FOBT), that primarily used colonoscopy to evaluate those patients, and that reported an intervention focused on improving follow-up. Two investigators then independently evaluated the full-text articles. Interventions covering more than 1 cancer type were included, but only the effect on fecal blood test follow-up was considered. Disagreements were resolved by consensus. Data Extraction and Quality Assessment Two investigators extracted data, using as the primary outcome measure the absolute difference between the intervention and control groups in the proportion of patients with positive fecal test results who had completed a colonoscopy by 180 days after the test. We chose 180 days because more than 90% of follow-up colonoscopies occur within that interval and longer delays have clinical implications (11, 13). Other periods were used if 180-day results were not available or the follow-up interval was not specified. Given that most patients had colonoscopy and colonoscopy is the examination of choice after a positive finding from a fecal test (27), all results were presented as the proportion of test-positive patients receiving a follow-up colonoscopy. When necessary, we contacted study authors to specify screening versus symptomatic patients and the absolute numbers of participants who had colonoscopy. One study was excluded because it included symptomatic patients (28), and another because the intervention was unclear without additional information (29). One author provided additional results not available in the report (30); 4 authors of included studies either did not respond or no longer had access to the study data set (3135). Two reviewers independently assigned each study a level for risk of bias (low, medium, high, or very high) for the absolute increase in colonoscopy completion (Appendix Table 2) (36, 37). Randomized controlled trials were considered to be at low risk of bias but were upgraded to moderate or high risk if they had flaws in recruitment, randomization, or follow-up. Observational or nonrandomized interventional studies were considered to be at high risk of bias and were downgraded to moderate risk if their design and measurement were particularly strong. Conversely, they were upgraded to very high risk if important flaws existed in their eligibility criteria, measurement, and loss to follow-up. Appendix Table 2. Criteria Used for Determining Risk of Bias of Individual Studies* Data Synthesis and Analysis Primary investigations were organized by type of intervention (patient-, provider-, or system-level). We first used a descriptive approach to summarize study characteristics and outcomes for each category. A 10percentage point increase in colonoscopy completion was considered to be clinically important (9). Stata, version 14 (StataCorp), was used to calculate the absolute change in colonoscopy completion with CIs and P values when not available in included articles. Two investigators (K.S. and J.L.) independently assigned overall strength-of-evidence ratings to each category using criteria from the Agency for Healthcare Research and Quality based on risk of bias, consistency, directness, and precision (36). Differences were resolved by consensus and input from a third reviewer (D.C.). Overall strength of evidence for each type of intervention was rated as high, moderate, or low on the basis of the level of confidence that the evidence reflected the true effect and the likelihood that future research will change the estimate. Role of the Funding Source The National Cancer Institute funded this study through the PROSPR (Population-based Research Optimizing Screening through Personalized Regimens) consortium (U54 CA163262 [Dr. Corley]). The funding sources had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript. Results After removal of duplicate records, the search identified 7232 studies, of which we evaluated 77 full-text articles (Figure 1). A total of 23 reports containing 26 comparisons were retained, including 7 randomized and 16 nonrandomized studies. Figure 2 provides an overview of the 26 comparisons, organized by intervention level and category, and Table 1 gives details of study populations and interventions. Three studies had low risk of bias (Van Roosbroeck and colleagues [38], Green and colleagues [39], and Raich and colleagues [40]). The number of fecal testpositive patients ranged from 14 to 39105; the number of patients included was not reported in 2 studies. Fourteen studies reported government funding, 2 corporate funding (38, 41), 1 funding from local volunteer organizations (42), and 9 did not specify any funding sources (7, 31, 32, 34, 4346). Five studies investigated follow-up of fecal immunochemical tests (38, 43, 4648) and 18 of guaiac-based FOBTs. Figure 1. Flow chart of study selection for interventions to improve follow-up of positive fecal blood tests for colorectal cancer screening. CENTRAL = Cochrane Central Register of Controlled Trials. Figure 2. Overview of included studies of interventions to improve follow-up of positive fecal blood tests for colorectal cancer screening, by intervention level and category. HR= hazard ratio; NA= not available; NR= not reported. * Studies with separate reporting of >1 comparison are listed as A, B, C, with further details in Table 1. For individual study, according to Agency for Healthcare Research and Quality and GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria (36, 37); see details in Appendix Table 2. Given only when specifically provided by authors; otherwise marked unspecified. Adjusted absolute change, as reported by study authors. Table 1. Details of Study Population, Interventions, and Controls, by Intervention Level and Type The proportions of test-positive patients who had follow-up colonoscopy with and without the intervention were available for 17 studies; the 6 remaining studies either had no control group or reported only coefficients of change in colonoscopy completion rates (31, 3335, 45, 48). The 17 studies with control and intervention proportions reported absolute differences of 7.4 percentage points (95% CI, 19 to 4.3 percentage points) to 25 percentage points (CI, 14 to 35 percentage points). Reported follow-up intervals varied between 30 days and 1 year, although 12 studies did not specify a time interval. Given the heterogeneity in study interventions, study design, and whether usual care was used as a control group, no meta-analysis was done. Patient-Level Interventions The 11 patient-level intervention studies used the following 3 general strategies: changes to the screening invitation strategy (38, 42), provision to patients of test results