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- Materials and methods
In this study, we have shown that colonoscopy was more effective than FIT in detecting CRC and premalignant lesions in individuals with a family history of CRC. Compared with colonoscopy, a single FIT was more likely to miss advanced neoplasms and cancer in individuals with a family history of CRC. Three cases of cancers that were picked up on colonoscopy were FIT negative.
Consistent with earlier case–control and cross-sectional studies our data confirmed an increased prevalence of colorectal neoplasms in relatives of subjects with a family history of CRC.[17, 18, 1] Most of the earlier studies have employed colonoscopy as the screening tool in individuals of moderate–high risk. Unlike in average-risk individuals, alternative screening strategies including flexible sigmoidoscopy or faecal blood tests have not been tested in individuals of increased risk.
Studies evaluating screening performances of six different qualitative FITs in average-risk individuals have shown highly variable results. The sensitivity for the detection of advanced adenomas ranged from 25% to 72%. The sensitivity of FIT for advanced lesions in our cohort was around 35–40%. Differences in test performance between studies can be due to several factors including differences in faecal sampling device (optimised or common), test methodologies (quantitative or qualitative), positive cut-off value (10 μg or 40 μg) and sample numbers (single or duplicate).[21, 22]
Once-only FIT calculation is likely to underestimate the actual detection rate because such lesions might not necessarily have been present on every occasion the FIT test was undertaken. The evidence for effectiveness of faecal occult blood screening requires repeated testing.[23-26] Subjects with negative FIT have been reported to have the lowest risk for the most advanced stage of neoplasm.
In our study, it is unknown if the three cancers (stage 1–3) that were detected on colonoscopy who were FIT negative initially would have had a positive FIT if they undergo repeated tests. Most FIT-based screening programmes currently recommend annual or biennial screening with one or two faecal samples. A large prospective CRC screening study from Taiwan has reported that small colonic lesion size (<15 mm) was associated with false-negative FIT results in average-risk individuals (adjusted odds ratio 2.72). FIT also had a lower sensitivity for nonpolypoid and proximal lesions. With better endoscopic tools including high definition colonoscope and image enhanced endoscopy, it is likely that smaller and flat lesions will become more easily detectable on colonoscopy. We found that FIT sensitivity was not influenced by the size or location of colonic lesions in those with a family history. The main concern is that two of the three cancers associated with negative FIT were quite advanced (stage II and III) in our cohort and it could be that subjects with a family history of CRC have a faster adenoma–carcinoma progression, but this more aggressive tumour behaviour has only been demonstrated for the Lynch syndrome and serrated polyposis. It also remains unclear if other FIT may have higher sensitivity for CRC screening in this population. In sub-analysis of 404 serrated lesions (including hyperplastic polyps and serrated adenomas), the sensitivity of FIT for these lesions was lower than that of advanced neoplasms. Others have shown that being a first-degree relative of a CRC patient was the only significant predictor of advanced colorectal neoplasia despite a negative FIT (including three cases of carcinoma).
Our study has several clinical implications. Current guidelines in population-based CRC screening programmes for average-risk individuals have been mostly applied to familial CRC. The specificity and false-negative rate of an FIT in detecting colorectal neoplasms in population-based screening cannot be accurately established as patients with a negative FIT are not generally considered for colonoscopy. Here, we have focused on colonoscopy findings in subjects with negative FIT and a family history of CRC who had been recruited within a community-based CRC screening programme. Furthermore, all subjects were asymptomatic. It is generally believed that colonoscopy should be the modality of screening in those with a family history, as has been suggested by International screening guidelines. In these subjects, our goal is to not to detect cancer but rather precancerous lesions. As confirmed in this study, colonoscopy is superior to FIT for the detection of cancer and advanced neoplasms. We have previously shown that family history of CRC and high self-perception of CRC risk resulted in higher odds of choosing colonoscopy as a screening test. Hence, test with a higher sensitivity may be important for individuals who perceived themselves as high-risk subjects for developing CRC. The benefits of a single FIT screening may differ according to tumour characteristics, and lower FIT performance may exist in patient subgroups. In this study, faecal samples were analysed within a few hours; therefore, false-negative FIT due to storage conditions or lag time is unlikely.
Our study has some limitations. First, the study population consists of self-referred subjects, thus self-selection bias might exist. It is also of modest sample size. However, self-volunteered subjects probably constitute the largest screening population in most countries and our data reflect real-life screening scenario. Second, the family history of CRC was self-reported and such history may be subjected to bias. Nonetheless, we have shown a higher prevalence of advanced neoplasms and cancer in individuals with a reported family history of CRC compared with those without such a history, suggesting that self-report history is likely to be accurate. Furthermore, we have focused on first-degree relatives because studies that have assessed the reliability of patient self-reporting of family history showed higher accuracy rates for positive first-degree relative history (70–83%), whereas the accuracy for self-reporting of family history in second-degree or third-degree relatives was lower (27–67%). Third, this study used a qualitative FIT. In average-risk populations, a quantitative test has been shown to have the advantage in terms of transparency and flexibility regarding the positivity threshold (e.g. specificity can be oriented towards available colonoscopy resources or personal risk profiles) and a higher level of standardisation for test analysis and interpretation. In addition, optimal cut-off specific to the population can be determined. A quantitative FIT may have higher sensitivity and specificity for this high-risk group, but this remains to be tested. Fourth, we have not shown any difference in CRC mortality for both screening tests. Such information will require longer term follow-up and this study is underpowered to detect this difference. Although evidence for familial risk stratification is available, there is a lack of prospective controlled data with mortality endpoints.[35, 36] Finally, this is not a randomised study and patterns of FIT usage and non-usage were random.
In conclusion, compared with colonoscopy, FIT is more likely to miss advanced neoplasms or cancer in individuals with a family history of CRC. Colonoscopy is the preferred choice for CRC screening in these high-risk subjects if healthcare resources permit.