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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgement
  9. References

Background

The role of a faecal immunochemical test (FIT) in screening individuals with a positive family history of colorectal cancer (CRC) is not clear.

Aim

To assess the diagnostic accuracy of FIT using colonoscopy findings as the gold standard in identifying colorectal neoplasms.

Methods

We analysed data from 4539 asymptomatic subjects aged 50–70 years who had both colonoscopy and FIT (Hemosure; W.H.P.M., Inc, El Monte, CA, USA) at our bowel cancer screening centre between 2008 and 2012. A total of 572 subjects (12.6%) had a family history of CRC. Our primary outcome was the sensitivity of FIT in detecting advanced neoplasms and cancers in subjects with a family history of CRC. A family history of CRC was defined as any first-degree relative with a history of CRC.

Results

Among 572 subjects with a family history of CRC, adenoma, advanced neoplasm and cancer were found at screening colonoscopy in 29.4%, 6.5% and 0.7% individuals, respectively. The sensitivity of FIT in detecting adenoma, advanced neoplasm and cancer was 9.5% [95% confidence interval (CI), 5.7–15.3], 35.1% (95% CI, 20.7–52.6) and 25.0% (95% CI, 1.3–78.1), respectively. Among FIT-negative subjects who have a family history of CRC, adenoma was found in 152 (29.6%), advanced neoplasm in 24 (4.7%) and cancer in 3 (0.6%) individuals.

Conclusion

Compared with colonoscopy, FIT is more likely to miss advanced neoplasms or cancers in individuals with a family history of CRC.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgement
  9. References

Individuals with a positive family history of colorectal cancer (CRC) have a two- to three-fold increased risk of CRC compared with the general population.[1-3] This increased risk can be attributed to the earlier initiation of adenoma formation and/or increased adenoma growth rates.[4, 5] Guidelines suggest that screening in this high-risk group should begin at an earlier age (before 50 years old) and at shorter intervals.[6-9] Nonrandomised studies have shown that colonoscopy is effective in reducing CRC incidence and mortality.[10, 11] The yield of colonoscopy for detecting colorectal neoplasm is also higher in first-degree relatives of subjects with CRC than those without a family history.[1, 12-14] However, few studies have assessed what screening test to use and how often to use it in individuals with nonhereditary familial CRC. Most existing guidelines recommend colonoscopy as the preferred test in patients with a family history of CRC.[15] The diagnostic performance of FIT in screening these individuals is not clear. The objective of this study is to determine the diagnostic accuracy of FIT compared with colonoscopy for screening colorectal neoplasms in asymptomatic subjects who have a first-degree relative with a history of CRC.

Materials and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgement
  9. References

Study population and setting

Consecutive asymptomatic subjects aged 50–70 years who had both FIT and colonoscopy were recruited between May 2008 and October 2012 from our bowel cancer screening community centre. The setting and method of recruitment have been described in detail previously.[16] Individuals were included if they had no symptoms in the past 6 months suggestive of CRC (i.e. haematochezia, melena, anorexia, change in bowel habit or weight loss greater than 5 kg) and no screening test for CRC performed in the past 5 years. Subjects were excluded if they had a personal history of CRC, colonic adenoma, inflammatory bowel disease, prosthetic heart valve or vascular graft surgery. Patients with suspected or known familial polyposis syndromes or Lynch syndrome were excluded. Information on age, gender, height, weight, smoking history, history of diabetes mellitus and hypertension was collected. Family history of CRC was defined as any first-degree relative (father, mother, siblings or children) with a history of CRC.

FIT

This study used the FIT Hemosure (W.H.P.M., Inc., El Monte, CA, USA), and dietary restriction was not required before the tests. This test is a qualitative test with a positive or negative result based on the presence of bands. Positive result was defined as two bands on the test device at 5 min when the level of human haemoglobin in faeces was >50 μg per gram faeces. Cut-off value was preset and determined subjectively. All tests were performed between 4 and 6 h of stool collection. The laboratory staffs were blinded to the colonoscopic findings.

Colonoscopy

Colonoscopies were performed by experienced endoscopists. All polyps were treated by endoscopic polypectomy. Advanced neoplasm was defined as lesions with one of the following characteristics: ≥10 mm in diameter, having a villous or tubulovillous component, or high-grade dysplastic lesions or carcinoma in situ. Cancer was defined as lesion that had malignant cells beyond the muscularis mucosae. Lesions proximal to the splenic flexure were regarded as proximal lesions. Endoscopists were blinded to the FIT results. The study was approved by the Clinical Research Ethics Committee of the Chinese University of Hong Kong.

Outcome measures

The primary outcome included the sensitivity of once-off FIT in detecting advanced neoplasms or cancers in individuals with a family history of CRC. Secondary outcomes included colonoscopic findings in subjects with a family history of CRC compared with those with no family history of CRC, and FIT sensitivity according to the site and characteristics of lesions. The false-negative and true-negative FITs were classified by defining colonoscopy and pathological outcome as the gold standard. A false-negative result was defined as the presence of advanced colorectal neoplasm detected on colonoscopy despite a negative FIT, whereas a true-negative FIT was defined as the absence of advanced neoplasm on colonoscopy after a negative FIT. FITs were performed within 2 weeks before the colonoscopy.

Statistics

The Statistical Package for Social Sciences (spss) version 19.0 (Chicago, IL, USA) was used for data entry and analyses. Simple descriptive statistics was used to evaluate the demographic data among individuals with and without a family history of CRC. Chi-squared test was used to compare the proportion of premalignant lesions and cancer between groups (family history of CRC vs. no family history of CRC; FIT positive vs. FIT negative). To determine the performance of FIT, we used test results and colonoscopic findings to calculate the sensitivity, specificity, positive predictive value, negative predictive value and the corresponding 95% confidence intervals (CI). P value of <0.05 was considered statistically significant.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgement
  9. References

Clinical demographics

A total of 4539 asymptomatic individuals with complete FIT and colonoscopy data were enrolled in the study period (2008–2012) for analysis. Of these, 2054 (45.3%) were male subjects. The mean age was 57.68 years (s.d. = 4.86 years). A total of 572 subjects (12.6%) had a family history of CRC in their first-degree relatives. The baseline demographic characteristics of all 4539 subjects are shown in Table 1. There were no significant differences in age, body mass index, gender, aspirin or NSAID use, history of smoking, diabetes and hypertension in subjects with family history of CRC vs. no family history of CRC. There were no serious adverse events (including perforation or bleeding) from any of the tests.

Table 1. Demographic characteristics of subjects with family history of CRC vs. no family history of CRC
 FH of CRC (N = 572)No FH of CRC (N = 3967)P value
  1. s.d., standard deviation; FH, family history.

  2. a

    Aspirin usage: use of aspirin ≥75 mg in the past 1 month.

Age (years), Mean (s.d.)57.50 (4.74)57.71 (4.87)0.33
Body mass index, Mean (s.d.)23.55 (3.25)23.48 (3.15)0.60
Male, n (%)255 (44.6)1799 (45.3)0.73
Nonsteroidal anti-inflammatory drugs, n (%)16 (2.8)176 (4.4)0.07
Aspirin, n (%)a16 (2.8)111 (2.8)0.99
Ever Smoker, n (%)26 (4.5)185 (4.7)0.90
Diabetes mellitus, n (%)37 (6.5)288 (7.3)0.49
Hypertension, n (%)126 (22.0)888 (22.4)0.85

Prevalence of colorectal neoplasms according to family history of CRC

The prevalence of advanced neoplasms or cancer (7.2% vs. 5.1%; P = 0.034) and all colorectal adenomas (36.6% vs. 30.5%; P = 0.003) were significantly higher in subjects with a family history of CRC than those without such a history. Four (0.7%) and 18 (0.5%) cancers were identified in subjects with and without a family history of CRC respectively (Table 2).

Table 2. Colonoscopy findings of subjects with family history of CRC vs. no family history of CRC
Colonoscopy findingsFH of CRC (N = 572)No FH of CRC (N = 3967)P value
  1. a

    Advanced neoplasm: size≥ 10 mm, adenoma with tubulovillous or villous component or high-grade dysplasia, or carcinoma in situ.

  2. b

    P value = cancer + advanced neoplasm + adenoma vs. all others.

  3. c

    P value = cancer + advanced neoplasm vs. all others.

  4. d

    P value = cancer vs. all others.

Normal330 (57.7%)2448 (61.7%)
Adenoma168 (29.4%)1009 (25.4%)0.003b
Advanced neoplasma37 (6.5%)182 (4.6%)0.034c
Colorectal cancer4 (0.7%)18 (0.5%)0.513d

Overall test performance of the FIT

The FIT was positive in 492 (10.8%) subjects and colonoscopic findings revealed adenoma in 127 (25.8%), advanced neoplasms in 85 (17.3%) and cancers in 12 (2.4%) of the subjects. The test performance of FIT in relation to the characteristics of the lesions is shown in Table 3. The sensitivity of FIT for the detection of adenomas, advanced adenomas and cancer was 10.8%, 38.8%, 54.5% respectively. There was no difference in the yield of FIT between proximal and distal colonic lesions (data not shown).

Table 3. Sensitivity of FIT for all subjects who had completed colonoscopy and FIT
Colonoscopy findingsFIT positive (= 492)FIT negative (N = 4047)Sensitivity (95% CI)Specificity (95% CI)PPV (95% CI)NPV (95% CI)
  1. PPV, positive predictive value; NPV, negative predictive value.

All neoplasm224 (44.1%)1194 (29.5%)15.8 (14.0–17.8)91.4 (90.4–92.4)45.5 (41.1–50.0)70.5 (69.1–71.9)
Adenoma127 (25.7%)1050 (25.9%)10.8 (9.1–12.7)89.1 (88.0–90.2)25.8 (22.0–30.0)74.1 (72.7–75.4)
Advanced neoplasm85 (17.3%)134 (3.3%)38.8 (32.4–45.6)90.6 (89.7–91.4)17.3 (14.1–21.0)96.7 (96.1–97.2)
Colorectal cancer12 (2.4%)10 (0.3%)54.5 (32.7–74.9)89.3 (88.4–90.2)2.4 (1.3–4.3)99.8 (99.5–99.9)

FIT performance in individuals with a family history of CRC

Among 572 subjects with a family history of CRC, the FIT was positive in 59 (10.3%) subjects. The sensitivity of FIT for the detection of adenomas, advanced neoplasms and cancer was 9.5%, 35.1% and 25% respectively. The prevalence of advanced neoplasms or cancers was significantly higher in individuals who were FIT positive compared with those who were FIT negative (23.7% vs. 5.3%; P < 0.001). However, three subjects who were FIT negative were found to have cancers on colonoscopy (Table 4). The three cancers were stage 1 (sigmoid colon), stage 2 (ascending colon) and stage 3 (rectum). Two subjects underwent surgery and one had endoscopic submucosal dissection. Twenty-four (4.7%) subjects who were FIT negative had advanced neoplasms on colonoscopy. Thirteen (54%) had tubulovillous adenomas and 4 (17%) had high-grade dysplasia on pathology. Fifteen (66%) of the advanced neoplasms were located proximal to the splenic flexure. Fourteen of the 24 subjects (59%) with advanced neoplasms had two or more adenomas. Eight (33%) of the lesions were <10 mm in size and 20 (83%) lesions were ≤15 mm in size.

Table 4. Diagnostic performance of FIT in subjects with and without a family history of CRC
Colonoscopy findingsFIT positiveFIT negativeSensitivity (95% CI)Specificity (95% CI)PPV (95% CI)NPV (95% CI)
All neoplasm
With FH30/59 (50.8%)179/513 (34.9%)14.3 (10.0–20.0)92.0 (88.6–94.5)50.8 (37.6–63.9)65.1 (60.8–69.2)
Without FH194/433 (44.8%)1015/3534 (28.7%)16.0 (14.0–18.3)91.0 (89.9–92.0)43.8 (39.1–48.6)71.3 (69.8–72.8)
Adenoma
With FH16/59 (27.1%)152/513 (29.6%)9.5 (5.7–15.3)89.4 (85.8–92.1)27.1 (16.7–40.5)70.4 (66.2–74.3)
Without FH111/433 (25.6%)898/3534 (25.4%)11.0 (9.2–13.1)89.1 (87.9–90.2)25.6 (21.6–30.1)74.6 (73.1–76.0)
Advanced neoplasm
With FH13/59 (22.0%)24/513 (4.7%)35.1 (20.7–52.6)91.4 (88.6–93.6)22.0 (12.7–35.1)95.3 (93.0–96.9)
Without FH72/433 (16.6%)110/3534 (3.1%)39.6 (32.5–47.1)90.5 (89.5–92.0)16.6 (13.3–20.5)96.9 (96.2–97.4)
Colorectal cancer
With FH1/59 (1.7%)3/513 (0.6%)25.0 (1.3–78.1)89.8 (86.9–92.1)1.7 (0.1–10.3)99.4 (98.2–99.8)
Without FH11/433 (2.5%)7/3534 (0.2%)61.1 (36.1–81.7)89.3 (88.3–90.3)2.5 (1.3–4.6)99.8 (99.6–99.9)

False-negative FIT was not significantly affected by the size or location of colorectal neoplasms in subjects with a family history of CRC. There was no difference in the yield of FIT for the detection of all colorectal neoplasms between subjects with a family history of CRC compared with those without a family history of CRC (14.3% vs. 16.6%; P = 0.553). There were also no differences in the yields of FIT for the detection of adenomas (9.5% vs. 11.0%; P = 0.568), advanced neoplasms (35.1% vs. 39.6%; P = 0.615) and cancers (25.0% vs. 61.1%; P = 0.190) between subjects with a family history of CRC compared with those without a family history of CRC. FIT sensitivity for the detection of cancer was higher in subjects without a family history of CRC (Table 4).

There were 404 serrated lesions in our cohort. The FIT positivity rate for these lesions was 8.1%. The FIT sensitivity, specificity, positive predictive value and negative predictive value for serrated lesions were 9.9% (95% CI, 7.2–13.3), 89.1 (95% CI, 88.1–90.0), 8.1% (95% CI, 5.9–11.0) and 91% (95% CI, 90.1–91.9) respectively.

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgement
  9. References

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[19] or faecal blood tests[20] 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.[27]

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).[28] 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.[29] It also remains unclear if other FIT may have higher sensitivity for CRC screening in this population.[30] 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).[31]

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.[32] 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.[28] 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.[1] 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%).[33] 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.[34] 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.

Authorship

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgement
  9. References

Guarantor of the article: Prof. Joseph JY Sung.

Author contribution: BYS, HWH and TYL recruited the patients. JJS and MW designed the study. SCN, SSN, JCW and JWL performed the colonoscopies. SCN, VC and JYC collected and analysed the data. SCN drafted the manuscript. FKC and JJS critically reviewed the article. All authors approved the final version of this manuscript.

Acknowledgement

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgement
  9. References

Declaration of personal interests: SC Ng has served as a speaker and received research funding from Ferring and Janssen. Justin Wu has served as a speaker for AstraZeneca and Lundbeck. Francis Chan has served as a speaker for Pfizer, Takeda and AstraZeneca. Joseph Sung has served as a speaker and advisory board member for AstraZeneca and Nycomed.

Declaration of funding interests: The study was supported by funding from the Hong Kong Jockey Club.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Authorship
  8. Acknowledgement
  9. References
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