1. Risks of interval colorectal cancer in a FIT-based screening program
목요세미나
Risks of interval colorectal cancer in a FIT-based screening program
서울대학교병원
이 현 정

2. Prevention of CRC by colonoscopy
Colonoscopic polypectomy
→ CRC mortality 53% reduction
CRC screening & colonoscopy
→ CRC incidence & mortality ↓
Zauber AG, et al. N Engl J Med 2012;
Patel SG, et al. CGH 2014

3. Interval colorectal cancer
Colorectal cancer diagnosed after a screening or surveillance exam in which no cancer is detected, and before the date of the next recommended exam
Interval CRC
≒ Missed CRC
≒ post colonoscopy CRC (PCCRC)
Prevalence: 1.8 – 9.0%
Location
Proximal interval CRC 6.5%
Distal interval CRC 2.9%
2.4 times more in proximal than distal compared with sporadic cancer
Singh S et al, Am J Gastroenterol 2014;
Sanduleanu S, et al. Gut 2015

4. Risk factors Patient-related factors Endoscopy-related factors
Age (OR 1.15, > 65 – 70 vs < 65 – 70)
Family history of CRC (OR 1.6)
Diverticular disease (OR 4.3)
Higher Charlson comorbidity index (OR 2.0)
Polypectomy on their index colonoscopy (OR 1.6)
Endoscopy-related factors
Non-gastroenterologist (Internist of family physician) (OR 1.53)
Lower polypectomy rate & lower procedure completion rates
Biology-related factors
Female no more likely than males (OR 1.06)
FHx: any first-degree relative or only those occurring at age < 50 year
Pathway/gene
Frequency within (%)
Sporadic CRC
Interval CRC
CIN
≤85 ND
MSI
10-15
25-30
CIMP
30-33
30-57
BRAF
5-22
22-28
KRAS
33-51
13-23
Singh S et al, Am J Gastroenterol 2014;
Patel SG, et al. CGH 2014;
Cisyk AL, et al. Dig Dis Sci 2014

5. Etiology of interval CRCs
Missed lesion
Incomplete resection
Incomplete colonoscopy
Newly developed cancer (rapid progression)
Patel SG, et al. CGH 2014;
Le Clercq CM, et al. Gut 2014

6. Missed lesions Etiology (1) N=6 (465 patients)
Adenoma miss rate: 6~27%
Polyp size ↓ → miss rate ↑
CRC 5%, polyp 22-28%, adenoma 20-24%
Van Rijn, et al. Am J Gastroenterol 2006

7. Incomplete resection Etiology (2) Incomplete resection rate
Overall 10.1%
10-20mm vs. <10mm: 17% vs 6.8%
SSA/P vs. adenoma: 31% vs. 7.2%
Pohl H, et al. Gastroenterol 2013

8. Incomplete colonoscopy
Etiology (3)
Impact of suboptimal bowel preparation
Adenoma miss rate: 42%
Advanced adenoma miss rate: 27%
Cecal intubation
Cecal intubation rate ↑
ADR ↑
Protection of Rt. Colon cancer
Lebwohl B, et al. Gastrointes Endosc 2011;
Baxter NN, et al. Gastroenterol 2011

9. Newly developed cancer
Etiology (4)
SSA/P with dysplasia is believed to play the important role in interval CRC
Serrated pathway
SSA/P: rapid progression, missed lesion, incomplete resection
Rex et al, Am J Gastroenterol 2012

10. Issues to be resolved in interval CRC
Procedural factors and biological features may be responsible for the occurrence of interval CRC, yet data regarding precise contribution and prevention are limited
There are insufficient data on high risk patients for interval CRC who may need intensive surveillance
Little is known about data on interval CRC especially in FIT-based screening program
Clinical data on interval CRC in eastern countries are also lacking

11. Population-based muticentre study in South-Limburg, the Netherlands from Jan 2001 to Dec 2010
Interval CRC definition: CRC diagnosed within 5 years after an index colonoscopy
Precise clinical and histopathology records including photographic documentation of CRC
In T1 CRC, more often flat in PCCRCs than prevalent CRCs
: 30.8% (8/26) vs 14.0% (68/486), p = 0.040
age-adjusted OR 2.78, 95% CI 1.16 to 6.68)

12. Non-polypoid (flat or depressed) colorectal adenomas contribute to the development of PCCRCs due to overlooked lesions, a more challenging resection or perhaps a more aggressive biological behavior
The majority of PCCRCs (86%) would most probably have been preventable, being caused by missed or incompletely removed lesions and inadequate examination or surveillance and quality improvements are needed
Limitation
Lack of biological feature (eg, serrated pathway)
Subgroup at high risk for interval CRC who may need intensive surveillance

13. Biennial FIT was offered to average-risk subjects aged 50–69 years
FIT positivity: 5.2%
대장내시경 수검율: 51.4%
Total IC N=162
Large, population-based data on subjects who received complete total colonoscopy after positive FITs in the Taiwanese Nationwide CRC Screening Program from 2004 to 2009
Biennial FIT was offered to average-risk subjects aged 50–69 years
Participants with positive tests were referred for colonoscopy by certified endoscopists (gastroenterologist or surgeon) within 6 months
FIT cut-off: 20ugHb/g feces
Interval CRC incidence rate: 1.14 per 1000 PY
Interval CRC rate 7.35% (162/2203)

14. Inadequate quality of colonoscopy (such as low ADR) is still the main cause responsible for the risk of IC
Missed lesion (85%), Incomplete resection (2%), Newly developed cancer (13%)
A high baseline FHbC was also associated with a significantly higher risk of developing IC, even in the subjects with negative colonoscopy
Second look endoscopy
Interval FIT before the next round of screening
Limitation
Accuracy of FIT test
Difference in characteristic of interval CRC between in eastern and western countries (Proximal vs distal 39% vs 61%)
FIT sensitivity for CRC 79%, specificity 94% (2014 meta-analysis)
FIT 수검율 (33.3%), FIT -> colonoscopy 수검율 (28.8%)
False FIT result..

15. Interval FIT before scheduled surveillance
1736 patients with a family history or past neoplasia; they received at least 2 colonoscopy examinations and were followed for a total of 8863 years
An FIT was offered yearly, in the interval between colonoscopies; if results were positive, the colonoscopy was performed earlier than scheduled
Interval FIT testing in a high-risk colonoscopy surveillance program is useful as a strategy for detecting missed or rapidly developing lesions
But, lack of data on findings and quality of index colonoscopy
1071 (61.7%) participated in FIT test and average 1.8 FITs were done
FIT sensitivity
: 86% for CRC (12/14), 63% for AA (60/96)
Reduction in time to diagnosis
: 25 months earlier for cancer
24 months earlier for advanced adenoma
Lane JM, et al. Gastroenterol 2010

16. Interval CRC in multiple rounds of FIT
Average-risk participants in pilot FIT-based biennial CRC screening program conducted between 2006 and 2014 in Netherlands (50 – 74 years)
Factors to be considered in a FIT-based CRC screening program
FIT test characteristics (sensitivity and specificity)
Adherence to screening with FIT
Follow-up colonoscopy in persons who are FIT-positive
(In Korean study, uptake of colonoscopy in FIT-positive participants was only 28.8%)
FIT interval cancer 23%
FIT positivity: 16%
Colonoscopy 92% adherence
Van Der Vlugt M, et al. Gastroenterol 2017;
Lee CK, et al. Cancer Res Treat 2018

17. Different characteristics in eastern countries
In Korean study,
Proximal colon 32.7% vs 17.4% (interval CRC vs screen-detected CRC)
Distal colon 61.9% vs 79.0% (interval CRC vs screen-detected CRC)
Biologic differences?
Le Clercq CM, et al. Gut 2014
OR for proximally located
interval cancer = 1.24
Chiu SY, et al. Gut 2017
Lee CK, et al. Cancer Res Treat 2018

18. Conclusion
The majority of interval CRC may probably have been preventable, being caused by missed or incompletely removed lesions and inadequate examination or surveillance
Fecal hemoglobin, independently of quality of colonoscopy, is also a significant predictor for interval CRC in subjects who received complete colonoscopy after positive FIT
Further study using big
Annual FIT-based CRC screening program in Korea (45 – 80 years)
Accuracy of FIT test
Sensitivity 79%, specificity 94%
Factors associated false FIT results
: age, gender, NSAIDs, anticoagulants, family hx, lipid profile, co-morbidity
Factors to follow-up colonoscopies for patients with positive FIT results
Risk of interval CRC in a FIT-based screening program in Korea
The role of interval FIT tests in detection of interval CRC
FIT 수검율 33.3% (2017년)

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