Risks of interval colorectal cancer in a FIT-based screening program 2018.9.27 목요세미나 Risks of interval colorectal cancer in a FIT-based screening program 서울대학교병원 이 현 정

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

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

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

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

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

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

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

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

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

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)

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

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)

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..

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

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

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

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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