Colorectal cancer (CRC) is the third most common cancer worldwide.1Bray F. et al.CA Cancer J Clin. 2018; 68: 394-424Crossref PubMed Scopus (51747) Google Scholar,2Dekker E. et al.Lancet. 2019; 394: 1467-1480Abstract Full Text Full Text PDF PubMed Scopus (1529) Google Scholar Screening reduces CRC incidence and mortality through the removal of precancerous lesions and early detection of cancer.2Dekker E. et al.Lancet. 2019; 394: 1467-1480Abstract Full Text Full Text PDF PubMed Scopus (1529) Google Scholar Although colonoscopy is a high-sensitivity screening method, cancers are sometimes diagnosed after a CRC-negative colonoscopy, a colonoscopy in which cancer was not detected. These post-colonoscopy colorectal cancers (PCCRCs) can lead to substantial morbidity and mortality,3Rutter M. Beintaris I. et al.Gastroenterology. 2018; 155: 909-925.e3Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar and identifying their etiologies can inform interventions to improve colonoscopy effectiveness. The World Endoscopy Organization (WEO) recently published a consensus statement to classify PCCRCs into their most plausible explanations (Figure 1).3Rutter M. Beintaris I. et al.Gastroenterology. 2018; 155: 909-925.e3Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar Few studies have used this methodology and all were European, single-center studies with modest sample sizes (ie, 47–107 PCCRC cases).4Beaton D. et al.Endoscopy. 2022; 54: 270-277Crossref PubMed Scopus (4) Google Scholar, 5Anderson R. et al.Gastroenterology. 2020; 158: 1287-1299.e2Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 6Aerts R. et al.Acta Gastroenterol Belg. 2021; 84: 401-405Crossref PubMed Scopus (4) Google Scholar To our knowledge, no studies have used the WEO methodology to investigate PCCRCs occurring within large, diverse community-based populations in the United States. To address this knowledge gap, we randomly selected 523 of 1497 CRC-negative colonoscopies performed by board-certified gastroenterologists in 2006 through June 30, 2018, among Kaiser Permanente Northern California health care plan members, which were followed by a CRC diagnosis 6 months to 10 years later (Supplementary Methods). These 523 procedures were associated with 533 PCCRC cases. Patient and endoscopist characteristics are provided in Supplementary Table 1. Of the 533 PCCRC cases, 197 (37.0%) were diagnosed more than 4 years after colonoscopy (Figure 1). Per WEO guidelines, these were classified as “likely new CRC”; however, in 25 of 197 cases (12.7%), an advanced adenoma was detected at their prior colonoscopy, with 9 (4.6%) detected in the same bowel segment as the subsequently diagnosed cancer; 30 of 197 cases (15.2%) had a low-risk adenoma detected at their prior colonoscopy, with 6 (3.0%) detected in the same bowel segment as the subsequently diagnosed cancer. For 13 of 197 cases (6.7%), the prior colonoscopy was incomplete or had an inadequate bowel preparation. For comparisons among studies with different lengths of follow-up, we calculated percentages for the other most plausible explanation categories based on the remaining 336 of 533 cases (63.0%) diagnosed within 4 years of the CRC-negative colonoscopy; of these, 48 had an advanced adenoma detected in the same bowel segment as the diagnosed cancer, 11 of 336 (3.3%) were unresected and classified as “detected lesion, not resected,” and 37 of 336 (11.0%) were classified as “likely incomplete resection of previously identified lesion.” Among 288 cases without an advanced adenoma detected in the same bowel segment as the diagnosed cancer (Figure 1), 236 of 336 (70.2%) followed a complete examination with adequate bowel preparation and were classified as “possible missed lesion, prior examination adequate” and 52 of 336 (15.5%) were classified as “possible missed lesion, prior examination negative but inadequate.” Our findings are in agreement with 2 prior studies that reported “possible missed lesion, prior examination adequate” as the most common plausible explanation for PCCRCs diagnosed within 4 years of the CRC-negative colonoscopy.4Beaton D. et al.Endoscopy. 2022; 54: 270-277Crossref PubMed Scopus (4) Google Scholar,6Aerts R. et al.Acta Gastroenterol Belg. 2021; 84: 401-405Crossref PubMed Scopus (4) Google Scholar A third study reported “possible missed lesion, prior examination negative but inadequate” as the most common plausible explanation; however, this discrepancy is likely explained by their definition of “adequate examination,” which required photo documentation of the cecum, ileocecal valve, or terminal ileum.5Anderson R. et al.Gastroenterology. 2020; 158: 1287-1299.e2Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar Regardless, all 4 studies identified the broader category of possible missed lesion as the most frequent plausible explanation for PCCRCs occurring within 4 years of a CRC-negative colonoscopy.4Beaton D. et al.Endoscopy. 2022; 54: 270-277Crossref PubMed Scopus (4) Google Scholar, 5Anderson R. et al.Gastroenterology. 2020; 158: 1287-1299.e2Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 6Aerts R. et al.Acta Gastroenterol Belg. 2021; 84: 401-405Crossref PubMed Scopus (4) Google Scholar An important colonoscopy quality metric for ensuring adequate inspection of the colon is physician adenoma detection rate (ADR), that is, the proportion of screening colonoscopies in which at least 1 adenoma is detected. Physician ADR is strongly inversely associated with patient risk of PCCRC.7Kaminski M.F. et al.N Engl J Med. 2010; 362: 1795-1803Crossref PubMed Scopus (1401) Google Scholar,8Schottinger J.E. Jensen C.D. et al.JAMA. 2022; 327: 2114-2122Crossref PubMed Scopus (13) Google Scholar The US Multi-Society Task Force recommends ADR benchmarks of ≥25% for men and women combined, although data consistently suggest substantial additional potential benefit with higher ADRs.8Schottinger J.E. Jensen C.D. et al.JAMA. 2022; 327: 2114-2122Crossref PubMed Scopus (13) Google Scholar Several interventions have been reported to help improve inspection of the colon and have resulted in higher ADRs and lower adenoma miss rates, including colon retroflexion in the right colon, water exchange, extending withdrawal time, distal attachment devices, chromoendoscopy, feedback, training, and artificial intelligence.9Lam A.Y. et al.Gastrointest Endosc Clin N Am. 2022; 32: 329-349Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar Incomplete lesion resection also represented a modifiable risk factor for PCCRC in our data. This finding is consistent with a report from England5Anderson R. et al.Gastroenterology. 2020; 158: 1287-1299.e2Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar and reflects the importance of optimizing polypectomy technique and ensuring complete resection of lesions. In a prospective study from the United States, 10.1% of polyps were found to be incompletely resected.10Pohl H. et al.Gastroenterology. 2013; : 144PubMed Google Scholar In addition, rates of incomplete resection varied by physician,10Pohl H. et al.Gastroenterology. 2013; : 144PubMed Google Scholar demonstrating another dimension of colonoscopy quality that needs further attention. However, unlike ADR, the feasibility of measuring polypectomy completeness through resection margin biopsies and/or histologic examination of en bloc resection specimens is challenging to implement due to the additional time, labor, and costs required. Thus, further research is needed on resection training and ascertaining competency, along with developing pragmatic approaches or artificial intelligence to measure polypectomy completeness. Given temporal changes in physician ADRs, we also evaluated 2 time periods (2006–2011 and 2012–2018). The latter period had higher ADRs among the physicians whose patients experienced a PCCRC (26.7% and 22.1%, respectively) and the ratio of likely missed lesions to likely incompletely or not resected lesions among PCCRCs diagnosed within 4 years was higher in the latter period (7.4/1 and 4.6/1, respectively) (Supplementary Table 2). Thus, these findings suggest that even with temporal increases in physician ADRs, missed and incompletely or not resected lesions should remain targets for quality improvement. In conclusion, using the WEO3Rutter M. Beintaris I. et al.Gastroenterology. 2018; 155: 909-925.e3Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar methodology for PCCRC classification, sampling within a large and demographically diverse population-based setting in the United States, and with a sample size that was many-fold larger than prior studies, we found nearly 40% of PCCRCs were classified as likely new cancers and missed lesions, despite a prior adequate examination, was the most common plausible explanation for PCCRCs. Lawrence Jun Leung, MD, MPH (Conceptualization: Equal; Data curation: Equal; Formal analysis: Equal; Investigation: Equal; Methodology: Equal; Validation: Equal; Writing – original draft: Equal; Writing – review & editing: Equal). Jeffrey K. Lee, MD, MPH (Conceptualization: Equal; Formal analysis: Equal; Funding acquisition: Equal; Investigation: Equal; Methodology: Equal; Supervision: Equal; Validation: Equal; Writing – original draft: Equal; Writing – review & editing: Equal). Sophie A. Merchant, MPH (Conceptualization: Equal; Data curation: Equal; Formal analysis: Equal; Investigation: Equal; Methodology: Equal; Validation: Equal; Writing – original draft: Equal; Writing – review & editing: Equal). Christopher D. Jensen, PhD, MPH (Conceptualization: Equal; Formal analysis: Equal; Funding acquisition: Equal; Investigation: Equal; Methodology: Equal; Validation: Equal; Writing – original draft: Equal; Writing – review & editing: Equal). Asim Alam, MD, PhD (Data curation: Equal; Formal analysis: Equal; Validation: Equal; Writing – review & editing: Supporting). Douglas A. Corley, MD, PhD (Conceptualization: Equal; Formal analysis: Equal; Funding acquisition: Equal; Investigation: Equal; Methodology: Equal; Validation: Equal; Writing – review & editing: Equal). This study was conducted within Kaiser Permanente Northern California (KPNC), a large integrated health system that provides comprehensive inpatient and outpatient services to more than 4.5 million members in suburban, urban, and semi-rural regions throughout Northern California. All KPNC members are insured with complete access to primary and specialty care. All patient encounters, medical diagnoses and procedures, laboratory results and vital statistics, as well as information on demographic characteristics, membership, and social behaviors are recorded in electronic databases. The membership within KPNC is similar in demographic and socioeconomic characteristics to the Northern California region.e1Krieger N. Am J Public Health. 1992; 82: 703-710Crossref PubMed Scopus (1433) Google Scholar This study was funded by the National Cancer Institute and conducted under the Population-Based Research to Optimize the Screening Process II (PROSPR II) consortium (UM1 CA222035), which conducts multisite, coordinated, transdisciplinary research to evaluate and improve cancer screening processes. The funding source was independent of the study design, data collection and management, analysis and interpretation of results, and preparation and submission of the manuscript. The study was approved by the KPNC Institutional Review Board, with informed consent waived. CRC diagnoses, defined as an adenocarcinoma of the colon or rectum, were extracted from the KPNC Cancer Registry using International Classification of Disease for Oncology, Third Editione2World Health Organization https://apps.who.int/iris/bitstream/handle/10665/96612/9789241548496_eng.pdfGoogle Scholar codes (C18.0, C18.2-C18.9, C19.9, C20.9) and morphology codese2World Health Organization https://apps.who.int/iris/bitstream/handle/10665/96612/9789241548496_eng.pdfGoogle Scholar (8000, 8010, 8020-8021, 8140-8141, 8143-8144, 8147, 8200, 8210-8211, 8215, 8220-8221, 8230, 8255, 8260-8263, 8323, 8410, 8430, 8440, 8470, 8480-8481, 8490, 8510, 8560, 8570-8574, 8576). Colonoscopies were extracted from the KPNC Virtual Data Warehouse procedure database using Current Procedural Terminologye3American Medical Association https://www.ama-assn.org/practice-management/cptGoogle Scholar codes (44388-44394, 44397, 44401-44402, 44404-44408, 45355, 45378-45393, 45398), International Classification of Diseasese4World Health Organization https://www.who.int/standards/classifications/classification-of-diseasesGoogle Scholar procedure codes (45.23, 98.04, V76.51, 0DBB8ZX, 0DBB8ZZ, 0DBC8ZX, 0DBC8ZZ, 0DBF8ZX, 0DBF8ZZ, 0DBH8ZX, 0DBH8ZZ, 0DBK8ZX, 0DBK8ZZ, 0DBL8ZX, 0DBL8ZZ, 0DBM8ZX, 0DBM8ZZ), Healthcare Common Procedure Coding System codes (G0105, G0121, G6019-G6020, G9252-G9253, G9659-G9661, G9935-G9937), and local KPNC-specific codes (106504, 129133, 204456, 204716, 207490-207493, 208340, 214417, 219377, 226145, 226395, 230847, 231512, 233387-233390, 235525, 242883, 244893, 244895, 246300-246301, 250625, 253994, 279802, 299458-299461, 566735, 643763-643764, 696739). A colonoscopy was considered cancer-negative if an adenocarcinoma of the colon or rectum was not diagnosed at or within 6 months after the procedure. We evaluated 868,755 eligible CRC-negative colonoscopies performed in 2006 through June 30, 2018, among 637,668 KPNC health plan members and identified 2611 for which a CRC diagnosis was made more than 6 months to 10 years after the procedure (3.0 per 1000 colonoscopies). These PCCRC cases comprised 1892 of 14,220 CRC cases (13.2%) diagnosed in 2006–2018 at or within 10 years of a colonoscopy. Of the 1892 PCCRC cases identified, 1497 were diagnosed by a subsequent colonoscopy and 412 were preceded by more than 1 CRC-negative colonoscopy; for these cases, the procedure closest to the cancer diagnosis was selected for analysis. The final cohort from which we randomly sampled 523 CRC-negative colonoscopies consisted of 1497 CRC-negative colonoscopies performed in 1492 patients. For each of the 533 randomly selected PCCRC cases, we manually abstracted from the CRC-negative colonoscopy report the extent of procedure and lesion location. Bowel preparation adequacy was obtained through natural language processing–based identification of qualitative terms for bowel preparation found in colonoscopy reports (eg, adequate, inadequate, excellent, good, fair, and poor). If the qualitative terms found were good, excellent, or adequate, the bowel preparation was categorized as “adequate.” If the terms found were inadequate, fair, or poor, the bowel preparation was categorized as “inadequate.” Pathology reports were manually examined to identify advanced adenomas. International Classification of Disease for Oncology, Third Edition codes were used to determine location of the diagnosed cancer. Patient characteristics were obtained from electronic health records; patient age, medical history, body mass index, and smoking status were ascertained at the time of the CRC-negative colonoscopy. Data elements were selected in accordance with the WEO method.3Rutter M. Beintaris I. et al.Gastroenterology. 2018; 155: 909-925.e3Abstract Full Text Full Text PDF PubMed Scopus (147) Google ScholarSupplementary Table 1Characteristics of a Random Sample of 523 Colorectal Cancer–Negative Colonoscopies Leading to 533 Post-Colonoscopy Colorectal CancersCharacteristicDataPatient Age, y, mean (SD)69.1 (9.7) Sex, n (%)Female241 (46.1)Male282 (53.9) Race and ethnicity, n (%)Asian or Pacific Islander54 (10.3)Black46 (8.8)Hispanic White55 (10.5)Non-Hispanic White366 (70.0)Other or unknown2 (0.4) Body mass index, n (%)>25 kg/m2110 (21.0)25–29.9 kg/m2198 (37.9)≥30 kg/m2215 (41.1) Smoking status, n (%)Ever smoker296 (56.6)Never smoker226 (43.2)Unknown1 (0.2) Charlson Comorbidity Index, n (%)0265 (50.7)1109 (20.8)276 (14.5)≥373 (14.0) Family history of CRC in first-degree relative, n (%)37 (7.1)Prior colectomy59 (11.3)Prior diverticular disease283 (54.1)Prior adenoma217 (41.5)Prior CRC65 (12.4)Prior inflammatory bowel disease41 (7.8)Hereditary CRC syndrome5 (1.0) Years between CRC-negative colonoscopy and CRC diagnosis, n (%)≤141 (7.8)1.1–291 (17.4)2.1–380 (15.3)3.1–4117 (22.4)>4194 (37.1) No. of tumors detected on diagnostic colonoscopy, n (%)1513 (98.1)210 (1.9)CharacteristicEndoscopists, n (%)Screening colonoscopy volume in the prior year median (IQR)Endoscopist characteristics at CRC-negative colonoscopy Performed screening colonoscopies in the prior year473 (90.4)132 (96–188) ADRaADR was calculated as the number of screening colonoscopies that detected an adenoma over the total number of screening colonoscopies performed by the endoscopist in the prior year. in the prior year<19144 (27.5)118 (87–157)19–24.9118 (22.6)139 (94–194)25–31.9120 (22.9)153 (101– 207)32–6191 (17.4)136 (101–193)Missing50 (9.6)—Endoscopist had a PCCRC attributed to a:nADRaADR was calculated as the number of screening colonoscopies that detected an adenoma over the total number of screening colonoscopies performed by the endoscopist in the prior year. in the prior year, %, mean (SD) Missed lesion28225.1 (9.5) Likely incompletely resected or unresected lesion4825.8 (9.2)IQR, interquartile range.a ADR was calculated as the number of screening colonoscopies that detected an adenoma over the total number of screening colonoscopies performed by the endoscopist in the prior year. Open table in a new tab Supplementary Table 2Endoscopist Adenoma Detection Rates and the Ratio of Missed to Incompletely Resected or Unresected Lesions in 2006–2011 vs 2012–2018Time intervalCRC-negative colonoscopiesPCCRC casesTotal n (%)CRC diagnosis, y, median (IQR)Physician ADR in the year prior, %, mean (SD)Total nLikely due to missed lesions, n (%)Likely due to incompletely or unresected lesions, n (%)Ratio of missed to incompletely or unresected lesions2006–2011132 (40.1)2.7 (1.7, 3.4)22.3 (9.0)135111 (82.2)24 (17.8)4.6/12012–2018197 (59.9)2.1 (1.3, 3.1)27.0 (9.2)201177 (88.1)24 (11.9)7.4/1IQR, interquartile range. Open table in a new tab IQR, interquartile range. IQR, interquartile range.