The Evolving Landscape of Colorectal Cancer Screening and Colonoscopy Practice: Insights from the Japan Polyp Study

Despite the absence of direct evidence from randomized controlled trials demonstrating its effectiveness in reducing colorectal cancer (CRC) incidence or related deaths, colonoscopy and polypectomy had been widely adopted as the standard of care in clinical practice for decades. This remained the case until the publication of results from last year's Nordic-European Initiative on Colorectal Cancer (NordICC) trial, which were much less satisfactory than expected. Alongside findings from earlier studies, these results sparked significant media attention and stirred controversy regarding the effectiveness of colonoscopies. This situation also provided the opportunity for rethinking the role of colonoscopy in CRC screening.1Bretthauer M. Løberg M. Wieszczy P. et al.Effect of colonoscopy screening on risks of colorectal cancer and related death.N Engl J Med. 2022; 387: 1547-1556Crossref PubMed Scopus (121) Google Scholar, 2Winawer S.J. Zauber A.G. Ho M.N. et al.Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup.N Engl J Med. 1993; 329: 1977-1981Crossref PubMed Scopus (4022) Google Scholar, 3Nishihara R. Wu K. Lochhead P. et al.Long-term colorectal-cancer incidence and mortality after lower endoscopy.N Engl J Med. 2013; 369: 1095-1105Crossref PubMed Scopus (1088) Google Scholar, 4Kahi C.J. Imperiale T.F. Juliar B.E. et al.Effect of screening colonoscopy on colorectal cancer incidence and mortality.Clin Gastroenterol Hepatol. 2009; 7: 770-775Abstract Full Text Full Text PDF PubMed Scopus (328) Google Scholar, 5Sohn E. Colonoscopies save lives. Why did a trial suggest they might not?.Nature. 2023; 613: 235-237Crossref PubMed Scopus (1) Google Scholar The anticipation of greater efficacy was rooted in advancements in colonoscopy technologies, such as improved scope maneuverability, the development of novel imaging technologies, and the introduction of new techniques in polypectomy.6Rex D.K. Ladabaum U. Anderson J.C. et al.Does screening colonoscopy have a future in the United States?.Clin Gastroenterol Hepatol. 2023; https://doi.org/10.1016/j.cgh.2023.05.034Abstract Full Text Full Text PDF Scopus (1) Google Scholar The fundamental assumption was that these advancements would result in a higher detection of neoplastic lesions and their effective management, consequently reducing the risk of ineffective detection and recurrence. These factors were considered major risk factors for postcolonoscopy CRC. In this issue of Clinical Gastroenterology and Hepatology, Sano et al7Sano Y. Hotta K. Matsuda T. et al.Endoscopic removal of premalignant lesions reduces long-term colorectal cancer risk: results from the Japan Polyp Study.Clin Gastroenterol Hepatol. 2023; https://doi.org/10.1016/j.cgh.2023.07.021Abstract Full Text Full Text PDF Scopus (1) Google Scholar reported the effectiveness of colonoscopy and polypectomy in reducing the incidence of CRC. They compared data from the Japan Polyp Study (JPS), a randomized controlled trial originally designed to assess different surveillance intervals after colonoscopic polypectomy, with that of the general population. The original JPS report found no significant difference between 1- and 3-year surveillance intervals in the risk of metachronous advanced neoplasm at the end of the trial. Notably, 62% of the metachronous advanced neoplasm in the JPS cohort were nonpolypoid neoplasms, and 83% of these were nongranular laterally spreading tumor (LST-NG) in morphology.8Matsuda T. Fujii T. Sano Y. et al.Randomised comparison of postpolypectomy surveillance intervals following a two-round baseline colonoscopy: the Japan Polyp Study Workgroup.Gut. 2020; 70: 1469-1478Crossref PubMed Scopus (26) Google Scholar This current study followed up the JPS subjects who underwent subsequent surveillance colonoscopies over a period of up to 12 years (median, 6.1 years). The results revealed that 717 individuals (37.8%) developed advanced neoplasm and had an 86% lower risk of CRC when compared with the general population. It is important to mention that the JPS was conducted in specialized centers dedicated to endoscopic diagnosis and treatment of early colorectal neoplasms, especially nonpolypoid neoplasms, and the procedures were performed by experts skilled in managing such lesions. Nonpolypoid neoplasms, particularly LST-NG, have been suggested as possible etiological factors for postcolonoscopy CRC: previous studies from Japan and other countries reported that LST-NG, especially those with pseudodepression morphology and similarities in biology with depressed neoplasms (0-IIc, 0-IIa+IIc or 0-IIc+IIa), exhibit significantly advanced histology at relatively small sizes compared with other LST subtypes and are believed to progress rapidly into invasive cancers.9Soetikno R.M. Kaltenbach T. Rouse R.V. et al.Prevalence of nonpolypoid (flat and depressed) colorectal neoplasms in asymptomatic and symptomatic adults.JAMA. 2008; 299: 1027-1035Crossref PubMed Scopus (525) Google Scholar, 10Chiu H.M. Lin J.T. Chen C.C. et al.Prevalence and characteristics of nonpolypoid colorectal neoplasm in an asymptomatic and average-risk Chinese population.Clin Gastroenterol Hepatol. 2009; 7: 463-470Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar, 11Yamada M. Saito Y. Sakamoto T. et al.Endoscopic predictors of deep submucosal invasion in colorectal laterally spreading tumors.Endoscopy. 2016; 48: 456-464Crossref PubMed Scopus (70) Google Scholar, 12Bogie R.M.M. Veldman M.H.J. Snijders L.A.R.S. et al.Endoscopic subtypes of colorectal laterally spreading tumors (LSTs) and the risk of submucosal invasion: a meta-analysis.Endoscopy. 2018; 50: 263-282Crossref PubMed Scopus (66) Google Scholar The specific entity known as "LST" was first reported and named by Kudo13Kudo S. Endoscopic mucosal resection of flat and depressed types of early colorectal cancer.Endoscopy. 1993; 25: 455-461Crossref PubMed Scopus (784) Google Scholar and such lesions are widely recognized in Japan. Furthermore, endoscopic diagnosis techniques, such as chromoendoscopy with pit pattern analysis for invasion depth assessment, and endoluminal resection methods, such as endoscopic mucosal resection or endoscopic submucosal dissection, and unique pathologic assessments and characterizations of endoscopically resected specimens, were developed and widely adopted in Japan and have influenced practices in other countries as well. Consequently, the results of this study could be considered a best-case scenario regarding the effectiveness of colonoscopy screening. Nonetheless, there are several important considerations that merit discussion. First, it is crucial to note that all the subjects chosen for randomization in JPS had neoplasms detected during their initial colonoscopy. Consequently, this cohort may not accurately represent the broader average-risk population, in whom more than 60% of individuals do not have any neoplasms, and was rather at higher risk for CRC. Therefore, the results of this study cannot be directly extrapolated to the outcomes of colonoscopy-based screening for the general population. Second, it is important to acknowledge that the current study was not a randomized trial, which means that confounding factors could potentially exist between the study group and the control group. For instance, using data from the population-based Osaka Cancer Registry to estimate the expected incidence of CRC raises concerns about whether this general population had been previously exposed to CRC screening tests, including colonoscopy. Individuals who underwent colonoscopy screening in the study group might have had healthier lifestyles, and the observed effectiveness in the study may not solely be attributed to colonoscopic screening. These limitations highlight the need to explore alternative methods for evaluating the effectiveness of population-based cancer screening programs using real-world databases. Third, as mentioned earlier, the colonoscopies performed in the JPS cohort were conducted by highly skilled experts with a keen ability to detect and diagnose neoplasms, particularly those with subtle nonpolypoid morphologies. The therapeutic interventions were also of the highest quality. Consequently, the study results may not be directly applicable to routine clinical settings in other countries. However, it does establish a high benchmark for the potential efficacy of colonoscopy in preventing CRC when performed at such a high standard. Furthermore, it underscores the fact that even when performed by experts, colonoscopy is not infallible, and postcolonoscopy CRC can still occur. Fourth, the practice of conducting consecutive baseline colonoscopies as done in this study, with 4 invasive cancers detected during the second round before randomization, is not standard procedure. Whether and to what extent this approach contributed to an exceptionally high level of effectiveness or potentially led to an overestimation of effectiveness remains unclear. Finally, the effectiveness of reducing CRC incidence by 86% after colonoscopy in the population who underwent polypectomy in the current study approached the estimated maximum effectiveness reported in the National Polyp Study, conducted decades ago. Although it is not appropriate to directly compare these 2 studies, the results reported in JPS provide reassurance that high-quality colonoscopy is highly effective in preventing CRC.2Winawer S.J. Zauber A.G. Ho M.N. et al.Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup.N Engl J Med. 1993; 329: 1977-1981Crossref PubMed Scopus (4022) Google Scholar Although determining whether colonoscopy is justified as the primary screening modality falls outside the scope of this study, which is related to public preference, endoscopic capacity, and funding concerns, the pursuit of high-quality colonoscopy remains a shared objective across all CRC screening programs. The findings of this study, along with those from the original JPS, offer valuable insights and a clear direction in this regard. Endoscopic Removal of Premalignant Lesions Reduces Long-Term Colorectal Cancer Risk: Results From the Japan Polyp StudyClinical Gastroenterology and HepatologyPreviewTo date, no regional evidence of long-term colorectal cancer (CRC) risk reduction after endoscopic premalignant lesion removal has been established. We aimed to analyze this over a long-term follow-up evaluation. Full-Text PDF