Endoscopic resection of T1 colorectal cancer with unfavorable histologic features: What shall we do next?

According to European colorectal screening programs, T1 colorectal cancer accounts for ≤17% of diagnosed cancers.1Taylor E.F. Morris E.J.A. Thomas J.D. et al.Major improvement in the stage profile of tumours diagnosed in the NHS bowel cancer screening programme.Gut. 2010; 59: A31Crossref PubMed Google Scholar Endoscopic resection of suspected T1 colorectal cancer is the standard of care. However, the resected specimen may show unfavorable histologic features with increased risk for lymph node metastasis, as outlined by the latest National Comprehensive Cancer Network (NCCN) guidelines, including tumor grades 3 and 4 (high-grade histologic features according to the World Health Organization in 2019), presence of lymphovascular invasion, and a positive resection margin.2Nagtegaal I.D. Arends M. Odze R. Tumours of the Colon and Rectum: WHO classification of tumours of the colon and rectum, TNM staging of carcinomas of the colon and rectum and the Introduction.in: Arends M. Ozde R.D. Lam A.K. World Health Organization Classification of Tumours of the Digestive System. 5 ed. IARC Press, 2019: 157-162Google Scholar,3Network NCCColon Cancer. NCCN clinical practice guidelines in oncology (NCCN guidelines®).2023Version: Version 3Google Scholar The Japanese Society for Cancer of the Colon and Rectum guidelines provide additional insight on unfavorable histologic features and include depth of submucosal invasion.4Hashiguchi Y. Muro K. Saito Y. et al.Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2019 for the treatment of colorectal cancer.Int J Clin Oncol. 2020; 25: 1-42Crossref PubMed Scopus (1011) Google Scholar The question is how to incorporate these guidelines into patient care while considering factors like the patient's wishes, preferences regarding potential risks and benefits, and the patient's performance status, among others. Several factors play a role in the decision-making process, including risk of lymph node metastasis, risk of local recurrence, and risk of distant metastasis. The patient's performance status is, however, not accounted for in the NCCN guidelines. The NCCN recommends surgical resection in the presence of any unfavorable histologic feature. Nevertheless, growing evidence shows that in the case of unfavorable histologic features, the risks of lymph node metastasis and local recurrence are low. A recent meta-analysis, which included 5167 patients with T1 colorectal cancer treated endoscopically, shows the pooled risk of colorectal cancer recurrence to be 3.3%. The pooled incidence of colorectal cancer recurrence in T1 cancer with unfavorable histologic features was 7%.5Dang H. Dekkers N. le Cessie S. et al.Risk and time pattern of recurrences after local endoscopic resection of T1 colorectal cancer: a meta-analysis.Clin Gastroenterol Hepatol. 2022; 20: e298-e314Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar Another meta-analysis, which included 21,238 patients, reported that the pooled risk of lymph node metastasis was 11.2% in T1 colorectal cancer.6Zwager L.W. Bastiaansen B.A.J. Montazeri N.S.M. et al.Deep submucosal invasion is not an independent risk factor for lymph node metastasis in T1 colorectal cancer: a meta-analysis.Gastroenterology. 2022; 163: 174-189Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar The risk of local recurrence and lymph node metastasis increases with unfavorable histologic features such as cancer grade, tumor budding, and lymphovascular invasion.6Zwager L.W. Bastiaansen B.A.J. Montazeri N.S.M. et al.Deep submucosal invasion is not an independent risk factor for lymph node metastasis in T1 colorectal cancer: a meta-analysis.Gastroenterology. 2022; 163: 174-189Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar The depth of submucosal invasion shows conflicting data for the local recurrence rate and risk of lymph node metastasis, with local recurrence rates increasing from submucosal (SM)1, 3.5% to SM2, 6% and SM3, 8.3%.7Arthursson V. Medic S. Syk I. et al.Risk of recurrence after endoscopic resection of nonpedunculated T1 colorectal cancer.Endoscopy. 2022; 54: 1071-1077Crossref PubMed Scopus (9) Google Scholar This is likely a result of higher risk for lymphovascular invasion with increased depth of cancer invasion.8Inoki K. Sakamoto T. Takamaru H. et al.Predictive relevance of lymphovascular invasion in T1 colorectal cancer before endoscopic treatment.Endosc Int Open. 2017; 5: E1278-E1283Crossref PubMed Google Scholar When it comes to treatment choice, another factor to consider is that the risk of lymph node metastasis does not increase by manipulating the tumor endoscopically compared with surgical resection.9Overwater A. Kessels K. Elias S.G. et al.Endoscopic resection of high-risk T1 colorectal carcinoma prior to surgical resection has no adverse effect on long-term outcomes.Gut. 2018; 67: 284-290Crossref PubMed Scopus (79) Google Scholar To take all of this into account, and in accordance with NCCN guidelines, T1 colorectal cancers with favorable histologic features are treated successfully with endoscopic resection and/or dissection. The decision on how to treat T1 colorectal cancers with unfavorable histologic features is harder to make. Patients with significant comorbidities and limited life expectancy are often followed up only with endoscopic and cross-sectional imaging surveillance because of the risk of surgical morbidity and mortality. These recommendations are made on a patient-to-patient basis during multidisciplinary tumor board discussions. The main question is what to do with the remaining patients who have T1 colorectal cancer with ≥1 unfavorable histologic features in the absence of significant comorbidities, in the knowledge that most patients will receive no oncologic benefit from surgical resection. The NCCN guidelines leave us only 1 option, which is surgical resection. In this issue of Gastrointestinal Endoscopy, Corre et al10Corre F. Albouys J. Tran V.-T. et al.Impact of surgery after endoscopically resected high-risk T1 colorectal cancer: results of an emulated target trial.Gastrointest Endosc. 2024; 99: 408-416.e2Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar provide additional insight for patients with T1 colorectal cancer with ≥1 unfavorable histologic features and the absence of significant comorbidities. The authors report their 7-year experience from 14 French tertiary centers with retrospectively collected data from 518 patients who underwent endoscopic resection of T1 colorectal cancer, who were then followed up by either surgical resection (treatment cohort) or only observation (control cohort). The authors excluded all the low-risk cancers (n = 176) (as defined by the NCCN guidelines) and patients with significant comorbidities (n = 33) who did not undergo surgical resection. In addition, patients with <3 months of follow-up care (n = 46) were excluded, as were patients with positive deep margins (n = 65), in which case surgery is always indicated. This resulted in 197 patients (median age 66 years) without significant comorbidities: 107 patients in the treatment cohort and 90 patients in the control cohort. All cases were evaluated by a GI pathologist and had at least 1 unfavorable histologic feature, including poor tumor differentiation (56.3% and 50.6%), lymphovascular invasion (37.9% and 16.9%), grade 2 and 3 budding (44.1 and 35.0%), and deep submucosal invasion (>1000 μm submucosal invasion: 85.6% and 77.9%). The primary outcome was distant cancer recurrence and overall survival. In the treatment cohort, 4 out of 107 patients died within 48 months (3.7%), including 2 patients who died of colorectal cancer. A total of 4 patients experienced distal recurrence within 48 months. In the control cohort, 6 out of 90 patients died within 48 months (6.7%), including 1 patient who died of colorectal cancer. All other deaths were not related to colorectal cancer. Two patients experienced distal recurrence (1 died), and 2 patients experienced local recurrence within 48 months. Both local recurrences were treated with salvage surgery. All patients in the control cohort underwent colonoscopy surveillance at the 1-year and 3-year intervals. In addition, all patients underwent CT every 6 months for 5 years. The median follow-up time for cancer recurrence was 3.3 years (IQR 2.5-3.9 years), and the median follow-up time for overall survival time was 4.2 years (IQR 3.3-5.7 years), with no patients lost to follow-up. There were significant differences between both cohorts in terms of baseline characteristics including tumor differentiation and depth of submucosal cancer invasion, cancer location, and the type of endoscopic resection. The authors controlled for these statistically significant differences with inverse probability treatment weighting. Using these statistical methods, Corre et al10Corre F. Albouys J. Tran V.-T. et al.Impact of surgery after endoscopically resected high-risk T1 colorectal cancer: results of an emulated target trial.Gastrointest Endosc. 2024; 99: 408-416.e2Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar found no significant differences in proportion of distant cancer metastasis and death between both cohorts. These are important findings, and we congratulate the authors for this study. This publication demonstrates that the risk of distant disease and death are low after only endoscopic resection and are comparable with those in patients who underwent surgical resection for T1 colorectal cancer with unfavorable histologic features. These data help us evaluate such patients during multidisciplinary tumor boards, and they aid in the discussion with the patients themselves. However, these findings are not ready for the NCCN guidelines yet. The limitations, including lack of statistical power and selection bias resulting from the retrospective nature of the study, limit the generalizability and must make us interpret these results with caution. To address these concerns, randomized controlled studies would be helpful. However, it is unlikely that such a study will be performed, given ethical concerns about not offering standard-of-care treatment for patients according to the NCCN guidelines. Furthermore, we also need to consider multiple other underlying factors such as the quality of endoscopic resection, the quality of detection of locoregional and distant disease, and the evolving understanding of tumor biology. Along these lines, the impact of circulating tumor DNA may provide guidance in the future to improve our patient stratification for T1 colorectal cancer with unfavorable histologic features. In summary, this study provides additional information and shows a low risk of distant cancer recurrence and death within 4 years after endoscopic resection of T1 colorectal cancer with unfavorable histologic features. The author disclosed no financial relationships.