Clinically Significant Metachronous Colorectal Pathology Detected Among Young-onset Colorectal Cancer Survivors: Implications for Post-resection Surveillance Guidelines

The incidence of colorectal cancer (CRC) has been increasing worldwide among young adults aged 18–50 years and the reason for it remains unknown.^{1, 2} Patients with sporadic young-onset CRC (YOCRC, diagnosed at ≤ 50 years) are postulated to have a more biologically active colorectum prone to malignant transformation earlier in life. Exposure risk factors, such as Western-style diet, obesity, physical inactivity, antibiotic use, and microbiome, overlaid with gene-environment interactions, have been implicated as plausible triggers.^{3, 4}

Survivors of CRC are recommended to undergo post-resection endoscopic surveillance aimed at intercepting and preventing future colorectal morbidity, through timely detection and clearance of premalignant or metachronous lesions.⁵ Consensus guidelines worldwide recommend first surveillance colonoscopy at 1 year (12 months) post-resection, and the next surveillance colonoscopy after an interval of 3 or more years (at 48 or more months post-resection).^5–8 However, these recommendations are generalized for all non-hereditary CRC patients regardless of age at index diagnosis. Specifically, it is unknown whether there is an elevated risk for metachronous pathology after the index YOCRC, and there have been no studies assessing the adequacy of the current surveillance recommendations. To fulfill these gaps in knowledge, we aimed to define this risk and to inform the post-resection endoscopic surveillance in sporadic YOCRC survivors, a population that is expected to grow.

After approval from the University of Texas MD Anderson Cancer Center Institutional Review Board, a prospectively maintained database was queried to identify consecutive patients who underwent curative-intent surgical resection of YOCRC (≤ 50 years) between 2009–2017. Patients with hereditary syndrome based on genetic testing, recurrent disease, or without endoscopy before resection and/or during follow-up were excluded. Demographic data, operative and treatment details, pathological staging, and surveillance endoscopy findings were extracted by natural language processing⁹ and verified by clinical and outside record review. Patients were followed to their last known medical encounter. Clinically significant metachronous colorectal pathology were defined as: high-risk adenoma (≥1cm in size, >3 in number, or villous/sessile serrated/high-grade dysplasia histology), intraluminal local recurrence, and second CRC. Person-years of follow-up was calculated from resection to the first post-resection endoscopy. The primary outcome was the rate of clinically significant metachronous pathology defined as the number of new incident cases divided by person-years at risk.

A total of 721 YOCRC patients underwent curative-intent resection. After excluding those with hereditary CRC (n=120, 16.5%), recurrent disease (n=45, 6.2%), or no recorded endoscopy (n=106, 14.6%), 457 YOCRC patients formed our study cohort. The median age at diagnosis was 44 years (interquartile range [IQR]: 39–48) and 227 (49.7%) were female. The median body mass index was 27.9 kg/m² (IQR 24.0–31.5). Disease arose from the proximal colon in 43 (9.4%) patients, distal colon in 105 (23.0%), and rectum in 309 (67.6%). Stage at diagnosis was I/II in 191 (41.8%) patients, III in 185 (40.5%) patients, and IV in the remaining 81 (17.7%). Surgical resections included partial colectomy in 99 (21.7%), proctectomy with or without sphincter preservation in 346 (75.7%), and extended resection in 12 (2.6%) patients for synchronous pathology not cleared by preoperative endoscopy.

The median follow-up was 48.1-months (IQR: 30.1–68.1). Thirty-eight patients had clinically significant lesions during 1,192 person-years of follow-up: 31 high-risk adenomas, 6 luminal recurrences, and 1, second CRC. The overall incident rate of clinically significant metachronous pathology was 32 per 1000 person-years. The median time of detection was 13.9 months (IQR: 11.8–33.1) post resection. Twenty-four (63.2%) incidents were detected within 15 months post-resection (allowing a 3-month window from the recommended 12-month timepoint), while another 9 (23.7%), in the remaining interval preceding the recommended 48-month timepoint. (Figure 1)

Figure 1:

Clinically significant metachronous colorectal pathology among survivors of sporadic young-onset colorectal cancer: A swimmer’s plot. Twenty-four (63.2%) incidents were detected within 15 months (dotted line) post-resection (allowing a 3-month window from the recommended 12-month timepoint), while another 9 (23.7%), in the remaining interval preceding the recommended 48-month timepoint.

This is the first study to assess post-resection surveillance and metachronous lesions in YOCRC survivors. We observed characteristic clinical features of YOCRC, with a predominance of cases occurring in the left colon and rectum, and being already locally advanced or metastatic at presentation.² These again highlight the need for effective strategies for earlier detection and interception. Based on real-life data as collected, clinically significant metachronous lesions were identified at an incidence rate of 32 per 1000 person-years of follow-up, with over half clustered around the first recommended timepoint of 12 months post-resection but nearly another quarter detected prior to the second recommended timepoint (48-month or later). These findings corroborate a recent meta-analysis revealing that the highest risk for metachronous CRC occurred within 24–36 months of the index resection, with the risk decreasing in a time-dependent fashion thereafter.¹⁰ Taken together, we highlight the critical importance of a high-quality endoscopy at 12 months post resection to ensure clearance of any lesions that potentially could have been missed from the index endoscopy diagnosing the YOCRC, and suggest a potential benefit in shortening the interval to the second surveillance scope to fewer than 48 months post-resection. Attending to these two aspects could better ensure the timely detection, interception and prevention of colorectal pathology among YOCRC survivors.

While our findings are informative for clinical care and practice guidelines in this unique patient population, they remain limited in their source from patients treated at a U.S. tertiary-referral cancer center, and warrant further validation ideally in a prospective, multicenter, and international manner. Furthermore, we could not determine the indications for post-resection endoscopies in all cases; often YOCRC patients and/or providers request more frequent endoscopy for cancer worry or anxiety with or without symptoms. Finally, the incidence of metachronous lesions post-resection is impacted by the quality of the pre-operative colonoscopy⁷ and we could not account for the heterogeneity in these scopes, typically having been performed prior to referral.

In conclusion, to inform a tailored surveillance strategy for the unique and growing population of YOCRC survivors, we conducted a first study assessing the risk of clinically significant metachronous pathology after curative-intent resection utilizing real-life data from a large cohort of patients with sporadic YOCRC. The substantial incidence rate identified, and the observed time pattern of detection suggest that these patients would benefit from close surveillance in the early post-resection years. Ensuring a high-quality colonoscopy at 12 months to establish post-resection baseline, and considering an interval shorter than 3 years until the next surveillance scope, could facilitate secondary prevention of colorectal pathology among survivors from YOCRC.