Colon and Rectal Cancer show similar survival in Advanced Early Onset Colorectal Cancer

Biology over Location: Survival in Advanced Early-Onset Colorectal Cancer: A Retrospective Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Biology over Location: Survival in Advanced Early-Onset Colorectal Cancer: A Retrospective Analysis Oluwabukunmi Modupe Salami, Hao Yi, Guangyi Liu, Yang Li This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9137238/v2 This work is licensed under a CC BY 4.0 License Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Abstract Objective: This study aimed to compare clinicopathological characteristics and survival outcomes between colon and rectal primaries in a young, advanced-stage cohort. Background : The rising incidence of early-onset colorectal cancer necessitates a clearer understanding of its clinical behaviour. Most studies group colon and rectal cancers, but they have different entities. The comparative prognosis in young patients with advanced disease remains undefined. Method : A retrospective cohort study was conducted of 162 patients under 50 with stage III-IV colorectal cancer treated at a single center (2018-2023), categorized into colon (n=82) and rectal (n=80) groups. Clinicopathological data, treatment patterns, and survival outcomes were analyzed using Kaplan-Meier estimates, propensity score matching, and multivariable Cox regression. Results : The cohorts exhibited distinct clinical presentations: rectal cancer patients had more hematochezia (60% vs. 25.6%, p<0.001), while colon cancer patients presented with more abdominal pain (59.8% vs. 15%, p<0.001). Left colon dominated in colon group, whereas low rectum succeeded in the rectal group. Treatment differed significantly, with rectal group receiving more neoadjuvant therapy (27.5% vs. 8.5%, p=0.002). Though unadjusted analysis showed no significant difference in DFS (p=0.18) or OS (p=0.32), after propensity score matching, survival curves remained congruent. On multivariable analysis, tumour location was not an independent predictor of DFS (HR=1.15, p=0.56) or OS (HR=1.39, p=0.16), while advanced stage and synchronous metastasis were. Conclusion: In young patients with advanced colorectal cancer, tumour location does not independently predict survival. Despite different clinical presentations and treatment pathways, prognosis appears driven by factors like disease stage and biology rather than anatomical location. locally advanced cancer Early onset colorectal cancer colon cancer rectal cancer Survival analysis prognosis Figures Figure 1 Figure 2 Figure 3 Statement of Translational Relevance Our research directly informs the future practice of oncology by challenging the conventional use of anatomical location (colon vs. rectum) as a primary prognostic factor in young patients with advanced colorectal cancer. We demonstrate that survival outcomes are equivalent after accounting for confounders, indicating that the aggressive biology common in early-onset CRC may override location-based prognostic differences. This finding urges a shift in clinical thinking: prognostic stratification and treatment intensification decisions should be guided more by comprehensive staging, pathological risk factors, and future molecular profiling than by the colon-rectum distinction alone. By redirecting focus from anatomy to biology, we believe our work paves the way for more personalised, risk-adapted management strategies, ultimately aiming to improve outcomes for young patients with colorectal cancer. Introduction Colorectal cancer (CRC) remains a leading cause of cancer morbidity and mortality worldwide, while incidence is decreasing in older adults owing to better screening modalities and treatment, there is increasing incidence among younger adults under the age of 50 1 . Colorectal cancer in younger patients under age 50 has been termed early-onset colorectal cancer (EO-CRC) or young onset colorectal cancer(YO-CRC). A study showed that in the United States, the prevalence of EO-CRC from 2011-2019 increased by 1.9% per year, especially in the 20–29 year age group, which was about 3.8% per year. Patients were predominantly female and were likely to present with abdominal pain and hematochezia 1,2 . In China, from 1990 to 2017, EOCRC has increased by about 140%, patients present at a more locally advanced stage, and predominantly in the left colon/rectum, incidence is higher in males, owing to alcoholism, smoking, and a low whole-grain diet 3-5 . This early-onset CRC group often present with distinct clinical and molecular characteristics 6 , owing to different environmental(diet and lifestyle habits) and genetic risk factors, not excluding immunological dysfunction, inflammation, and gut microbiota changes 7,8 , necessitating tailored therapeutic approaches 9 . While often studied as a single entity in this cohort, colorectal cancer is a heterogenous disease. Cancers of the colon and rectum differ in their embryological origin, vascular supply, surgical management, and molecular profiles 10 . Treatment strategies for locally advanced rectal and colon cancers traditionally involve surgical resection as the major curative intervention. However, neoadjuvant therapy including chemotherapy and radiotherapy, has increasingly been adopted in advanced rectal cancer to improve tumour downstaging, reduce local recurrence, and enhance sphincter preservation, even in early onset disease 11-13 . In contrast, for colon cancer, upfront surgical resection followed by adjuvant chemotherapy remains the main treatment modality for advanced disease, with neoadjuvant therapy currently reserved for select cases within clinical trials 14 . Despite the advances in EOCRC incidence and molecular characteristics, there remains little information on the optimal sequence of multimodal therapies for early-onset CRC patients. The National Comprehensive Cancer Network (NCCN) guidelines 15 dictate surgical resection alone for stage I disease and surgical resection and systemic chemotherapy for stage II and III disease, with added radiation therapy for rectal cancer 16,17 . However, these guidelines are predominantly based on studies and RCTs with combined age groups, or all disease stages, potentially diluting the unique characteristics and unmet needs of this young, high-risk population 18 . This subgroup, despite recorded better survival outcomes and chemotherapy tolerability, due to their distinct clinical and molecular characteristics, tends to be overtreated and therefore, prone to unnecessary long-term treatment toxicities and quality-of-life impacts, which warrant close monitoring 19 . Moreover, it remains unclear whether primary tumour location itself is an independent determinant of prognosis in the specific context of young-onset, advanced-stage disease and the utility of pathological downstaging as a surrogate marker for long-term prognosis is yet to be fully elucidated in this population. Therefore, the main purpose of this study was to characterise and compare the clinicopathological features, treatment modalities, and survival outcomes between young patients with advanced (Stage III and IV) colon cancer and rectal cancer. By focusing specifically on this advanced-stage early-onset group, we seek to provide insights that can inform clinical decision-making and prognostic discussions in younger patients. Understanding these differences could refine personalized treatment strategies and improve clinical decision-making in this patient group. Methods 1.1 Study design and population This is a retrospective cohort study of patients surgically treated for early onset locally advanced colon and rectal cancer in a single centre, The Second Affiliated Hospital of Chongqing Medical University, based in Chongqing Province of China between January 2018 and December 2023. The patients were then categorized into two groups based on the primary tumor location; those with tumors located from the caecum to the sigmoid colon, and those with tumours located in the rectum, defined as within 15 cm of the anal verge by rigid sigmoidoscopy or below the sacral promontory on imaging. Inclusion criteria were age less than 50 at diagnosis, advanced clinical TNM stage III and IV, and availability of complete clinical and follow-up data. Exclusion criteria were non-primary colorectal cancer, recurrent CRC, incomplete or missing follow-up data. Patients with clinically or pathologically confirmed stage III and IV colorectal cancer were selected for inclusion in this study. We focused on clinical stage III and IV colorectal cancer, confirmed with CT and MRI Scans, in this advanced disease cohort due to the distinct clinical management choices and prognostic considerations associated with these stages, where treatment sequencing decisions between neoadjuvant therapy and upfront surgery are most clinically relevant. Follow-up time was till August 31, 2025. Neoadjuvant and Postoperative chemotherapy regimens, included FOLFOX (5-FU + oxaliplatin), FOLFIRI (5-FU + irinotecan), FOLFIXIRI (5-FU + oxaliplatin+ irinotecan), and CAPOX (capecitabine + oxaliplatin), were typically administered based on tumor staging, pathology type, and patient health status. In high-risk cases, radiotherapy and targeted therapies like anti-EGFR (cetuximab) or anti-VEGF (bevacizumab) antibodies were also added. 1.2. Data collection The study retrospectively identified and utilized data from the institutional electronic medical records. Demographics, lifestyle factors (smoking, alcohol consumption), tumor characteristics such as location, histology, and stage; Left-sided colon was defined as the descending colon, right-sided colon was defined as the cecum and ascending colon; treatment details (surgical type, neoadjuvant regimen, post-surgical chemotherapy regimen, length of hospital stay-calculated from surgical date to discharge) and postoperative outcomes were collected. Tumour location was then subcategorized anatomically. Metastatic status was recorded at two time points: synchronous metastases identified around surgery, and metachronous metastases detected during follow-up, with detailed sites specified (e.g., liver, lung, peritoneum). 1.3. Outcome Measures The primary outcome was: (1) Disease-Free Survival (DFS), which was defined as the time from surgery to the first documented recurrence, metastasis or death from any cause. (2) Overall Survival (OS), defined as the time from surgery to death from any cause or last follow-up. (3) Cancer-Specific Survival (CSS), defined as the time from surgery to death due to colorectal cancer. Patients without an event were censored at the date of last follow up. And last, patterns of recurrence and metastasis site distribution. Secondary outcomes include: rates of pathological response (in patients receiving neoadjuvant therapy) and recurrence patterns. Pathological tumour downstaging, defined as a reduction in tumor stage from clinical preoperative assessment to pathological postoperative staging according to AJCC 8th edition criteria. 1.4. Statistical Analysis Continuous variables were represented as means ± standard deviation, and compared using Student’s t-test or Mann-Whitney U tests as appropriate. Categorical variables were presented as counts and percentages, with group comparisons performed via chi-square or Fisher’s exact tests. Survival analyses were conducted using Kaplan-Meier, with differences between treatment groups and tumor locations assessed by log-rank tests. Multivariable Cox proportional hazards models adjusted for potential confounders including age, sex, comorbidities, tumor location, histology, and pathological stage. Propensity score matching was applied to reduce selection bias, matching patients in colon and rectal groups based on baseline characteristics including age, sex, tumor stage, and comorbidities. Given the observed differential use of neoadjuvant therapy in rectal cancer, an exploratory subgroup analysis was performed within the rectal cancer cohort only to compare outcomes between patients who received neoadjuvant therapy and those who underwent upfront surgery. This analysis was considered hypothesis-generating due to the small sample size. Statistical significance was set at p < 0.05. Analyses were performed using IBM SPSS Statistics for Windows, Version 28.0 (IBM Corp., Armonk, N.Y., USA) and Python 3.9.12. 1.5. Ethical Considerations The study was approved by the Institutional Review Board of second affiliated hospital of Chongqing Medical University with a waiver of informed consent due to retrospective data use and anonymization of patient identifiers. This study was designed, analyzed, and reported in accordance with the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) statement. Results 2.1. Baseline Characteristics A total of 249 patients with early colorectal cancer, by our definition- age less than 50, who underwent surgical treatment at our centre, were identified. After extensive exclusion, a total of 162 patients with no missing information were included in this study, which were then divided into the colon group (n=82, 50.6%) and the Rectal group (n=80, 49.4%), based on the tumor location ( Figure 1 ). The mean age was approximately 41 years across groups. Gender distribution was fairly balanced though male predominated in colon cancer (53.7%) and females in rectal cancer (57.5%, p=0.155). Significant differences in alcohol consumption were noted, being higher in colon cancer (37.8% vs. 20%, p=0.013). Clinically, hematochezia was markedly more frequent in rectal cancer (60% vs. 25.6%, p<0.001), whereas abdominal pain was more common in colon cancer (59.8% vs. 15%, p<0.001). Anemia and weight loss as collateral symptoms were also significantly observed in colon cancer groups (p=0.014 and 0.041 respectively). Time to diagnosis varied significantly, with 42.6% diagnosed within 1 month overall but higher proportion for colon cancer diagnosed earlier than rectal cancer (p=0.036), with a longer diagnostic delay (>1 year) more often seen. Family history was also more frequent in colon cancer patients (8.5% vs. 1.3%, p=0.032). ( Table 1 ) 2.2. Treatment and surgical details Surgical approach, and perioperative details were similar across groups with no significant differences in surgical methods, or blood transfusions or time from surgery to discharge ( Table 2 ). Most surgeries were laparoscopic (84.6%) with no significant difference in surgery type between groups. Stoma creation was significantly higher in rectal cancer patients (30% vs 14.6%, p=0.019), consistent with anatomical considerations. Synchronous metastasis treatment was comparable across groups (p=0.621). Use of neoadjuvant therapy was significantly more prevalent in rectal cancers (27.5% vs 8.5% in colon cancer, p=0.002), including neoadjuvant radiotherapy being exclusively used in rectal cancer (11.3%, p=0.002). Postoperative immunotherapy was also more common in rectal cancer (28.8% vs. 15.9%, p=0.048). Time from surgery to chemotherapy was longer in rectal cancer patients (p=0.020). Complication rates were also comparable between groups (p=0.231), and the average length of hospital stay was similar (p=0.388). 2.3. Pathological characteristics Pathological examination revealed several notable differences between colon and rectal cancers. Tumor sublocation was significantly different: left colon and transverse colon dominated in colon cancer, whereas low rectal subsites were more common in rectal cancer (p=0.000). Clinical staging showed borderline significance with more stage 3 in rectal cancer, and stage 4 more in colon cancer(p=0.050). The T stage and pathological stage differed; rectal cancer showed higher T0-2 rates, but colon cancer had higher T3-4 rates (p = 0.018). Additionally, rectal cancer had more pathological stage 0 and III lesions (2.5% and 57.5%) than colon cancer (0% and 30.5%) (p = 0.002). Histological subtypes and tumor neurovascular invasion patterns were similar, though the dataset did not explore molecular subtypes due to data limitations. Lymph node involvement was more frequent in rectal cancer (72.5% vs. 53.7%, p=0.013), though the number of lymph nodes harvested was higher in colon cancer (15.2 vs 13.3, p=0.035). Median positive lymph nodes were also higher in rectal cancer (2 vs. 1, p<0.001). Positive resection margin was longer in colon cancer (5.8 cm vs. 2.8 cm, p<0.001). Overall synchronous metastasis was more common in colon cancer (36.6% vs. 22.5%, p=0.050), with a higher incidence of peritoneal metastases (9.8% vs. 1.3%, p=0.018), while rectal cancers had more inguinal lymph node metastases (7.5% vs. 1.2%, p=0.049). ( Table 3 ) 2.4. Survival outcomes The overall median follow-up time is 70 months. The mean OS of the Colon and Rectal group was (36.5 ± 24.5) and (39.7 ± 25.1) months, respectively (P = 0.580), with a median DFS of (32 ± 27.4) months for the Colon group and (28.4 ± 23.5) months for the Rectal group (P = 0.058). There was a higher frequency of disease-free survival (DFS) events in the rectal cancer group compared to the colon cancer group (39/80 [48.8%] vs. 26/82 [31.7%], p=0.02), suggesting an initial association between rectal primary and poorer DFS. However, after propensity score matching to balance baseline characteristics, this difference was no longer statistically significant (12/66 [18.2%] vs. 4/66 [6.1%], p=0.18). A similar pattern was observed for recurrence; however, the rates of overall survival events were comparable between groups both before and after matching ( Table 4 ). In the Colon group, the 1-year, 3-year and 5-year DFS rates were slightly higher (94.9% and 71.1% and 59.3%) respectively, and (90.9% and 65.2% and 43.8%) in the Rectal group, the difference was not statistically significant (P = 0.058). However, the 1-year, 3-year, and 5-year OS rates were similar in both groups, (85% and 61.9% and 56.5%) in the Rectal group, and (85.4% and 60.5% and 55%) in the Colon group and these differences were also not statistically significant (P = 0.580) ( Figure 2a, b ). 2.5. Multivariate Cox regression analysis On multivariable Cox regression analysis controlling for key clinicopathological variables(age, sex, clinical stage, treatment modality, and key pathological factors), the tumor group (Colon vs. Rectal) was not an independent predictor of either DFS (Hazard Ratio [HR]=1.15, 95% CI 0.70–1.90, p=0.56) or OS (HR=1.39, 95% CI 0.87–2.25, p=0.16). Significant independent predictors of worse DFS included higher preoperative stage (HR=2.84, 95% CI 1.72-4.67, p<0.001), nodal involvement (N stage, HR=1.56, 95% CI 1.16-2.09, p=0.003), neurovascular invasion (HR=1.59, 95% CI 1.24-2.03, p<0.001), and synchronous metastases to the liver (HR=2.49, 95% CI 1.35-4.58, p=0.003) or lungs (HR=5.22, 95% CI 2.12-12.86, p<0.001). For OS, significant predictors included preoperative stage (HR=1.65, 95% CI 1.02-2.67, p=0.03), T stage (HR=1.44, 95% CI 1.00-2.08, p=0.05), neurovascular invasion (HR=1.26, 95% CI 1.00-1.59, p=0.04), and postoperative stage (HR=1.86, 95% CI 1.14-3.02, p=0.01). ( Table 5 ). 2.6. Exploratory Analysis: Treatment Effect in Rectal Cancer Subgroup Given the differential use of neoadjuvant therapy, we conducted an exploratory analysis within the rectal cancer cohort (n=80) comparing outcomes between patients who received neoadjuvant therapy (n=22) versus upfront surgery (n=58). This analysis was limited by a small sample size but showed no significant difference in DFS (HR=0.47, 95% CI 28.59- 46.37, p=0.49) or OS (HR=0.84, 95% CI 39.28- 58.57, p=0.35) between these treatment approaches( Figures 3a and b ). Discussion This study provides a comprehensive analysis of advanced stage III-IV colon and rectal cancers within a specific and increasing cohort of CRC patients, EOCRC patients (age <50), looking at the clinicopathological characteristics and survival outcomes. Our principal findings show that in the EO-CRC group, despite significant differences in presentation patterns and treatment approaches, primary tumour location does not independently predict survival outcome. After robust adjustment for confounders using both propensity score matching and multivariable Cox regression, the survival curves for colon and rectal cancer patients were virtually superimposable, and tumour location was not significantly associated with either disease-free or overall survival. This suggests that in young-onset advanced CRC, overarching disease biology and stage may exert a stronger influence on prognosis than anatomical subsite alone. The distinct clinical presentations we observed align with well-known anatomical and physiological considerations: rectal cancers more commonly caused hematochezia due to their distal location, while colon cancers presented more frequently with abdominal pain 20 , possibly reflecting larger tumour size or obstruction. The differential treatment patterns reflect current standard practices, with rectal cancer patients more frequently receiving neoadjuvant therapy, particularly radiotherapy, consistent with established protocols for locally advanced rectal cancer 11 . Our findings confirm that the recommended management guidelines are being applied in real-world practice for young patients too 16,21 . The unadjusted analysis suggested a worse DFS for rectal cancer patients, which is consistent with historical data 22,23 . However, this apparent disadvantage was nullified after statistically controlling for confounding variables through propensity score matching. This key finding indicates that the observed difference in DFS was not intrinsically due to the rectal location itself, but was likely driven by other prognostic factors unevenly distributed between the groups, such as treatment patterns, staging, pathological characteristics and the presence of synchronous metastases. Our multivariable analysis confirmed that these established factors, including lymph node involvement and neurovascular invasion, were the dominant predictors of survival, while tumor location was not. The most significant and novel contribution of our study is the demonstration that tumor location is not an independent prognostic factor in this cohort. This finding appears to contrast with some studies in older or all-stage CRC populations that have reported survival differences between colon and rectal cancers 24-30 . Several factors may explain this discrepancy. First, the aggressive biology frequently observed in EOCRC, characterized by a higher prevalence of adverse features such as signet ring cell histology and poor differentiation 6 , which may represent a universal driver of poor prognosis that overwhelms any subtle differences that can be attributed to anatomical subsite. Essentially, the shared aggressive biology of advanced EO-CRC may create a "ceiling" of poor prognosis, making it difficult to discern a survival difference based on location alone. Second, our cohort was exclusively composed of advanced-stage (III and IV) patients. It is plausible that at these advanced stages, the determinants of outcome shift decisively toward factors like metastatic burden and tumor invasiveness, diminishing the relative prognostic weight of the primary tumour's location. Third, modern multimodal therapy may effectively mitigate the historical survival disadvantage associated with rectal cancer, leading to a convergence of outcomes in contemporarily treated patients 31 . Multivariable Cox regression analysis confirmed that established prognostic factors such as advanced clinical and pathological stages, lymph node involvement, tumor neurovascular invasion, and synchronous metastases were significant predictors of survival, aligning with established prognostic factors in colorectal cancer 32,33 , emphasizing that disease biology and burden, rather than anatomical origin, are the critical factors in this population. The fact that tumor location did not retain significance in a model containing these powerful covariates strongly suggests that the initial, unadjusted difference in DFS was not causal but was instead confounded by the imbalanced distribution of these other prognostic factors between the colon and rectal groups. This finding has important clinical implications, suggesting that prognostic stratification and treatment intensification decisions in young patients with advanced CRC should be based on tumor biology and stage rather than location alone 34 . Our finding that tumor location lacks independent prognostic significance appears to contrast with studies in older, all-stage CRC populations. This discrepancy with other studies in older, all-stage CRC populations can be explained by the unique molecular biology of EOCRC, which is increasingly recognized as a distinct disease entity. Recent transcriptomic analyses reveal that EOCRC is characterized by a marked predominance of the CMS2 (canonical) and CMS3 (metabolic) molecular subtypes, which together can account for up to 94% of cases 35 . They are also associated with an absence of BRAF mutations and the methylator phenotype 36 . These subtypes are associated with chromosomal instability (CIN) and activated oncogenic pathways like Wnt/β-catenin, driving a cell cycle-driven, proliferative tumor phenotype 35,37 . With respect to tumour location, previous studies on molecular and biological markers in EOCRC, where loss of MLH1 and PMS2 was detected more frequently in the colon rather than in the rectum, and PIK3CA and KRAS mutation mostly in the left-sided rather than the right-sided colon or rectum 34 , though other studies saw KRAS and CTNNB1 mutations in right colon tumors 38 . Conversely, late-onset CRC (LOCRC) has a significantly higher proportion of CMS1 (MSI immune) and CMS4 (mesenchymal) subtypes, which are more immunogenic 39 . The molecular profile of EOCRC effectively creates an "immune desert" tumour microenvironment, while LOCRC exhibits greater immune cell infiltration 35 . This fundamental biological distinction suggests that EOCRC, regardless of colon or rectal origin, is often propelled by a shared set of aggressive, cell-cycle-driven pathways. This common biological backdrop may overwhelm any more modest prognostic influences related to anatomical subsite, particularly in advanced-stage disease where tumor burden and invasiveness are the primary determinants of outcome. Our exploratory analysis within the rectal cancer subgroup, while limited by the small sample size and the constitutional biases in treatment selection, found no significant survival difference between patients receiving neoadjuvant therapy and those undergoing upfront surgery. This hypothesis-generating observation highlights the need for larger, prospective studies to definitively determine the optimal treatment sequence for young patients with rectal cancer, a population often under-represented in clinical trials. The strengths of our study include its focus on a well-defined, homogeneous cohort of young patients with advanced disease, the comprehensive clinicopathological data, and the use of both propensity score matching and multivariable regression to address confounding. However, several limitations must be acknowledged. The retrospective, single-center design introduces potential for selection bias, and limits the generalizability of our findings, though we employed statistical methods to mitigate this. The sample size, particularly for the exploratory rectal subgroup analyses, also limits the power to detect small differences. The lack of molecular and genetic data also prevents analysis of how biological subtypes might interact with tumor location to influence outcomes. Future prospective multicenter studies incorporating molecular profiling is essential to move from an anatomical to a biological understanding of prognosis in EOCRC. In conclusion, our study demonstrates that while young patients with advanced colon and rectal cancer present and are treated differently, their ultimate survival outcomes are remarkably similar. This finding challenges the assumption that tumor location is a primary determinant of prognosis in this population and shifts the focus toward the critical roles of disease stage and underlying biology. For clinicians, this implies that prognostic stratification and decisions regarding treatment intensity in young patients with advanced CRC should be guided more by comprehensive staging and pathological risk factors than by anatomical subsite alone. Future research efforts should prioritize the molecular characterization of EOCRC to identify the true biological drivers of outcome and pave the way for biology-driven, rather than location-driven, personalized therapy. Conclusion In this cohort of young patients with advanced colorectal cancer, colon and rectal primaries exhibit distinct clinical presentations and receive different treatment regimens. However, after adjusting for confounders, tumor location was not an independent predictor of survival. This suggests that in early-onset advanced disease, overall disease biology and stage may be more critical determinants of outcome than anatomical subsite. Future research should focus on molecular characterisation to identify biology-driven, rather than location-driven, treatment strategies for this growing patient population. Abbreviations Early onset colorectal cancer (EOCRC), Declarations Author contributions OMS designed the study, collected, analyzed the data and wrote the first and final draft of the manuscript. HY collected the final follow up data, analyzed the data, revised manuscript draft, GL wrote the final version of the manuscript, contributed to the conception, and did the manuscript revision. YL provided resources, gave intellectual suggestions and overall supervision for the article. All authors have read and approved the final manuscript. Acknowledgements statement: None Assistance with the study: None Financial support and sponsorship: None Funding: None Conflicts of interest: The authors declare no potential conflicts of interest Data availability: Available under reasonable request Ethics Statement: The study was approved by the Institutional Review Board of second affiliated hospital of Chongqing Medical University with a waiver of informed consent due to retrospective data use and anonymization of patient identifiers. 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Secular trends in colon and rectal cancer relative survival. Journal of the National Cancer Institute . 2013;105(23):1806-1813. Zhu J, Lian J, Xu B, et al. Neoadjuvant immunotherapy for colorectal cancer: Right regimens, right patients, right directions? Frontiers in immunology . 2023;14:1120684. doi:10.3389/fimmu.2023.1120684 Chen K, Collins G, Wang H, Toh JWT. Pathological features and prognostication in colorectal cancer. Current Oncology . 2021;28(6):5356-5383. Mehrkhani F, Nasiri S, Donboli K, Meysamie A, Hedayat A. Prognostic factors in survival of colorectal cancer patients after surgery. Colorectal disease . 2009;11(2):157-161. Chen Y, Chen Z, Huang J, et al. Clinicopathological and molecular characteristics of early-onset vs late-onset colorectal cancer according to tumor location. International journal of clinical oncology . Apr 2022;27(4):749-755. doi:10.1007/s10147-021-02101-9 Guinney J, Dienstmann R, Wang X, et al. The consensus molecular subtypes of colorectal cancer. Nature medicine . 2015;21(11):1350-1356. Kirzin S, Marisa L, Guimbaud R, et al. Sporadic early-onset colorectal cancer is a specific sub-type of cancer: a morphological, molecular and genetics study. PloS one . 2014;9(8):e103159. Giannakis M, Ng K. A common cancer at an uncommon age. Science (New York, NY) . Mar 17 2023;379(6637):1088-1090. doi:10.1126/science.ade7114 Alshenaifi JY, Vetere G, Maddalena G, et al. Mutational and co-mutational landscape of early onset colorectal cancer. Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals . Feb 2025;30(1):64-76. doi:10.1080/1354750x.2024.2447089 Menter DG, Davis JS, Broom BM, Overman MJ, Morris J, Kopetz S. Back to the Colorectal Cancer Consensus Molecular Subtype Future. Current Gastroenterology Reports . 2019/01/30 2019;21(2):5. doi:10.1007/s11894-019-0674-9 Tables Tables are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files ColonvsRectalTABLES.docx Cite Share Download PDF Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9137238","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":615256843,"identity":"6b81a68e-e1af-492c-94e9-8aa82fec5793","order_by":0,"name":"Oluwabukunmi Modupe Salami","email":"","orcid":"","institution":"Second Affiliated Hospital of Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Oluwabukunmi","middleName":"Modupe","lastName":"Salami","suffix":""},{"id":615256844,"identity":"40e4758f-28e0-4793-857f-3d8ee917d15a","order_by":1,"name":"Hao Yi","email":"","orcid":"","institution":"Second Affiliated Hospital of Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Hao","middleName":"","lastName":"Yi","suffix":""},{"id":615256845,"identity":"5ca1aeb2-ee51-4e4c-a835-f283cdacda16","order_by":2,"name":"Guangyi Liu","email":"","orcid":"","institution":"Second Affiliated Hospital of Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Guangyi","middleName":"","lastName":"Liu","suffix":""},{"id":615256846,"identity":"18337e7d-0999-40a3-ab91-7d582e8e436e","order_by":3,"name":"Yang Li","email":"data:image/png;base64,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","orcid":"","institution":"Second Affiliated Hospital of Chongqing Medical University","correspondingAuthor":true,"prefix":"","firstName":"Yang","middleName":"","lastName":"Li","suffix":""}],"badges":[],"createdAt":"2026-03-16 11:27:47","currentVersionCode":2,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-9137238/v2","doiUrl":"https://doi.org/10.21203/rs.3.rs-9137238/v2","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":105814218,"identity":"7659fdf7-abd2-406c-ab9d-cd9fea953dd7","added_by":"auto","created_at":"2026-03-24 05:44:19","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":22788,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlowchart of EOCRC patients from 2018-2023\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Picture1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8087824/v1/5cc85e0c29cc222c8d554d14.jpg"},{"id":105814221,"identity":"70b4df37-a53c-4cf3-8f13-1393ec8fe7a2","added_by":"auto","created_at":"2026-03-24 05:44:19","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":79490,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e2a. Kaplan–Meier curves for Disease-free survival by tumor location. Figure 2b. Kaplan–Meier curves for overall specific survival by tumor location.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8087824/v1/cf8c6d9f3bfb74c1bfd60af8.jpg"},{"id":105814223,"identity":"f50b995b-47b6-4675-b708-38418a6a4b78","added_by":"auto","created_at":"2026-03-24 05:44:19","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":99716,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e3a. Rectal only sub-group: Kaplan–Meier curves for Overall specific survival stratified by Treatment group. Figure 3b. Adjusted Kaplan–Meier curves for disease-free survival stratified by Treatment group.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8087824/v1/afaceb6c8c0a6b5ca46df618.jpg"},{"id":105814216,"identity":"42be3140-d6d0-468c-b451-fa75e2909354","added_by":"auto","created_at":"2026-03-27 12:50:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1045937,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8087824/v1/bf50e12b-ab5c-4f1f-9e54-2f50c85bc939.pdf"},{"id":105814217,"identity":"632581d0-4a1a-4121-9dd4-b948b83df9f5","added_by":"auto","created_at":"2026-03-24 05:44:19","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":52411,"visible":true,"origin":"","legend":"","description":"","filename":"ColonvsRectalTABLES.docx","url":"https://assets-eu.researchsquare.com/files/rs-8087824/v1/4d84a313478b9aaa4e9bd245.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Biology over Location: Survival in Advanced Early-Onset Colorectal Cancer: A Retrospective Analysis","fulltext":[{"header":"Statement of Translational Relevance","content":"\u003cp\u003eOur research directly informs the future practice of oncology by challenging the conventional use of anatomical location (colon vs. rectum) as a primary prognostic factor in young patients with advanced colorectal cancer. We demonstrate that survival outcomes are equivalent after accounting for confounders, indicating that the aggressive biology common in early-onset CRC may override location-based prognostic differences. This finding urges a shift in clinical thinking: prognostic stratification and treatment intensification decisions should be guided more by comprehensive staging, pathological risk factors, and future molecular profiling than by the colon-rectum distinction alone. By redirecting focus from anatomy to biology, we believe our work paves the way for more personalised, risk-adapted management strategies, ultimately aiming to improve outcomes for young patients with colorectal cancer.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eColorectal cancer (CRC) remains a leading cause of cancer morbidity and mortality worldwide, while incidence is decreasing in older adults owing to better screening modalities and treatment, there is increasing incidence among younger adults\u0026nbsp;under the age of 50\u003csup\u003e1\u003c/sup\u003e. Colorectal cancer in younger patients under age 50 has been termed early-onset colorectal cancer (EO-CRC) or young onset colorectal cancer(YO-CRC). A study showed that in the United States, the prevalence of EO-CRC from 2011-2019 increased by 1.9% per year, especially in the 20–29 year age group, which was about 3.8% per year. Patients were predominantly female and were likely to present with abdominal pain and hematochezia\u003csup\u003e1,2\u003c/sup\u003e. In China, from 1990 to 2017, EOCRC has increased by about 140%, patients present at a more locally advanced stage, and predominantly in the left colon/rectum, incidence is higher in males, owing to alcoholism, smoking, and a low whole-grain diet\u003csup\u003e3-5\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eThis early-onset CRC group often present with distinct clinical and molecular characteristics\u003csup\u003e6\u003c/sup\u003e, owing to different environmental(diet and lifestyle habits) and genetic risk factors, not excluding immunological dysfunction, inflammation, and gut microbiota changes\u003csup\u003e7,8\u003c/sup\u003e, necessitating tailored therapeutic approaches\u003csup\u003e9\u003c/sup\u003e. While often studied as a single entity in this cohort, colorectal cancer is a heterogenous disease. Cancers of the colon and rectum differ in their embryological origin, vascular supply, surgical management, and molecular profiles\u003csup\u003e10\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eTreatment strategies for locally advanced rectal and colon cancers traditionally involve surgical resection as the major curative intervention. However, neoadjuvant therapy including chemotherapy and radiotherapy, has increasingly been adopted in advanced rectal cancer to improve tumour downstaging, reduce local recurrence, and enhance sphincter preservation, even in early onset disease\u003csup\u003e11-13\u003c/sup\u003e. In contrast, for colon cancer, upfront surgical resection followed by adjuvant chemotherapy remains the main treatment modality for advanced disease, with neoadjuvant therapy currently reserved for select cases within clinical trials\u003csup\u003e14\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eDespite the advances in EOCRC incidence and molecular characteristics, there remains little information on the optimal sequence of multimodal therapies for early-onset CRC patients. The National Comprehensive Cancer Network (NCCN) guidelines\u003csup\u003e15\u003c/sup\u003e dictate surgical resection alone for stage I disease and surgical resection and systemic chemotherapy for stage II and III disease, with added radiation therapy for rectal cancer\u003csup\u003e16,17\u003c/sup\u003e.\u0026nbsp;However, these guidelines are predominantly based on studies and RCTs with combined age groups, or all disease stages, potentially diluting the unique characteristics and unmet needs of this young, high-risk population\u003csup\u003e18\u003c/sup\u003e. This subgroup, despite recorded better survival outcomes and chemotherapy tolerability, due to their distinct clinical and molecular characteristics, tends to be overtreated and therefore, prone to unnecessary long-term treatment toxicities and quality-of-life impacts, which warrant close monitoring\u003csup\u003e19\u003c/sup\u003e. Moreover, it remains unclear whether primary tumour location itself is an independent determinant of prognosis in the specific context of young-onset, advanced-stage disease and the utility of pathological downstaging as a surrogate marker for long-term prognosis is yet to be fully elucidated in this population.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTherefore, the main purpose of this study was to characterise and compare the clinicopathological features, treatment modalities, and survival outcomes between young patients with advanced (Stage III and IV) colon cancer and rectal cancer. By focusing specifically on this advanced-stage early-onset group, we seek to provide insights that can inform clinical decision-making and prognostic discussions in younger patients. Understanding these differences could refine personalized treatment strategies and improve clinical decision-making in this patient group.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003e1.1 Study design and population\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis is a retrospective cohort study of patients surgically treated for early onset locally advanced colon and rectal cancer in a single centre, The Second Affiliated Hospital of Chongqing Medical University, based in Chongqing Province of China between January 2018 and December 2023. The patients were then categorized into two groups based on the primary tumor location; those with tumors located from the caecum to the sigmoid colon, and those with tumours located in the rectum, defined as within 15 cm of the anal verge by rigid sigmoidoscopy or below the sacral promontory on imaging. Inclusion criteria were age less than 50 at diagnosis, advanced clinical TNM stage III and IV, and availability of complete clinical and follow-up data. Exclusion criteria were non-primary colorectal cancer, recurrent CRC, incomplete or missing follow-up data.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePatients with clinically or pathologically confirmed stage III and IV colorectal cancer were selected for inclusion in this study. We focused on clinical stage III and IV colorectal cancer, confirmed with CT and MRI Scans, in this advanced disease cohort due to the distinct clinical management choices and prognostic considerations associated with these stages, where treatment sequencing decisions between neoadjuvant therapy and upfront surgery are most clinically relevant. Follow-up time was till August 31, 2025.\u003c/p\u003e\n\u003cp\u003eNeoadjuvant and Postoperative chemotherapy regimens, included FOLFOX (5-FU + oxaliplatin), FOLFIRI (5-FU + irinotecan), FOLFIXIRI (5-FU + oxaliplatin+ irinotecan), and CAPOX (capecitabine + oxaliplatin), were typically administered based on tumor staging, pathology type, and patient health status. In high-risk cases, radiotherapy and targeted therapies like anti-EGFR (cetuximab) or anti-VEGF (bevacizumab) antibodies were also added.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1.2.\u0026nbsp; \u0026nbsp;\u0026nbsp;Data collection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study retrospectively identified and utilized data from the institutional electronic medical records. Demographics, lifestyle factors (smoking, alcohol consumption), tumor characteristics such as location, histology, and stage; Left-sided colon was defined as the descending colon, right-sided colon was defined as the cecum and ascending colon; treatment details (surgical type, neoadjuvant regimen, post-surgical chemotherapy regimen, length of hospital stay-calculated from surgical date to discharge) and postoperative outcomes were collected. Tumour location was then subcategorized anatomically. Metastatic status was recorded at two time points: synchronous metastases identified around surgery, and metachronous metastases detected during follow-up, with detailed sites specified (e.g., liver, lung, peritoneum).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1.3.\u0026nbsp; \u0026nbsp;\u0026nbsp;Outcome Measures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary outcome was: (1) Disease-Free Survival (DFS), which was defined as the time from surgery to the first documented recurrence, metastasis or death from any cause. (2) Overall Survival (OS), defined as the time from surgery to death from any cause or last follow-up. (3) Cancer-Specific Survival (CSS), defined as the time from surgery to death due to colorectal cancer. Patients without an event were censored at the date of last follow up. And last, patterns of recurrence and metastasis site distribution.\u003c/p\u003e\n\u003cp\u003eSecondary outcomes include: rates of pathological response (in patients receiving neoadjuvant therapy) and recurrence patterns. Pathological tumour downstaging, defined as a reduction in tumor stage from clinical preoperative assessment to pathological postoperative staging according to AJCC 8th edition criteria.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1.4.\u0026nbsp; \u0026nbsp;\u0026nbsp;Statistical Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eContinuous variables were represented as means ± standard deviation, and compared using Student’s t-test or Mann-Whitney U tests as appropriate. Categorical variables were presented as counts and percentages, with group comparisons performed via chi-square or Fisher’s exact tests.\u003c/p\u003e\n\u003cp\u003eSurvival analyses were conducted using Kaplan-Meier, with differences between treatment groups and tumor locations assessed by log-rank tests. Multivariable Cox proportional hazards models adjusted for potential confounders including age, sex, comorbidities, tumor location, histology, and pathological stage. Propensity score matching was applied to reduce selection bias, matching patients in colon and rectal groups based on baseline characteristics including age, sex, tumor stage, and comorbidities.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGiven the observed differential use of neoadjuvant therapy in rectal cancer, an exploratory subgroup analysis was performed within the rectal cancer cohort only to compare outcomes between patients who received neoadjuvant therapy and those who underwent upfront surgery. This analysis was considered hypothesis-generating due to the small sample size. Statistical significance was set at p \u0026lt; 0.05. Analyses were performed using IBM SPSS Statistics for Windows, Version 28.0 (IBM Corp., Armonk, N.Y., USA) and Python 3.9.12.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e1.5.\u0026nbsp; \u0026nbsp;\u0026nbsp; Ethical Considerations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the Institutional Review Board of second affiliated hospital of Chongqing Medical University with a waiver of informed consent due to retrospective data use and anonymization of patient identifiers. This study was designed, analyzed, and reported in accordance with the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) statement.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003e2.1. Baseline Characteristics\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 249 patients with early colorectal cancer, by our definition- age less than 50, who underwent surgical treatment at our centre, were identified. After extensive exclusion, a total of 162 patients with no missing information were included in this study, which were then divided into the colon group (n=82, 50.6%) and the Rectal group (n=80, 49.4%), based on the tumor location (\u003cstrong\u003eFigure 1\u003c/strong\u003e). The mean age was approximately 41 years across groups. Gender distribution was fairly balanced though male predominated in colon cancer (53.7%) and females in rectal cancer (57.5%, p=0.155). Significant differences in alcohol consumption were noted, being higher in colon cancer (37.8% vs. 20%, p=0.013).\u003c/p\u003e\n\u003cp\u003eClinically, hematochezia was markedly more frequent in rectal cancer (60% vs. 25.6%, p\u0026lt;0.001), whereas abdominal pain was more common in colon cancer (59.8% vs. 15%, p\u0026lt;0.001). Anemia and weight loss as collateral symptoms\u0026nbsp;were also significantly observed in colon cancer groups (p=0.014 and 0.041 respectively). Time to diagnosis varied significantly, with 42.6% diagnosed within 1 month overall but higher proportion for colon cancer diagnosed earlier than rectal cancer (p=0.036), with a longer diagnostic delay (\u0026gt;1 year) more often seen. Family history was also more frequent in colon cancer patients (8.5% vs. 1.3%, p=0.032). (\u003cstrong\u003eTable 1\u003c/strong\u003e)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.2.\u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003e \u003cstrong\u003eTreatment and surgical details\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSurgical approach, and perioperative details were similar across groups with no significant differences in surgical methods, or blood transfusions or time from surgery to discharge (\u003cstrong\u003eTable 2\u003c/strong\u003e). Most surgeries were laparoscopic (84.6%) with no significant difference in surgery type between groups. Stoma creation was significantly higher in rectal cancer patients (30% vs 14.6%, p=0.019), consistent with anatomical considerations. Synchronous metastasis treatment was comparable across groups (p=0.621).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eUse of neoadjuvant therapy was significantly more prevalent in rectal cancers (27.5% vs 8.5% in colon cancer, p=0.002), including neoadjuvant radiotherapy being exclusively used in rectal cancer (11.3%, p=0.002). Postoperative immunotherapy was also more common in rectal cancer (28.8% vs. 15.9%, p=0.048). Time from surgery to chemotherapy was longer in rectal cancer patients (p=0.020). Complication rates were also comparable between groups (p=0.231), and the average length of hospital stay was similar (p=0.388).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.3.\u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003e \u003cstrong\u003ePathological characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePathological examination revealed several notable differences between colon and rectal cancers. Tumor sublocation was significantly different: left colon and transverse colon dominated in colon cancer, whereas low rectal subsites were more common in rectal cancer (p=0.000). Clinical staging showed borderline significance with more stage 3 in rectal cancer, and stage 4 more in colon cancer(p=0.050). The T stage and pathological stage differed; rectal cancer showed higher T0-2 rates, but colon cancer had higher T3-4 rates (p = 0.018). Additionally, rectal cancer had more pathological stage 0 and III lesions (2.5% and 57.5%) than colon cancer (0% and 30.5%) (p = 0.002).\u003c/p\u003e\n\u003cp\u003eHistological subtypes and tumor neurovascular invasion patterns were similar, though the dataset did not explore molecular subtypes due to data limitations. Lymph node involvement was more frequent in rectal cancer (72.5% vs. 53.7%, p=0.013), though the number of lymph nodes harvested was higher in colon cancer (15.2 vs 13.3, p=0.035). Median positive lymph nodes were also higher in rectal cancer (2 vs. 1, p\u0026lt;0.001). Positive resection margin was longer in colon cancer (5.8 cm vs. 2.8 cm, p\u0026lt;0.001). Overall synchronous metastasis was more common in colon cancer (36.6% vs. 22.5%, p=0.050), with a higher incidence of peritoneal metastases (9.8% vs. 1.3%, p=0.018), while rectal cancers had more inguinal lymph node metastases (7.5% vs. 1.2%, p=0.049). (\u003cstrong\u003eTable 3\u003c/strong\u003e)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.4.\u0026nbsp; \u0026nbsp;\u0026nbsp;Survival outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe overall median follow-up time is 70 months. The mean OS of the Colon and Rectal group was (36.5 ± 24.5) and (39.7 ± 25.1) months, respectively (P = 0.580), with a median DFS of (32 ± 27.4) months for the Colon group and (28.4 ± 23.5) months for the Rectal group (P = 0.058). There was a higher frequency of disease-free survival (DFS) events in the rectal cancer group compared to the colon cancer group (39/80 [48.8%] vs. 26/82 [31.7%], p=0.02), suggesting an initial association between rectal primary and poorer DFS. However, after propensity score matching to balance baseline characteristics, this difference was no longer statistically significant (12/66 [18.2%] vs. 4/66 [6.1%], p=0.18). A similar pattern was observed for recurrence; however, the rates of overall survival events were comparable between groups both before and after matching (\u003cstrong\u003eTable 4\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eIn the Colon group, the 1-year, 3-year and 5-year DFS rates were slightly higher (94.9% and 71.1% and 59.3%) respectively, and (90.9% and 65.2% and 43.8%) in the Rectal group, the difference was not statistically significant (P = 0.058).\u0026nbsp;However, the 1-year, 3-year, and 5-year OS rates were similar in both groups, (85% and 61.9% and 56.5%) in the Rectal group, and (85.4% and 60.5% and 55%) in the Colon group and these differences were also not statistically significant (P = 0.580) (\u003cstrong\u003eFigure 2a, b\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.5.\u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;Multivariate\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eCox regression\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOn multivariable Cox regression analysis controlling for key clinicopathological variables(age, sex, clinical stage, treatment modality, and key pathological factors), the tumor group (Colon vs. Rectal) was not an independent predictor of either DFS (Hazard Ratio [HR]=1.15, 95% CI 0.70–1.90, p=0.56) or OS (HR=1.39, 95% CI 0.87–2.25, p=0.16). Significant independent predictors of worse DFS included higher preoperative stage (HR=2.84, 95% CI 1.72-4.67, p\u0026lt;0.001), nodal involvement (N stage, HR=1.56, 95% CI 1.16-2.09, p=0.003), neurovascular invasion (HR=1.59, 95% CI 1.24-2.03, p\u0026lt;0.001), and synchronous metastases to the liver (HR=2.49, 95% CI 1.35-4.58, p=0.003) or lungs (HR=5.22, 95% CI 2.12-12.86, p\u0026lt;0.001).\u003c/p\u003e\n\u003cp\u003eFor OS, significant predictors included preoperative stage (HR=1.65, 95% CI 1.02-2.67, p=0.03), T stage (HR=1.44, 95% CI 1.00-2.08, p=0.05), neurovascular invasion (HR=1.26, 95% CI 1.00-1.59, p=0.04), and postoperative stage (HR=1.86, 95% CI 1.14-3.02, p=0.01). (\u003cstrong\u003eTable 5\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.6.\u0026nbsp; \u0026nbsp;\u0026nbsp; Exploratory Analysis: Treatment Effect in Rectal Cancer Subgroup\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGiven the differential use of neoadjuvant therapy, we conducted an exploratory analysis within the rectal cancer cohort (n=80) comparing outcomes between patients who received neoadjuvant therapy (n=22) versus upfront surgery (n=58). This analysis was limited by a small sample size but showed no significant difference in DFS (HR=0.47, 95% CI 28.59- 46.37, p=0.49) or OS (HR=0.84, 95% CI 39.28- 58.57, p=0.35) between these treatment approaches(\u003cstrong\u003eFigures 3a and b\u003c/strong\u003e).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study provides a comprehensive analysis of advanced stage III-IV colon and rectal cancers within a specific and increasing cohort of CRC patients, EOCRC patients (age \u0026lt;50), looking at the clinicopathological characteristics and survival outcomes. Our principal findings show that in the EO-CRC group, despite significant differences in presentation patterns and treatment approaches, primary tumour location does not independently predict survival outcome. After robust adjustment for confounders using both propensity score matching and multivariable Cox regression, the survival curves for colon and rectal cancer patients were virtually superimposable, and tumour location was not significantly associated with either disease-free or overall survival. This suggests that in young-onset advanced CRC, overarching disease biology and stage may exert a stronger influence on prognosis than anatomical subsite alone.\u003c/p\u003e\n\u003cp\u003eThe distinct clinical presentations we observed align with well-known anatomical and physiological considerations: rectal cancers more commonly caused hematochezia due to their distal location, while colon cancers presented more frequently with abdominal pain\u003csup\u003e20\u003c/sup\u003e, possibly reflecting larger tumour size or obstruction. The differential treatment patterns reflect current standard practices, with rectal cancer patients more frequently receiving neoadjuvant therapy, particularly radiotherapy, consistent with established protocols for locally advanced rectal cancer\u003csup\u003e11\u003c/sup\u003e. Our findings confirm that the recommended management guidelines are being applied in real-world practice for young patients too\u003csup\u003e16,21\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eThe unadjusted analysis suggested a worse DFS for rectal cancer patients, which is consistent with historical data\u003csup\u003e22,23\u003c/sup\u003e. However, this apparent disadvantage was nullified after statistically controlling for confounding variables through propensity score matching. This key finding indicates that the observed difference in DFS was not intrinsically due to the rectal location itself, but was likely driven by other prognostic factors unevenly distributed between the groups, such as treatment patterns, staging, pathological characteristics and the presence of synchronous metastases. Our multivariable analysis confirmed that these established factors, including lymph node involvement and neurovascular invasion, were the dominant predictors of survival, while tumor location was not.\u003c/p\u003e\n\u003cp\u003eThe most significant and novel contribution of our study is the demonstration that tumor location is not an independent prognostic factor in this cohort. This finding appears to contrast with some studies in older or all-stage CRC populations that have reported survival differences between colon and rectal cancers\u003csup\u003e24-30\u003c/sup\u003e. Several factors may explain this discrepancy. First, the aggressive biology frequently observed in EOCRC, characterized by a higher prevalence of adverse features such as signet ring cell histology and poor differentiation\u003csup\u003e6\u003c/sup\u003e, which may represent a universal driver of poor prognosis that overwhelms any subtle differences that can be attributed to anatomical subsite. Essentially, the shared aggressive biology of advanced EO-CRC may create a \"ceiling\" of poor prognosis, making it difficult to discern a survival difference based on location alone. Second, our cohort was exclusively composed of advanced-stage (III and IV) patients. It is plausible that at these advanced stages, the determinants of outcome shift decisively toward factors like metastatic burden and tumor invasiveness, diminishing the relative prognostic weight of the primary tumour's location. Third, modern multimodal therapy may effectively mitigate the historical survival disadvantage associated with rectal cancer, leading to a convergence of outcomes in contemporarily treated patients\u003csup\u003e31\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eMultivariable Cox regression analysis confirmed that established prognostic factors such as advanced clinical and pathological stages, lymph node involvement, tumor neurovascular invasion, and synchronous metastases were significant predictors of survival, aligning with established prognostic factors in colorectal cancer\u003csup\u003e32,33\u003c/sup\u003e, \u0026nbsp;emphasizing that disease biology and burden, rather than anatomical origin, are the critical factors in this population. The fact that tumor location did not retain significance in a model containing these powerful covariates strongly suggests that the initial, unadjusted difference in DFS was not causal but was instead confounded by the imbalanced distribution of these other prognostic factors between the colon and rectal groups. This finding has important clinical implications, suggesting that prognostic stratification and treatment intensification decisions in young patients with advanced CRC should be based on tumor biology and stage rather than location alone\u003csup\u003e34\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eOur finding that tumor location lacks independent prognostic significance appears to contrast with studies in older, all-stage CRC populations. This discrepancy with other studies in older, all-stage CRC populations can be explained by the unique molecular biology of EOCRC, which is increasingly recognized as a distinct disease entity. Recent transcriptomic analyses reveal that EOCRC is characterized by a marked predominance of the CMS2 (canonical) and CMS3 (metabolic) molecular subtypes, which together can account for up to 94% of cases\u003csup\u003e35\u003c/sup\u003e. They are also associated with an absence of BRAF mutations and the methylator phenotype\u003csup\u003e36\u003c/sup\u003e. These subtypes are associated with chromosomal instability (CIN) and activated oncogenic pathways like Wnt/β-catenin, driving a cell cycle-driven, proliferative tumor phenotype\u003csup\u003e35,37\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eWith respect to tumour location, previous studies on molecular and biological markers in EOCRC, where loss of MLH1 and PMS2 was detected more frequently in the colon rather than in the rectum, and PIK3CA and KRAS mutation mostly in the left-sided rather than the right-sided colon or rectum\u003csup\u003e34\u003c/sup\u003e, though other studies saw KRAS and CTNNB1 mutations in right colon tumors\u003csup\u003e38\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConversely, late-onset CRC (LOCRC) has a significantly higher proportion of CMS1 (MSI immune) and CMS4 (mesenchymal) subtypes, which are more immunogenic\u003csup\u003e39\u003c/sup\u003e. The molecular profile of EOCRC effectively creates an \"immune desert\" tumour microenvironment, while LOCRC exhibits greater immune cell infiltration\u003csup\u003e35\u003c/sup\u003e. This fundamental biological distinction suggests that EOCRC, regardless of colon or rectal origin, is often propelled by a shared set of aggressive, cell-cycle-driven pathways. This common biological backdrop may overwhelm any more modest prognostic influences related to anatomical subsite, particularly in advanced-stage disease where tumor burden and invasiveness are the primary determinants of outcome.\u003c/p\u003e\n\u003cp\u003eOur exploratory analysis within the rectal cancer subgroup, while limited by the small sample size and the constitutional biases in treatment selection, found no significant survival difference between patients receiving neoadjuvant therapy and those undergoing upfront surgery. This hypothesis-generating observation highlights the need for larger, prospective studies to definitively determine the optimal treatment sequence for young patients with rectal cancer, a population often under-represented in clinical trials.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe strengths of our study include its focus on a well-defined, homogeneous cohort of young patients with advanced disease, the comprehensive clinicopathological data, and the use of both propensity score matching and multivariable regression to address confounding. However, several limitations must be acknowledged. The retrospective, single-center design introduces potential for selection bias, and limits the generalizability of our findings, though we employed statistical methods to mitigate this. The sample size, particularly for the exploratory rectal subgroup analyses, also limits the power to detect small differences. The lack of molecular and genetic data also prevents analysis of how biological subtypes might interact with tumor location to influence outcomes. Future prospective multicenter studies incorporating molecular profiling is essential to move from an anatomical to a biological understanding of prognosis in EOCRC.\u003c/p\u003e\n\u003cp\u003eIn conclusion, our study demonstrates that while young patients with advanced colon and rectal cancer present and are treated differently, their ultimate survival outcomes are remarkably similar. This finding challenges the assumption that tumor location is a primary determinant of prognosis in this population and shifts the focus toward the critical roles of disease stage and underlying biology. For clinicians, this implies that prognostic stratification and decisions regarding treatment intensity in young patients with advanced CRC should be guided more by comprehensive staging and pathological risk factors than by anatomical subsite alone. Future research efforts should prioritize the molecular characterization of EOCRC to identify the true biological drivers of outcome and pave the way for biology-driven, rather than location-driven, personalized therapy.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn this cohort of young patients with advanced colorectal cancer, colon and rectal primaries exhibit distinct clinical presentations and receive different treatment regimens. However, after adjusting for confounders, tumor location was not an independent predictor of survival. This suggests that in early-onset advanced disease, overall disease biology and stage may be more critical determinants of outcome than anatomical subsite. Future research should focus on molecular characterisation to identify biology-driven, rather than location-driven, treatment strategies for this growing patient population.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eEarly onset colorectal cancer (EOCRC),\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOMS designed the study, collected, analyzed the data and wrote the first and final draft of the manuscript. HY collected the final follow up data, analyzed the data, revised manuscript draft, GL wrote the final version of the manuscript, contributed to the conception, and did the manuscript revision. YL provided resources, gave intellectual suggestions and overall supervision for the article. All authors have read and approved the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements statement:\u0026nbsp;\u003c/strong\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssistance with the study:\u0026nbsp;\u003c/strong\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFinancial support and sponsorship:\u0026nbsp;\u003c/strong\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e None\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest:\u0026nbsp;\u003c/strong\u003eThe authors declare no potential conflicts of interest\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability:\u0026nbsp;\u003c/strong\u003eAvailable under reasonable request\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Statement:\u0026nbsp;\u003c/strong\u003eThe study was approved by the Institutional Review Board of second affiliated hospital of Chongqing Medical University with a waiver of informed consent due to retrospective data use and anonymization of patient identifiers.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e: Not applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHuman And Animal Rights\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or research committee and with the 1975 Declaration of Helsinki, as revised in 2013.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSiegel RL, Giaquinto AN, Jemal A. 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Back to the Colorectal Cancer Consensus Molecular Subtype Future. \u003cem\u003eCurrent Gastroenterology Reports\u003c/em\u003e. 2019/01/30 2019;21(2):5. doi:10.1007/s11894-019-0674-9\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"Second Affiliated Hospital of Chongqing Medical University","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"locally advanced cancer, Early onset colorectal cancer, colon cancer, rectal cancer, Survival analysis, prognosis","lastPublishedDoi":"10.21203/rs.3.rs-9137238/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9137238/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective:\u003c/strong\u003e This study aimed to compare clinicopathological characteristics and survival outcomes between colon and rectal primaries in a young, advanced-stage cohort.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: The rising incidence of early-onset colorectal cancer necessitates a clearer understanding of its clinical behaviour. Most studies group colon and rectal cancers, but they have different entities. The comparative prognosis in young patients with advanced disease remains undefined.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethod\u003c/strong\u003e: A retrospective cohort study was conducted of 162 patients under 50 with stage III-IV colorectal cancer treated at a single center (2018-2023), categorized into colon (n=82) and rectal (n=80) groups. Clinicopathological data, treatment patterns, and survival outcomes were analyzed using Kaplan-Meier estimates, propensity score matching, and multivariable Cox regression.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: The cohorts exhibited distinct clinical presentations: rectal cancer patients had more hematochezia (60% vs. 25.6%, p\u0026lt;0.001), while colon cancer patients presented with more abdominal pain (59.8% vs. 15%, p\u0026lt;0.001). Left colon dominated in colon group, whereas low rectum succeeded in the rectal group. Treatment differed significantly, with rectal group receiving more neoadjuvant therapy (27.5% vs. 8.5%, p=0.002). Though unadjusted analysis showed no significant difference in DFS (p=0.18) or OS (p=0.32), after propensity score matching, survival curves remained congruent. On multivariable analysis, tumour location was not an independent predictor of DFS (HR=1.15, p=0.56) or OS (HR=1.39, p=0.16), while advanced stage and synchronous metastasis were.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eIn young patients with advanced colorectal cancer, tumour location does not independently predict survival. Despite different clinical presentations and treatment pathways, prognosis appears driven by factors like disease stage and biology rather than anatomical location.\u003c/p\u003e","manuscriptTitle":"Biology over Location: Survival in Advanced Early-Onset Colorectal Cancer: A Retrospective Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2026-03-24 05:44:14","doi":"10.21203/rs.3.rs-9137238/v2","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2026-03-18 09:01:11","doi":"10.21203/rs.3.rs-9137238/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1cc085e0-1d13-4981-b5f9-770d740dd999","owner":[],"postedDate":"March 24th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-03-31T12:06:52+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-24 05:44:14","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v2","identity":"rs-9137238","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9137238","identity":"rs-9137238","version":["v2"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}