Abstract
Background
Right‐sided colon cancer (RSCC) exhibits distinct characteristics, yet specific prognostic determinants remain insufficiently defined. This multicentre retrospective study evaluated clinicopathological and surgical factors influencing survival in a real‐world cohort undergoing curative resection for non‐metastatic RSCC.
Methods
We analysed 800 adults undergoing curative‐intent resection for non‐metastatic RSCC across 28 centres (2018–2024). The primary outcome was 3‐year overall survival (OS). Multivariate Cox model identified prognostic factors. An exploratory, post hoc subgroup analysis evaluated the impact of complete mesocolic excision (CME) on OS, stratified by tumour anatomical subsite.
Results
The mean age was 62.8 years, and 24% required emergency surgery. CME was performed in 57.1% of patients, with baseline characteristics reflecting significant real‐world selection bias against CME in complex clinical presentations. At 3 years (OS: 86%), multivariate analysis identified age (HR 1.071, 95% CI: 1.023–1.122, p = 0.004) and adjacent organ invasion (HR 3.642, 95% CI: 1.360–9.750, p = 0.010) as independent mortality predictors. Unadjusted post hoc analysis suggested CME was associated with improved OS for ascending colon and hepatic flexure tumours (p = 0.003).
Conclusion
Although CME showed an exploratory site‐specific survival advantage, the critical lack of molecular profiling (MSI, RAS, BRAF) prevents adjustment for major biological confounders. Consequently, these findings are strictly hypothesis‐generating, highlighting real‐world surgical bias and require prospective multi‐institutional validation before altering standard practice.
Keywords: colorectal surgery, lymph node harvest, mesocolon excision, prognosis, right‐sided colon cancer, survival
What does this paper add to the literature?
This large multicentre study provided a pragmatic, real‐world snapshot of contemporary surgical management of non‐metastatic right‐sided colon cancer. It documented the inherent selection bias in applying complete mesocolic excision (CME) in daily practice and generates novel hypotheses regarding its site‐specific survival benefits, establishing a robust foundation for future prospective clinical audits.
INTRODUCTION
Colorectal cancer (CRC) remains one of the leading causes of cancer‐related morbidity and mortality worldwide [1]. Over the past decades, increasing evidence has highlighted significant biological and clinical differences between right‐sided and left‐sided colon cancers [2, 3, 4, 5, 6]. Tumours arising in the right colon—typically proximal to the splenic flexure—display distinct molecular profiles, including higher rates of microsatellite instability (MSI), BRAF mutations and CpG island methylator phenotype (CIMP) [7]. These differences are associated with particular pathological features, patterns of metastasis and therapeutic responses [8]. Right‐sided colon adenocarcinomas are frequently diagnosed at more advanced stages, often presenting with anaemia or vague abdominal symptoms rather than overt obstruction [9]. Consequently, patients with right‐sided tumours tend to have poorer outcomes compared to those with left‐sided disease, even after adjustment for stage and treatment. However, prognostic factors specific to right‐sided colon cancer remain incompletely defined, particularly regarding the relative impact of clinical, pathological and molecular variables on long‐term survival. Although several studies have investigated prognostic determinants in colorectal cancer [10, 11], most have analysed the colon as a single entity or have included heterogeneous populations with small numbers of right‐sided cases. Given the distinct biological behaviour and surgical implications of right‐sided tumours, a dedicated analysis of prognostic factors in this subgroup is warranted. The present multicentre study aimed to identify independent prognostic factors associated with overall and disease‐free survival in patients undergoing curative resection for right‐sided colon cancer (RSCC). By analysing a large cohort from multiple institutions, we sought to provide a comprehensive evaluation of clinicopathological, surgical and molecular parameters influencing patient outcomes.
METHODS
Study design and bias mitigation
This study is a multicentre, retrospective cohort analysis derived from the ATCCR database, including consecutive patients who underwent curative‐intent surgery for right‐sided colon adenocarcinoma at 28 centres between January 2018 and December 2024. The study was conducted in accordance with the principles of the Declaration of Helsinki [12] and followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines [13] (supplementary file S1). To ensure a homogeneous cohort of non‐metastatic right‐sided colon cancer patients, rigorous a priori inclusion and exclusion criteria were established. While this minimized baseline cohort heterogeneity, inherent treatment allocation biases (e.g. selection for CME in real‐world practice) were anticipated. To address these confounding biases, we avoided selecting variables based solely on univariable statistical significance. Instead, variables identified as known or plausible clinical confounders were selected a priori and included in a multivariable Cox proportional hazards regression model to appropriately adjust for baseline imbalances [14, 15].
Patient selection
Eligible patients were adults (≥18 years old) with histologically confirmed adenocarcinoma of the right colon, defined as tumours located from the caecum to the proximal two‐thirds of the transverse colon. Exclusion criteria included: (1) presence of distant metastases at the time of surgery (Stage IV disease), (2) palliative or non‐curative resections (R2), (3) synchronous colorectal cancers, (4) incomplete clinicopathological or follow‐up data.
Data collection and variables
Demographic, clinical, surgical and pathological data were retrieved from prospectively maintained institutional databases and verified through medical record review. Collected variables included age, gender, comorbidities, preoperative laboratory values of tumour markers (carcinoembryonic antigen [CEA] and carbohydrate antigen [CA19‐9]), surgical approach (open vs. laparoscopic), tumour size and tumour anatomical location (rigorously defined based on a correlation between preoperative endoscopy, explicit descriptions in the operative reports and final pathological assessment), type of resection (with or without complete mesocolic excision), histological grade, lymphovascular and perineural invasion, number of lymph nodes examined, tumour–node–metastasis (TNM) stage (AJCC 8th edition) [16] and resection margin status. Adjuvant chemotherapy regimens and postoperative complications were also recorded.
Pathological and molecular analysis
All surgical specimens were examined by pathologists at each participating institution. Tumours were classified according to the World Health Organization (WHO) criteria [17]. Microsatellite instability (MSI) status and mutational profiles (RAS, BRAF) were assessed using standardized PCR‐based or immunohistochemical methods, depending on local protocols.
Regarding molecular profiling, data availability within this national database was limited: exact MSI status was available for only 6.2% of patients, and RAS mutation data were available for 1.4%. Given this extremely high rate of missing data, molecular profiles were excluded from the multivariable survival analyses to prevent severe model distortion.
Outcomes
The primary endpoint was overall survival (OS), defined as the time from surgery to death from any cause. Follow‐up information was obtained from outpatient visits and imaging records.
Statistical analysis
Continuous variables were expressed as mean ± standard deviation (SD) or median (interquartile range) and compared using the Student's t‐test or Mann–Whitney U‐test, as appropriate. Categorical variables were analysed using the chi‐squared or Fisher's exact test.
Variables selected a priori based on clinical relevance as potential confounders, along with variables showing a significant association in the univariate analysis, were initially entered into a multivariate Cox proportional hazards model. To identify the final independent prognostic factors of 3‐year OS, a backward stepwise elimination method was applied. A p‐value <0.05 was considered statistically significant. Variables were reported with their Hazard ratio (HR) and 95% confidence interval (95% CI). Statistical analyses were performed using SPSS version 21. Missing data were managed by complete‐case analysis [18], and the proportion of missing data for each variable was assessed prior to inclusion in the models.
In addition to the primary multivariable model, an exploratory, post hoc subgroup analysis was conducted to evaluate the impact of CME on OS stratified by anatomical tumour location. Survival within these subgroups was compared using the unadjusted log‐rank test. Due to the post hoc nature of this analysis, limited sample sizes within certain subgroups (e.g. right transverse colon), and baseline clinical imbalances between the treatment groups, a formal statistical interaction test (CME × tumour location) within a Cox proportional hazards model was not performed. Consequently, these specific subgroup evaluations were treated as strictly descriptive and hypothesis‐generating.
Ethical considerations
The study was approved by the Institutional Review Board (IRB) of Fattouma Bourguiba University Hospital of Monastir under the approval number IORG0009738 N286/ OMB 0990‐0279. There was no priori study protocol. The study was conducted in accordance with the Declaration of Helsinki [12] and our IRB approved the use of anonymised data without the need for individual consent.
RESULTS
A total of 800 patients were included in this multicentre study. The mean age was 63.1 ± 13.4 years. Emergency surgery was performed in 24% of cases (n = 189), and complete mesocolic excision (CME) was achieved in 57.1% (n = 457). Thirteen patients (1.8%) died within 30 days postoperatively. The median follow‐up duration was 18.5 months [8–43.5]. Table 1 shows the baseline characteristics of our patients.
TABLE 1.
Baseline characteristics of our patients.
| Total effect size (N) | 800 |
|---|---|
| Age, years (mean ± SD) | 63.1 ± 13.4 |
| Gender, n (%) | |
| Male | 441 (55.2) |
| Female | 359 (44.9) |
| ASA score, n (%) | |
| I‐II | 696 (87) |
| III‐IV | 104 (13) |
| Emergency surgery, n (%) | 189 (24) |
| Intraoperative tumour location, n (%) | |
| Caecum | 334 (41.7) |
| Ascending colon | 213 (22.6) |
| Hepatic flexure | 187 (23.4) |
| Right transverse | 66 (8.3) |
| Invasion of adjacent organ, n (%) | 114 (14.3) |
| Tumour perforation, n (%) | 39 (4.9) |
| Complete mesocolic excision, n (%) | 457 (57.1) |
| Pathological TNM classification, n (%) | |
| Stage 0 | 15 (1.9) |
| Stage I | 94 (11.7) |
| Stage II | 350 (43.7) |
| Stage III | 341 (42.7) |
| Number of retrieved lymph nodes (mean ± SD) | 19.6 ± 11.1 |
| R0 resection, n (%) | 734 (91.8) |
| Anastomotic leakage, n (%) | 53 (6.6) |
| 30‐day deaths, n (%) | 13 (1.6) |
Abbreviations: n, effect size; SD, standard deviation.
To explore potential selection bias regarding the surgical approach, baseline demographic and clinical characteristics were compared between patients who underwent CME (n = 457) and those who received a standard resection (n = 393) (Table 2). As anticipated for real‐world practices, significant differences were observed; patients in the non‐CME group were more likely to present with factors technically limiting complex dissections, such as overweight (p = 0.02) and acute obstruction (p = 0.03).
TABLE 2.
Baseline demographic, preoperative and tumour characteristics according to type of lymphadenectomy (CME vs. non‐CME).
| Variable | CME (n = 457) | Non‐CME (n = 343) | p |
|---|---|---|---|
| Age (years, mean ± SD) | 62.9 ± 13.2 | 63.6 ± 13.7 | 0.49 |
| Male gender, n (%) | 255 (55.8) | 186 (54.2) | 0.66 |
| ASA I–II, n (%) | 410 (89.7) | 286 (83.4) | 0.01 |
| Overweight/obese (BMI > 25 kg/m2), n (%) | 195 (42.7) | 117 (34.1) | 0.02 |
| Preoperative CEA ≥5 ng/m, n L (%) | 70 (15.3) | 69 (20.1) | 0.12 |
| Intraoperative tumour location | 0.14 | ||
| Caecum, n (%) | 188 (41.1) | 146 (42.6) | |
| Ascending colon (%) | 134 (29.3) | 78 (22.7) | |
| Hepatic flexure (%) | 100 (21.9) | 86 (25.1) | |
| Right transverse colon (%) | 33 (7.2) | 33 (9.6) | |
| Mean tumour size (cm, SD) | 5.4 ± 2.5 | 5.3 ± 2.6 | 0.92 |
| Stricturing tumour, n (%) | 132 (28.9) | 123 (35.9) | 0.03 |
| Acute obstruction, n (%) | 70 (15.3) | 72 (21) | 0.03 |
| Infective/abscess complication, n (%) | 38 (8.3) | 41 (11.9) | 0.09 |
| Radiological nodal involvement, n (%) | 192 (42) | 163 (47.5) | 0.20 |
| Local invasion, n (%) | 67 (14.7) | 47 (13.7) | 0.67 |
| Perforated tumour, n (%) | 19 (4.1) | 20 (5.8) | 0.30 |
| Radiological stage II–III, n (%) | 392 (85.8) | 295 (86) | 0.18 |
Abbreviations: %, percentage; ASA score, American Society of Anaesthesiologist score; BMI, body mass index; cm, centimetre; CME, complete mesocolic excision; kg/m2, kilograms per square metre; N, number; ng/mL, nanograms per millilitre; SD, standard deviation.
Overall survival
At 3‐years, the OS rate was 86%. In univariate analysis, emergency surgery, advanced TNM stage, absence of complete mesocolic excision and locally invasive tumours were significantly associated with poorer OS (Table 3). The initial multivariate model included age, ASA score, emergency surgery, TNM stage, completeness of mesocolon excision and locally invasive tumour. The missing data for the included variables were <5% and managed by complete‐case analysis. Following the backward stepwise elimination, only age (HR 1.071, 95% CI 1.023–1.122; p = 0.004) and intraoperative invasion of adjacent organs (HR 3.642, 95% CI 1.360–9.750; p = 0.010) remained independent predictors of mortality (Table 3).
TABLE 3.
Univariate and multivariate analyses for 3‐year overall survival (OS).
| Variable | Univariate p‐value | Multivariate HR (95% CI) | p‐value |
|---|---|---|---|
| Age (years) | – | 1.071 (1.023–1.122) | 0.004 |
| Locally invasive tumour | <0.001 | 3.642 (1.360–9.750) | 0.010 |
| Complete mesocolic excision | 0.047 | – | – |
| Elective surgery | 0.025 | – | – |
| TNM stage | 0.001 | – | – |
Abbreviations: CI, confidence interval; HR, Hazard ratio.
Exploratory post hoc subgroup analysis
In an exploratory, post hoc approach to further assess the impact of surgical technique on OS, unadjusted subgroup analyses were performed according to tumour location and CME. When stratified by tumour site, a significant survival difference was observed among patients with tumours located at the ascending colon and the hepatic flexure. As shown in Figures 1 and 2, in unadjusted univariate analysis, patients who underwent a CME demonstrated a significantly better OS compared with those with standard resection (the log‐rank test (Mantel‐Cox) p = 0.003). However, this association must be interpreted with extreme caution, as it does not account for the baseline clinical imbalances documented between the two groups. This association was not statistically significant for tumours located in the caecum or proximal transverse colon.
FIGURE 1.
Kaplan–Meier analysis of overall survival stratified by completeness of mesocolon excision in patients with adenocarcinoma of the ascending colon. The green curve represents patients who underwent CME, and the blue curve represents those with standard resection. Unadjusted univariate analysis suggested a survival trend in favour of CME (p = 0.003), which requires validation through adjusted models.
FIGURE 2.
Kaplan–Meier analysis of overall survival stratified by completeness of mesocolon excision in patients with adenocarcinoma of the hepatic flexure. The green curve represents patients who underwent CME, and the blue curve represents those with standard resection. Unadjusted univariate analysis suggested a survival trend in favour of CME (p = 0.003), which requires validation through adjusted models.
DISCUSSION
This large‐scale, multicentre retrospective study provides a pragmatic, real‐world snapshot of contemporary surgical practices and prognostic determinants in non‐metastatic RSCC. Our primary multivariate analysis confirmed that advanced age (HR 1.071, 95% CI: 1.023–1.122, p = 0.004) and intraoperative adjacent organ invasion (HR 3.642, 95% CI: 1.360–9.750, p = 0.010) remain robust, independent predictors of poor 3‐year OS. Crucially, regarding the ongoing debate on CME, our exploratory, unadjusted post hoc subsite analysis suggested a potential survival advantage specifically for tumours located in the ascending colon and hepatic flexure. However, rather than establishing definitive therapeutic superiority, these findings primarily unmask the profound baseline selection biases that dictate real‐world surgical choices. When interpreted alongside our critical lack of molecular data (MSI, RAS, BRAF) and limited follow‐up, these results must be viewed strictly as descriptive and hypothesis‐generating.
It is noteworthy that the overall CME rate in this national cohort was 57%. This non‐uniformity reflects ‘real‐world’ surgical practices across a diverse range of healthcare settings, rather than a strictly controlled experimental environment. Achieving CME is technically demanding and its implementation at a national level is influenced by multiple factors, including surgeon expertise, hospital volume and the gradual learning curve associated with the technique [19]. Furthermore, patient‐specific factors such as emergency presentations, severe obesity or complex tumour anatomy frequently preclude the safe execution of a standardized CME in everyday clinical practice [19, 20].
Although current literature increasingly emphasizes the role of molecular markers (such as MSI status or RAS and BRAF mutations) in understanding the biology of right‐sided tumours [21], the lack of comprehensive molecular profiling data in our registry limits our ability to evaluate their specific prognostic value. Nevertheless, this limitation reflects a pragmatic clinical reality: in the absence of available molecular profiling, aggressive tumour presentation (such as perforation or adjacent organ invasion) and the quality of surgical resection remain the cornerstones of prognostic assessment and survival.
A notable finding of our exploratory analysis is the survival benefit associated with CME specifically for tumours located in the ascending colon and hepatic flexure. From a technical standpoint, the surgical planes and vascular dissection (involving the ileocolic and right colic vessels) in these segments are standardized, which may maximize the reproducibility and oncological quality of CME. Moreover, the variable lymphatic drainage networks in these specific areas might render them more vulnerable to incomplete clearance during conventional surgery, thereby making a radical mesocolic dissection more clinically impactful. Conversely, the vascular anatomy of the transverse colon is notoriously complex, and our limited sample size in this subsite (n = 69) rendered the analysis underpowered to detect a true difference.
Crucially, these exploratory observations must be interpreted with extreme caution and should under no circumstances be used to justify omitting CME in daily practice. The baseline clinical imbalances documented in Table 2; where high‐risk patients presenting with acute obstruction or high BMI preferentially underwent non‐CME approaches, introduce significant residual confounding. Furthermore, due to the retrospective nature of our study, the lack of molecular profiling and the limited follow‐up duration, hard conclusions regarding the selective utility of CME based on anatomical subsites cannot be drawn. Our findings are strictly hypothesis‐generating. They do not challenge the current standard of care but rather suggest that the magnitude of CME benefit may vary anatomically, which merits further investigation in well‐powered prospective trials.
In fact, the role of CME has gained increasing attention in recent years [22, 23]. Following Hohenberger's concept [24], CME aims to achieve monobloc resection of the mesocolon with intact fascial planes and high vascular ligation, improving lymph node yield and potentially reducing locoregional recurrence, although there is still no strong evidence that CME provides better long‐term oncological outcomes than D2 dissection [25]. A large controlled trial (RCT), by Lu et al., failed to demonstrate that CME is associated with better DFS [26]. From a surgical perspective, these findings reinforce the importance of meticulous oncological resection with CME and high vascular ligation. Further prospective RCTs of CME according to tumour site, with longer follow‐up, are necessary to better assess its impact on long‐term oncological outcomes.
By focusing on optimizing surgical technique where it offers the greatest benefit, surgeons can significantly improve long‐term outcomes for these patients, independent of their underlying molecular profile.
Furthermore, in our study, age of patients and invasion of adjacent organs were independent factors of poorer OS. These results are aligned with a previous study by Dulskas et al [27].
In addition, histopathological features such as vascular emboli, perineural invasion and lymph node ratio remained strong prognostic indicators, consistent with the biological aggressiveness of the disease [7]. The number of metastatic lymph nodes and the adequacy of nodal harvest have consistently been reported as key predictors of survival [28]. Several series have demonstrated that patients with more than 12 nodes examined have improved survival, likely reflecting both the quality of surgical resection and accurate staging [29, 30].
The main strengths of this study include its large sample size, multicentre design and comprehensive assessment of surgical and pathological variables. However, limitations should be acknowledged when interpreting its findings. First, the retrospective, multicentre design inherently carries the risk of potential inconsistencies in data recording or surgical protocols across the 28 participating institutions. Second, a primary limitation of our study is the relatively short median follow‐up period. Because of the constraints of the current database release, the follow‐up is insufficient to draw definitive conclusions regarding long‐term oncological outcomes. Consequently, our analysis is robustly powered only for medium‐term outcomes, specifically 3‐year overall survival. Any data extending beyond this period is currently immature and should be interpreted with extreme caution. Future studies with extended follow‐up are mandatory to confirm these medium‐term trends. Third, a significant limitation regarding our subgroup analysis is the lack of multivariable adjustment or propensity score matching. Since the CME and non‐CME groups presented significant baseline imbalances in terms of comorbidities, emergency surgeries and BMI, the site‐specific survival benefit observed in the univariate log‐rank test may be subject to residual confounding and selection bias. Fourth, the database lacks granular clinical details regarding the specific patterns of cancer recurrence and subsequent salvage treatments, restricting our ability to analyse post‐recurrence patient trajectories. Finally, there is a lack of comprehensive molecular profiling data specifically concerning MSI status and RAS or BRAF mutations. Given that right‐sided colon cancers are historically characterized by distinct molecular phenotypes that strongly influence disease biology, recurrence patterns and therapeutic responses [21], the lack of molecular data in our multivariate model prevents us from comparing their prognostic role with that of the identified clinical and surgical factors.
CONCLUSION
In conclusion, while the retrospective nature and limited follow‐up of this study preclude any definitive survival claims, this large multicentre cohort provided a pragmatic snapshot of real‐world surgical practices in right‐sided colon cancer. Our findings highlight significant baseline selection biases in the implementation of CME and generate new hypotheses regarding the reproducibility of this technique across different anatomical subsites. A major limitation of our study remains the critical lack of molecular characterization which prevents any multivariable adjustment for these powerful biological confounders (including MSI, RAS and BRAF mutations). Rather than altering current clinical guidelines, these results must be viewed strictly as hypothesis‐generating, underscore the need for complete data collection, and highlight the urgent need for prospective, long‐term multi‐institutional audits that integrate both surgical and molecular parameters.
AUTHOR CONTRIBUTIONS
Salsabil Nasri: Data curation; conceptualization; methodology; validation; formal analysis; writing – original draft; writing – review and editing. Mohamed Ali Chaouch: Conceptualization; methodology; data curation; writing – review and editing; validation; investigation; formal analysis; writing – original draft. Imen Mlouki: Methodology; formal analysis; validation; writing – review and editing; writing – original draft. Mohamed Ben Hassine: Data curation; formal analysis; writing – original draft. Amal Bouchrika: Data curation; writing – original draft; methodology; formal analysis. Amine Ben Safta: Data curation; formal analysis; writing – original draft. Aya Ajmi Blout: Methodology; formal analysis. Emna Hariz: Methodology; formal analysis; writing – original draft; writing – review and editing. Sana El Mhamdi: Methodology; formal analysis; writing – original draft; writing – review and editing. Hiba Ben Hassine: Conceptualization; data curation; methodology; writing – review and editing. Khadija Zouari: Conceptualization; methodology; investigation; validation; visualization; writing – review and editing; data curation; formal analysis. Ramzi Nouira: Conceptualization; validation; visualization; writing – review and editing; methodology; data curation; formal analysis; writing – original draft.
FUNDING INFORMATION
The study received no funding.
CONFLICT OF INTEREST STATEMENT
All authors have no conflict of interest to disclose.
ETHICS APPROVAL STATEMENT
The study was approved by the institutional review boards of Fattouma Bourguiba University Hospital of Monastir under the approval number IORG0009738 N286/OMB 0990‐0279 (File S2).
PATIENT CONSENT STATEMENT
Given the retrospective nature of the study and the anonymization of patient data, the requirement for informed consent was waived in accordance with local regulations.
Supporting information
File S1.
File S2.
ACKNOWLEDGEMENTS
The authors would like to express their sincere gratitude to all the participating centres and their respective surgical, pathological and data management teams. Their invaluable contribution to patient inclusion, meticulous data collection and continuous collaboration was essential to the realization of this multicentre study. Open Access funding enabled and organized by CNUDST.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
File S1.
File S2.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.