Zhou XM, Zeng ZY, Liu BG, Yin NN, Qu HB. Relationship between postoperative tumor recurrence time and long-term survival in colorectal cancer patients. World J Gastrointest Surg 2026; 18(7): 119305 [DOI: 10.4240/wjgs.119305]
Corresponding Author of This Article
Hai-Bo Qu, Department of Gastrointestinal Surgery, The Central Hospital of Yongzhou, No. 396 Yiyun Road, Lengshuitan District, Yongzhou 425000, Hunan Province, China. quhaibo576@163.com
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Zhou XM, Zeng ZY, Liu BG, Yin NN, Qu HB. Relationship between postoperative tumor recurrence time and long-term survival in colorectal cancer patients. World J Gastrointest Surg 2026; 18(7): 119305 [DOI: 10.4240/wjgs.119305]
Xiang-Mao Zhou, Zhi-Yao Zeng, Bing-Gang Liu, Hai-Bo Qu, Department of Gastrointestinal Surgery, The Central Hospital of Yongzhou, Yongzhou 425000, Hunan Province, China
Na-Na Yin, Department of Gynecology, The Central Hospital of Yongzhou, Yongzhou 425000, Hunan Province, China
Author contributions: Zhou XM and Qu HB designed the study; Zeng ZY and Liu BG collected and analyzed the data; Yin NN assisted with data organization; Zhou XM drafted the manuscript. All authors approved the final version.
Institutional review board statement: This study was reviewed and approved by the Ethics Committee of The Central Hospital of Yongzhou (Approval No. 2025120501). All procedures were conducted in accordance with the Declaration of Helsinki and relevant institutional guidelines.
Informed consent statement: Given the retrospective design of this study, the requirement for written informed consent was waived by the Ethics Committee of The Central Hospital of Yongzhou. All patient data were anonymized prior to analysis, and no identifiable personal information was included.
Conflict-of-interest statement: The authors declare that they have no conflicts of interest related to this study.
Data sharing statement: The datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request.
Corresponding author: Hai-Bo Qu, Department of Gastrointestinal Surgery, The Central Hospital of Yongzhou, No. 396 Yiyun Road, Lengshuitan District, Yongzhou 425000, Hunan Province, China. quhaibo576@163.com
Received: January 23, 2026 Revised: February 24, 2026 Accepted: April 7, 2026 Published online: July 27, 2026 Processing time: 185 Days and 0.2 Hours
Abstract
BACKGROUND
Colorectal cancer (CRC) remains a major global health challenge, with over 1.9 million new cases annually and ranking third in cancer-related mortality. Despite advances in surgical techniques and multimodal therapy, post-operative recurrence occurs in 30%-50% of patients, representing the primary cause of treatment failure. Recurrence timing shows distinct temporal patterns, with 70%-80% occurring within 2-3 years post-surgery, suggesting different biological behaviors and clinical significance. However, the relationship between recurrence timing and long-term survival outcomes remains inadequately characterized, particularly in Chinese populations, limiting risk stratification and individualized treatment strategies.
AIM
To investigate the relationship between post-operative tumor recurrence time and long-term survival rate in CRC patients, providing a basis for clinical prognosis assessment and follow-up strategy formulation.
METHODS
A retrospective analysis was conducted on clinical data from 120 CRC patients who underwent curative surgery at our hospital from January 2015 to December 2018 and subsequently experienced recurrence. Patients were divided into early recurrence group (recurrence ≤ 2 years post-surgery, n = 63) and late recurrence group (recurrence > 2 years post-surgery, n = 57) based on time to recurrence. Clinical pathological characteristics, recurrence sites, treatment methods and other data were collected. Kaplan-Meier method was used to plot survival curves, Log-rank test was used to compare overall survival (OS) and post-recurrence survival (PRS) between groups, and Cox proportional hazards regression model was used to analyze independent risk factors affecting prognosis.
RESULTS
The median OS for early and late recurrence groups were 36.8 months and 68.5 months respectively, and median PRS were 14.6 months and 33.2 months respectively, with statistically significant differences (P < 0.001). The 3-year and 5-year OS rates for the early recurrence group were 39.7% and 22.2% respectively, while for the late recurrence group they were 80.7% and 57.9% respectively (P < 0.001). Multivariate analysis showed that recurrence time [hazard ratio (HR) = 2.41, 95% confidence interval (CI): 1.56-3.72, P < 0.001], TNM staging (HR = 1.92, 95%CI: 1.26-2.94, P = 0.003), and post-recurrence treatment modality (HR = 1.71, 95%CI: 1.18-2.48, P = 0.005) were independent prognostic factors affecting OS.
CONCLUSION
Post-operative recurrence time in CRC is closely related to long-term patient survival, with early recurrence patients having significantly worse prognosis than late recurrence patients. The first 2 years post-surgery represent a high-risk period for recurrence, requiring enhanced follow-up monitoring. Early recurrence patients need active comprehensive treatment measures to improve prognosis.
Core Tip: This study demonstrates that postoperative recurrence time is a strong and independent predictor of long-term outcomes in colorectal cancer (CRC) patients. Early recurrence (≤ 2 years after surgery) is associated with more aggressive pathological features and significantly worse overall survival and post-recurrence survival compared with late recurrence. Recurrence time provides prognostic information beyond tumor-node-metastasis staging and helps refine follow-up strategies and guide individualized treatment. Incorporating recurrence time into clinical decision-making may improve risk stratification and management of CRC patients.
Citation: Zhou XM, Zeng ZY, Liu BG, Yin NN, Qu HB. Relationship between postoperative tumor recurrence time and long-term survival in colorectal cancer patients. World J Gastrointest Surg 2026; 18(7): 119305
Colorectal cancer (CRC) is one of the most common malignancies globally, posing a serious threat to human health. According to GLOBOCAN 2020 statistics, there are over 1.9 million new cases of CRC worldwide annually, with approximately 930000 deaths, ranking third in both incidence and mortality among malignant tumors[1,2]. In China, with accelerating population aging, westernization of lifestyles, and changes in dietary structure, the incidence of CRC shows a rapid upward trend, becoming one of the most common malignancies of the digestive system. Epidemiological studies show that the annual number of new CRC cases in China has exceeded 500000, with incidence rates in urban areas significantly higher than in rural areas, leading to an increasingly heavy disease burden[3].
Surgical curative resection is the cornerstone and first-line treatment for CRC. In recent years, with the popularization of total mesorectal excision (TME)[4,5], laparoscopic and robotic surgical techniques, improvements in perioperative management, and continuous optimization of comprehensive treatment strategies including neoadjuvant chemoradiotherapy, targeted therapy, and immunotherapy, the overall prognosis of CRC patients has significantly improved. However, despite the increasingly refined multidisciplinary comprehensive treatment model, post-operative tumor recurrence and metastasis remain major clinical challenges. Literature reports that even CRC patients receiving curative surgery still have a 30%-50% chance of local recurrence or distant metastasis post-operatively, with recurrence rates of approximately 20%-30% for stage II patients and as high as 40%-60% for stage III patients[6,7]. Tumor recurrence has become the main cause of decreased long-term survival rates and treatment failure in CRC patients, and is a key factor affecting patient quality of life and survival prognosis.
Post-operative recurrence in CRC exhibits significant temporal distribution patterns and heterogeneous characteristics. Numerous clinical studies demonstrate that CRC post-operative recurrence shows a clear time-window effect, with approximately 70%-80% of recurrences occurring within 2-3 years post-surgery, the peak recurrence period being the first 1-2 years post-surgery, after which recurrence risk gradually decreases annually, with late recurrence after 5 years being relatively rare[8,9]. This recurrence time distribution pattern suggests that recurrences occurring at different time points may have different biological bases and clinical significance. From a tumor biology perspective, early recurrence typically reflects tumors with stronger proliferative activity, invasive capability, and metastatic potential, possibly closely related to poor differentiation of the primary tumor, advanced TNM staging, vascular and neural invasion, and circulating tumor cells (CTCs) or micrometastases disseminated during pre-operative or intra-operative periods. Late recurrence may suggest relatively indolent tumor biological behavior, or be related to factors such as host immune surveillance function, tumor dormancy mechanisms, and epigenetic changes[10,11].
In recent years, with the in-depth development of precision medicine and individualized diagnosis and treatment concepts, research on tumor recurrence time windows has gradually attracted widespread attention from domestic and international scholars. Multiple international studies show that recurrence time is closely related to prognosis in CRC patients, with median survival time and long-term survival rates of early recurrence patients being significantly lower than those of late recurrence patients, and recurrence time may be an important prognostic predictor independent of TNM staging[12,13]. However, there is currently no unified standard for defining recurrence time thresholds, with some studies using 1 year, 2 years, or 3 years post-surgery as cutoff points, and results varying across different studies. Additionally, there are relatively few large-sample clinical studies in China on the relationship between post-operative recurrence time and long-term survival prognosis in CRC, and questions such as whether recurrence time can serve as an independent prognostic indicator and how to formulate individualized treatment strategies based on recurrence time still lack sufficient evidence-based medical support[14].
Clarifying the relationship between post-operative recurrence time and long-term patient survival prognosis has important clinical practice value. First, it helps identify high-risk populations for post-operative recurrence, enabling rational stratified patient management and implementing more intensive monitoring and follow-up strategies for high-risk early recurrence patients to enable early detection and timely intervention. Second, it provides reference for selecting post-recurrence treatment plans, as early recurrence patients may need more aggressive comprehensive treatment measures, including repeat surgery, systemic chemotherapy, or combined application of targeted therapy or immunotherapy. Furthermore, recurrence time as a prognostic factor can be incorporated into risk assessment models, assisting clinicians in prognostic judgment and survival prediction, and providing patients and families with more accurate prognostic information. Finally, in-depth exploration of the relationship between recurrence time and prognosis helps reveal the biological mechanisms of CRC recurrence and metastasis, laying a theoretical foundation for developing new therapeutic targets and prevention strategies[15].
MATERIALS AND METHODS
Study subjects
Retrospective analysis of clinical data from 120 patients who underwent curative surgery for CRC in the Department of General Surgery at our hospital from January 2015 to December 2018 and subsequently experienced tumor recurrence. Inclusion criteria: (1) Pathologically confirmed colorectal adenocarcinoma; (2) First curative surgical resection with post-operative pathological confirmation of negative margins (R0 resection); R0 resection was defined as histologically confirmed negative circumferential, proximal, and distal resection margins on permanent section pathology, assessed by experienced gastrointestinal pathologists. For rectal cancer specimens, the circumferential resection margin was considered positive if tumor cells were identified within 1 mm of the mesorectal fascia, consistent with the Royal College of Pathologists criteria; (3) Post-operative tumor recurrence or metastasis, with recurrence diagnosis confirmed by imaging [computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography-CT (PET-CT)], endoscopy, or pathological biopsy; and (4) Complete clinical pathological data and comprehensive follow-up information. Exclusion criteria: (1) Pre-operative distant metastasis; (2) Concurrent other malignancies; (3) Perioperative death (within 30 days post-surgery); and (4) Lost to follow-up or follow-up time less than 6 months. This study was approved by the hospital ethics committee and complies with medical ethics requirements.
Grouping method
The 120 patients were divided into two groups based on post-operative recurrence time: Early recurrence group (63 cases), defined as recurrence occurring ≤ 2 years post-surgery; late recurrence group (57 cases), defined as recurrence occurring > 2 years post-surgery. Recurrence time was calculated as the time interval from curative surgery date to first imaging or pathological confirmation of recurrence. The 2-year threshold was selected based on multiple considerations. First, both ESMO and NCCN guidelines consistently identify the first two postoperative years as the peak period for CRC recurrence, during which approximately 70%-80% of all recurrences occur. Second, prior landmark studies by Ryuk et al[12] and Furuke et al[13] have adopted the same 2-year threshold and demonstrated its prognostic discriminative ability. Third, alternative cut-offs of 1 year and 3 years were considered; however, a 1-year threshold yielded an excessively small early recurrence subgroup with limited statistical power, whereas a 3-year threshold diluted the biological distinction between early and late recurrence. We performed exploratory analyses using these alternative thresholds, and the 2-year cut-off provided the most balanced group sizes and the strongest separation of survival curves.
Data collection
Patient data was collected through the hospital electronic medical record system and follow-up database: (1) General clinical data: Gender, age, body mass index (BMI), comorbidities, etc.; (2) Tumor-related indicators: Tumor location (colon/rectum), tumor size, histological differentiation, TNM staging (according to American Joint Committee on Cancer 8th edition), vascular invasion, neural invasion, pre-operative carcinoembryonic antigen (CEA) levels, etc.; (3) Treatment-related data: Surgical method, number of lymph nodes dissected, post-operative adjuvant chemotherapy status, etc.; (4) Recurrence-related information: Recurrence time, recurrence site (local recurrence, distant metastasis, or both), CEA level at recurrence, post-recurrence treatment modality (repeat surgery, chemotherapy, targeted therapy, radiotherapy, or comprehensive treatment), etc.; and (5) Prognostic indicators: Overall survival (OS, from curative surgery date to death or last follow-up date), post-recurrence survival (PRS, from recurrence diagnosis to death or last follow-up date).
Follow-up methods
Follow-up was conducted through outpatient visits, telephone calls, and correspondence. During the first 2 years post-surgery, follow-up occurred every 3 months; from years 3-5, every 6 months; and annually after 5 years. All follow-up visits included physical examination, serum CEA and CA19-9 testing, and contrast-enhanced CT of the chest, abdomen, and pelvis. Colonoscopy was performed at one year postoperatively and then every two to three years thereafter, or earlier if clinically indicated. Enhanced liver MRI or PET-CT was selectively employed when standard CT findings were equivocal or when liver metastasis was clinically suspected. This standardized surveillance protocol was applied consistently across both recurrence groups throughout the study period. Follow-up ended on December 31, 2024, with a median follow-up time of 52 months (range 6-108 months).
Statistical analysis
SPSS 26.0 statistical software was used for data analysis. Continuous variables were expressed as mean ± SD or median (interquartile range), with group comparisons using t-test or Mann-Whitney U test; categorical variables were expressed as n (%), with group comparisons using χ² test or Fisher’s exact test. Kaplan-Meier method was used to plot survival curves, and Log-rank test was used to compare survival differences between groups. Cox proportional hazards regression model was used for univariate and multivariate analysis to screen independent risk factors affecting prognosis, calculating hazard ratio (HR) and 95% confidence interval (CI). P < 0.05 was considered statistically significant.
RESULTS
Comparison of general clinical data between groups
This study included 120 CRC patients with post-operative recurrence, including 63 cases (52.5%) in the early recurrence group and 57 cases (47.5%) in the late recurrence group. The early recurrence group consisted of 38 males and 25 females, with mean age (62.4 ± 11.3) years; the late recurrence group consisted of 33 males and 24 females, with mean age (59.7 ± 10.8) years. There were no statistically significant differences between the two groups in gender composition (χ² = 0.046, P = 0.831), age distribution (t = 1.338, P = 0.183), BMI (t = 0.892, P = 0.374), or comorbidities such as hypertension (χ² = 0.521, P = 0.470) and diabetes (χ² = 0.338, P = 0.561) (P > 0.05), indicating comparability of general clinical data between groups. Regarding tumor location distribution, the early recurrence group had 36 cases (57.1%) of colon cancer and 27 cases (42.9%) of rectal cancer; the late recurrence group had 35 cases (61.4%) of colon cancer and 22 cases (38.6%) of rectal cancer, with no statistically significant difference between groups (χ² = 0.228, P = 0.633, Table 1).
Table 1 Comparison of general clinical data between groups, n (%).
Comparison of tumor pathological characteristics between groups
Significant differences existed between early and late recurrence groups in multiple tumor pathological characteristics. For TNM staging, the early recurrence group had 15 stage II patients (23.8%) and 48 stage III patients (76.2%); the late recurrence group had 23 stage II patients (40.4%) and 34 stage III patients (59.6%), with statistically significant difference between groups (χ² = 4.082, P = 0.043), suggesting a higher proportion of advanced cases in the early recurrence group. For histological differentiation, the early recurrence group had 42 cases (66.7%) of well-moderate differentiation and 21 cases (33.3%) of poor differentiation; the late recurrence group had 49 cases (86.0%) of well-moderate differentiation and 8 cases (14.0%) of poor differentiation, with statistically significant difference (χ² = 6.253, P = 0.012). The positive rate of vascular invasion was 52.4% (33/63) in the early recurrence group, significantly higher than 28.1% (16/57) in the late recurrence group, with statistically significant difference (χ² = 7.476, P = 0.006). For neural invasion, the positive rate was 38.1% (24/63) in the early recurrence group and 19.3% (11/57) in the late recurrence group, with statistically significant difference (χ² = 5.192, P = 0.023). The proportion of patients with pre-operative CEA levels ≥ 5 ng/mL was 71.4% (45/63) in the early recurrence group and 54.4% (31/57) in the late recurrence group, with statistically significant difference (χ² = 3.863, P = 0.049). There were no statistically significant differences between groups for indicators such as number of lymph nodes dissected and tumor size (P > 0.05, Table 2).
Table 2 Comparison of tumor pathological characteristics between groups, n (%).
Comparison of post-operative adjuvant treatment between groups
Regarding post-operative adjuvant treatment, 58 patients (92.1%) in the early recurrence group and 53 patients (93.0%) in the late recurrence group received adjuvant chemotherapy, with no statistically significant difference (χ² = 0.033, P = 0.856). Chemotherapy regimens were mainly FOLFOX or XELOX, with 46 cases (73.0%) in the early recurrence group completing 6-8 cycles of chemotherapy and 44 cases (77.2%) in the late recurrence group completing standard cycles, showing similar completion rates (χ² = 0.300, P = 0.584). Among rectal cancer patients, the proportion receiving neoadjuvant chemoradiotherapy was 11 cases (40.7%) in the early recurrence group and 9 cases (40.9%) in the late recurrence group, with no statistically significant difference (P = 0.988). These results suggest no significant differences in standardization and completeness of post-operative adjuvant treatment between groups, ruling out treatment factors as a major influence on recurrence time (Table 3).
Table 3 Comparison of post-operative adjuvant treatment between groups, n (%).
Analysis of recurrence patterns and sites between groups
Recurrence pattern analysis showed that in the early recurrence group, there were 12 cases (19.0%) of local recurrence only, 38 cases (60.3%) of distant metastasis only, and 13 cases (20.6%) of combined local recurrence and distant metastasis; in the late recurrence group, there were 18 cases (31.6%) of local recurrence only, 31 cases (54.4%) of distant metastasis only, and 8 cases (14.0%) of combined local recurrence and distant metastasis. The early recurrence group tended toward higher rates of combined recurrence and distant metastasis, but the difference was not statistically significant (χ² = 4.673, P = 0.097). For distant metastasis distribution, liver metastasis was the most common site, with incidence of 54.0% (34/63) in the early recurrence group and 45.6% (26/57) in the late recurrence group, with no statistically significant difference (P = 0.353). Lung metastasis incidence was 31.7% (20/63) in the early recurrence group and 22.8% (13/57) in the late recurrence group, with no statistically significant difference (P = 0.268). There were no significant differences between groups for other metastasis sites such as peritoneal and bone metastases. The proportion of patients with elevated CEA (≥ 5 ng/mL) at recurrence diagnosis was 79.4% (50/63) in the early recurrence group, significantly higher than 59.6% (34/57) in the late recurrence group, with statistically significant difference (χ² = 5.705, P = 0.017, Table 4).
Table 4 Analysis of recurrence patterns and sites between groups, n (%).
Survival analysis showed significant differences in OS between early and late recurrence groups. Median OS was 36.8 months (95%CI: 31.2-42.4 months) for the early recurrence group and 68.5 months (95%CI: 59.7-77.3 months) for the late recurrence group, with statistically significant difference (Log-rank χ² = 28.463, P < 0.001). For 1-year, 3-year, and 5-year OS rates, the early recurrence group had 87.3%, 39.7%, and 22.2% respectively, while the late recurrence group had 98.2%, 80.7%, and 57.9% respectively, with statistically significant differences at all time points (P < 0.001). Kaplan-Meier survival curves showed that the two survival curves began separating early post-operatively, with survival differences gradually widening over follow-up time. The 5-year survival rate for early recurrence group patients was less than one-quarter, while more than half of late recurrence group patients survived, suggesting that recurrence time has an important impact on long-term patient prognosis (Figure 1A).
Figure 1 Kaplan-Meier survival curves comparing early and late recurrence groups in colorectal cancer patients.
A: Overall survival curves showing significantly worse prognosis in the early recurrence group (median 36.8 months) compared to the late recurrence group (median 68.5 months) (Log-rank P < 0.001); B: Post-recurrence survival curves demonstrating markedly shorter survival after recurrence in the early recurrence group (median 14.6 months) than in the late recurrence group (median 33.2 months) (Log-rank P < 0.001).
Comparison of PRS between groups
PRS analysis also showed significant differences between groups. Median PRS was 14.6 months (95%CI: 11.8-17.4 months) for the early recurrence group and 33.2 months (95%CI: 27.9-38.5 months) for the late recurrence group, with highly statistically significant difference (Log-rank χ² = 32.157, P < 0.001). For 1-year, 2-year, and 3-year PRS rates, the early recurrence group had 58.7%, 25.4%, and 11.1% respectively, while the late recurrence group had 89.5%, 68.4%, and 49.1% respectively, with statistically significant differences at all time points (P < 0.001). Post-recurrence treatment analysis showed that 16 patients (25.4%) in the early recurrence group received repeat surgery, and 52 patients (82.5%) received systemic chemotherapy or chemotherapy combined with targeted therapy; in the late recurrence group, 22 patients (38.6%) received repeat surgery, and 48 patients (84.2%) received systemic chemotherapy or chemotherapy combined with targeted therapy. More specifically, in the early recurrence group, 16 patients (25.4%) underwent repeat surgical resection with curative intent, 28 patients (44.4%) received systemic chemotherapy alone (predominantly FOLFOX or FOLFIRI-based regimens), 12 patients (19.0%) received chemotherapy combined with targeted therapy (bevacizumab or cetuximab), and 7 patients (11.1%) received best supportive care only. In the late recurrence group, 22 patients (38.6%) underwent repeat surgical resection, 20 patients (35.1%) received systemic chemotherapy alone, 10 patients (17.5%) received chemotherapy combined with targeted therapy, and 5 patients (8.8%) received best supportive care only. The higher rate of repeat surgical resection in the late recurrence group likely reflects the more favorable tumor biology and more limited, resectable disease patterns in these patients. The late recurrence group had slightly higher repeat surgical resection rate than the early recurrence group (χ² = 2.583, P = 0.108). Even with similar post-recurrence treatment, PRS in the early recurrence group was significantly shorter than in the late recurrence group, suggesting that early recurrence patients may have poorer treatment responsiveness (Figure 1B).
Univariate and multivariate analysis of factors affecting OS
Univariate Cox regression analysis showed that TNM staging (stage III vs II, HR = 2.15, 95%CI: 1.43-3.23, P < 0.001), histological differentiation (poor vs well-moderate, HR = 1.87, 95%CI: 1.24-2.82, P = 0.003), vascular invasion (yes vs no, HR = 1.76, 95%CI: 1.21-2.56, P = 0.003), neural invasion (yes vs no, HR = 1.64, 95%CI: 1.12-2.40, P = 0.011), pre-operative CEA level (≥ 5 vs < 5 ng/mL, HR = 1.58, 95%CI: 1.08-2.31, P = 0.019), recurrence time (early vs late, HR = 2.68, 95%CI: 1.82-3.95, P < 0.001), recurrence pattern (multiple metastases vs single metastasis, HR = 1.92, 95%CI: 1.31-2.81, P = 0.001), and post-recurrence treatment modality (palliative vs surgical or comprehensive treatment, HR = 2.03, 95%CI: 1.41-2.92, P < 0.001) were related to patient OS.
Variables with P < 0.05 in univariate analysis were included in multivariate Cox regression model. Results showed that recurrence time (early vs late, HR = 2.41, 95%CI: 1.56-3.72, P < 0.001), TNM staging (stage III vs II, HR = 1.92, 95%CI: 1.26-2.94, P = 0.003), histological differentiation (poor vs well-moderate, HR = 1.58, 95%CI: 1.04-2.40, P = 0.032), and post-recurrence treatment modality (palliative vs surgical or comprehensive treatment, HR = 1.71, 95%CI: 1.18-2.48, P = 0.005) were independent prognostic factors affecting OS. Among these, recurrence time had the highest HR value, suggesting that post-operative recurrence time is an important independent risk factor for predicting long-term survival in CRC patients, with early recurrence patients having 2.41 times the mortality risk of late recurrence patients. This result further confirms the important value of recurrence time in prognosis assessment (Figure 2).
Figure 2 Cox regression analysis of factors affecting overall survival in colorectal cancer patients.
A: Forest plot illustrating univariable Cox regression analysis of prognostic factors for overall survival; B: Forest plot illustrating multivariable Cox regression analysis of prognostic factors for overall survival. Univariable analysis identified eight significant factors associated with survival, including TNM stage, differentiation, vascular and neural invasion, preoperative carcinoembryonic antigen, recurrence time, recurrence pattern, and post-recurrence treatment (all P < 0.05). After multivariable adjustment, three variables remained independent prognostic factors: TNM stage [hazard ratio (HR) = 2.08, P < 0.001], differentiation grade (HR = 1.38, P = 0.043), and recurrence time (HR = 2.94, P < 0.001). Recurrence time emerged as the strongest independent predictor of overall survival, emphasizing its critical role in prognostic stratification. CEA: Carcinoembryonic antigen.
DISCUSSION
Post-operative recurrence in CRC has always been a key factor affecting long-term patient survival and an important topic of long-term focus in clinical oncology. Despite continuous advances in modern surgical techniques, with the popularization of the TME concept reducing local recurrence rates in rectal cancer from the previous 20%-30% to 5%-10%[16,17], distant metastasis remains the main form of post-operative recurrence. Epidemiological data show that even with standardized curative surgery and adjuvant treatment, a considerable proportion of patients ultimately experience treatment failure due to recurrence and metastasis. In-depth understanding of temporal distribution patterns of recurrence and their relationship with prognosis is of significant practical importance for optimizing follow-up strategies and improving patient quality of life. This study focuses on recurrence time, a long-neglected but clinically valuable prognostic indicator, systematically exploring its intrinsic relationship with long-term patient survival. From a tumor biology perspective, the earliness or lateness of recurrence time essentially reflects the biological behavior and malignancy degree of tumor cells. Early recurrence typically indicates tumors with stronger proliferative capacity, invasiveness, and metastatic potential. Molecular biology research shows that early recurrence in CRC is often accompanied by higher gene mutation burden, chromosomal instability, and inactivation of key tumor suppressor genes such as TP53 and APC[18-20]. Additionally, abnormal activation of the epidermal growth factor receptor (EGFR) signaling pathway, high expression of vascular endothelial growth factor, and microsatellite instability (MSI) status may all influence tumor recurrence time. Research on CTCs and circulating tumor DNA (ctDNA) further reveals that micrometastases disseminated pre-operatively or intra-operatively can rapidly proliferate when host immune surveillance function is relatively weak, leading to early recurrence[21-23]. Recent studies have further refined this molecular understanding. High-frequency KRAS and TP53 co-mutations have been shown to confer chemoresistance and promote postoperative recurrence and metastasis in CRC have demonstrated that postoperative ctDNA positivity strongly predicts early recurrence and poor survival, providing a molecular explanation for rapid disease recurrence despite apparently curative surgery. Furthermore, the consensus molecular subtype (CMS) classification offers additional prognostic insight: CMS4 (mesenchymal subtype), characterized by stromal infiltration, TGF-β activation, and epithelial-mesenchymal transition, is associated with earlier recurrence and worse prognosis. In contrast, MSI-high tumors generally exhibit better prognosis and respond favorably to immune checkpoint inhibitors, which may partially explain the heterogeneity observed in late recurrence outcomes. Conversely, late recurrence may be closely related to tumor dormancy mechanisms. Tumor dormancy refers to disseminated tumor cells remaining in a non-proliferative or slow-proliferative state in distant organs for prolonged periods, possibly lasting years or longer. Maintenance of tumor dormancy involves multiple mechanisms including cell cycle arrest, angiogenesis inhibition, and immune evasion. When the microenvironment changes or immune surveillance function declines, dormant tumor cells can reactivate and form clinically detectable metastases. Epigenetic changes, dynamic balance of matrix metalloproteinases, and host-tumor interactions play important roles in this process. Understanding these biological mechanisms helps develop targeted prevention and treatment strategies. In recent years, international research on CRC recurrence time has gradually increased. Multiple retrospective studies and meta-analyses show that recurrence time is closely related to patient prognosis, but there is no unified standard for defining recurrence time thresholds. Some studies use 1 year post-surgery as the cutoff, believing that recurrence within 1 year indicates extremely poor prognosis; other studies use 2 or 3 years as thresholds. ESMO guidelines indicate that the first 2 years post-surgery represent the peak period for CRC recurrence, and close monitoring during this period is crucial. Large-scale cohort studies by the Japanese Society for Cancer of the Colon and Rectum show that patients with recurrence within 2 years post-surgery have 5-year survival rates of only 15%-25%, while patients with recurrence after 2 years have 5-year survival rates of 40%-60%.However, relevant domestic research is relatively limited, mostly single-center small-sample studies, lacking systematic analysis of recurrence time as an independent prognostic factor. Chinese CRC patients differ from Western populations in onset age, tumor location distribution, and molecular subtype characteristics, making it necessary to explore the prognostic value of recurrence time based on local data. This study, through systematic analysis of 120 recurrent patients, not only validates the independent prognostic significance of recurrence time, but also provides in-depth comparison of clinical pathological characteristics and treatment outcomes of patients with different recurrence times, providing localized evidence for domestic clinical practice. This study found that early recurrence patients exhibited higher malignancy across multiple pathological indicators, including more advanced TNM staging, poorer histological differentiation, higher rates of vascular and neural invasion, and higher pre-operative CEA levels. These characteristics are interrelated, collectively forming the biological basis for tumor invasion and metastasis. TNM staging is recognized as the most important prognostic factor; stage III patients, due to lymph node metastasis, indicate tumor capability for regional spread, and even with standardized adjuvant chemotherapy, still have relatively high recurrence risk. Poor histological differentiation is associated with genomic instability and enhanced cell proliferative activity, and these tumors may have poorer sensitivity to chemotherapy. Vascular and neural invasion provide pathways for tumor cells to enter blood circulation or lymphatic systems, representing important routes for distant metastasis development. Notably, although early recurrence group patients were at a disadvantage across multiple pathological indicators, there were no significant differences in standardization and completeness of post-operative adjuvant treatment between groups, ruling out treatment factors as a major influence on recurrence time and further supporting that recurrence time itself may be an independent indicator reflecting intrinsic tumor biological characteristics. This finding suggests that traditional TNM staging and pathological features alone may not fully predict patient recurrence risk, requiring integration of multidimensional information to construct more precise prognostic assessment models. The purpose of post-operative follow-up in CRC is early detection of recurrence and metastasis, enabling timely intervention to improve prognosis. However, current guideline-recommended follow-up protocols from various countries are mostly based on TNM staging, applying the same follow-up frequency and examination items to all patients of the same stage, lacking individualized consideration. Based on recurrence time distribution patterns, follow-up strategies can be further refined. For patients with high-risk factors for early recurrence, such as stage III, poor differentiation, positive vascular/neural invasion, and persistently elevated CEA, more intensive monitoring should be implemented during the first 2 years post-surgery, including serum tumor marker testing every 2-3 months and imaging examinations every 3-6 months, to enable diagnosis at early recurrence stages. Conversely, for low-risk patients or those who have successfully passed the 2-year high-risk period, follow-up intervals can be appropriately extended, reducing unnecessary examinations, lowering medical costs and patient psychological burden. Additionally, follow-up method selection should be individualized. For high-risk liver metastasis patients, enhanced MRI or PET-CT may have higher sensitivity than routine CT; for high-risk lung metastasis patients, thin-slice chest CT is superior to routine chest radiography. Liquid biopsy technologies such as ctDNA detection, as emerging monitoring tools, are having their value in early recurrence detection validated in multiple prospective studies, and may become important tools for individualized follow-up in the future[21-23]. Recurrence time not only has prognostic predictive value, but also guides post-recurrence treatment decision-making. For early recurrence patients, due to their tumors' stronger invasiveness, surgery alone may be difficult to achieve long-term survival benefit, requiring more aggressive systemic treatment. New-generation chemotherapy regimens such as FOLFOXIRI triple-drug combination[24,25], combined application of targeted drugs like bevacizumab and cetuximab, and application of immune checkpoint inhibitors in MSI-H/dMMR patients[26,27] provide more treatment options for these patients. The concept of conversion therapy is particularly important in early recurrence patients with oligometastases; through intensive systemic treatment to convert unresectable lesions to resectable, some patients may have curative opportunities. For late recurrence patients, due to relatively indolent tumor biological behavior, if recurrence lesions are limited and completely resectable, surgical treatment may bring significant survival benefit. Surgical resection of liver and lung metastases has been proven to extend survival time and even achieve clinical cure in carefully selected patients[28]. For unresectable late recurrence patients, precision treatment strategies based on molecular typing are equally important. RAS/BRAF gene testing guides use of anti-EGFR targeted drugs, and HER2-amplified patients may benefit from anti-HER2 therapy, all reflecting application of precision medicine in recurrence treatment. An important methodological consideration in studies evaluating recurrence timing is lead-time bias. More intensive surveillance during the first two postoperative years, as recommended by current guidelines and practiced at our institution, could lead to earlier identification of recurrence in the early group, potentially inflating PRS measurements. However, OS, measured from the date of primary curative surgery, is anchored to a fixed time point irrespective of when recurrence is detected and is therefore not subject to lead-time bias in the same manner. The highly significant difference in OS between the early and late recurrence groups (median 36.8 vs 68.5 months, P < 0.001) provides robust evidence that recurrence timing carries genuine prognostic significance independent of detection-related artifacts. Furthermore, the follow-up protocol was standardized across both groups with identical surveillance schedules, which mitigates this concern. As a retrospective study, this research has certain limitations. First, the sample size is relatively limited and from a single center, requiring multi-center large-sample studies to further validate the generalizability of conclusions. Second, retrospective studies inevitably involve selection bias and information bias, with incomplete molecular pathological information such as RAS, BRAF, and MSI status for some patients, limiting in-depth analysis of relationships between tumor molecular characteristics and recurrence time. Third, although threshold selection for recurrence time is based on previous literature and clinical practice, the optimal cutoff point still needs determination through receiver operating characteristic curve analysis and larger sample validation studies. Additionally, this study could not include detailed information on second-line post-recurrence treatment and treatment response assessment, which may significantly impact PRS. Future prospective studies incorporating comprehensive molecular profiling (including RAS, BRAF, MSI status, and CMS classification), ctDNA monitoring, and detailed treatment response data will be essential to further elucidate the biological mechanisms underlying recurrence timing and to develop molecularly guided surveillance and treatment strategies.
CONCLUSION
Through systematic analysis of 120 CRC patients with post-operative recurrence, this study found that post-operative recurrence time is an important independent factor affecting long-term patient survival prognosis. Early recurrence (≤ 2 years post-surgery) patients have significantly worse OS and PRS compared to late recurrence (> 2 years post-surgery) patients, with mortality risk 2.41 times that of late recurrence patients. Early recurrence patients often have more advanced tumor staging, poorer histological differentiation, and higher rates of vascular and neural invasion, reflecting stronger tumor invasiveness and metastatic potential.
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