Development of a risk prediction model for personalized assessment of postoperative recurrence risk in colon cancer patients

Introduction

As lifestyle and dietary modifications persist in China, there has been a consistent rise in the prevalence of colon cancer, particularly among younger demographics (1). Presently, surgical intervention remains the predominant form of clinical treatment for colon cancer. Although radical surgery in conjunction with postoperative adjuvant therapy has demonstrated efficacy in lowering early recurrence rates for highly hazardous stages II and III intestinal cancer patients, not all individuals experience equal benefits from this strategy. Despite advancements in treatment, the recurrence rate following radical surgery for middle and advanced colon cancer remains notably elevated, typically falling within the range of 20% to 30% (2). Various risk factors, including tumor pathology, surgical outcomes, patient health status, immune function, and lifestyle choices, are known to contribute to postoperative recurrence (3). Current research in this area primarily focuses on examining individual or multiple risk factors associated with postoperative recurrence in patients with middle- and late-stage colon cancer. The individualized prediction of postoperative recurrence risk is crucial for clinical practice, highlighting the need for the creation of reliable risk prediction models. This research aims to determine the independent variables that affect patients with intermediate and advanced colon cancer’s likelihood of postoperative recurrence. The objective is to construct a columnar graph model to identify high-risk patients early on, leading to timely interventions that can potentially decrease metastasis recurrence rates and enhance overall patient survival. We present this article in accordance with the TRIPOD reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-948/rc).

Methods

Subjects

A cohort of 209 patients with postoperative colon cancer were chosen from admissions to The First Affiliated Hospital of Bengbu Medical University between January 2020 and April 2021. Inclusion criteria for this study were: patients with colorectal cancer undergoing surgery for the first time who have a definitive postoperative pathologic diagnosis of colorectal cancer, pathologic stage II–IV, and negative margins (no residual tumor cells) on postoperative pathology. These patients have not received any radiation therapy, targeted therapy or immunotherapy prior to surgery. Patients with later staging received chemotherapy with the XELOX regimen (oxaliplatin + capecitabine) after surgery. All patients had an expected survival of more than 2 years and complete clinical data were retained. Conversely, exclusion criteria for this investigation comprised patients undergoing therapies that could potentially influence the study’s results, such as medications affecting albumin levels or coagulation (e.g., furosemide, penicillin, aspirin, ibuprofen, warfarin, etc.). Patients with co-morbidities such as malignant tumors at other sites, autoimmune disorders, severe psychiatric disorders, and pregnant or breastfeeding women would be excluded from the analysis. Additionally, patients experiencing complications from other diseases that may impact study results during the observation period, those who passed away, or had their return visit terminated prematurely were also excluded. These patients were followed up until May 2024. The study received approval from The First Affiliated Hospital of Bengbu Medical University {No. [2023] 414}, and all participants provided informed consent. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Specimen characteristics

All patients in the study underwent surgical treatment and were followed up for a minimum of 3 years. Data on patients’ “gender”, “age”, “body mass index (BMI)”, “disease duration”, “underlying disease”, “smoking history”, “alcohol consumption history” were collected. “Underlying disease”, “smoking history”, “alcohol consumption”, “tumor stage”, “tumor differentiation”, “lymph node metastasis”, “tumor location”, “histological type”, “intestinal obstruction”, “adjuvant chemotherapy”, “laboratory results (C-reactive protein level, D-dimer level, serum albumin level, serum carcinoembryonic antigen level, etc.)” were collected. Criteria for ‘adjuvant chemotherapy’: (I) postoperative pathological staging of stage II with microsatellite stability (MSS) or proficient mismatch repair (pMMR), combined with high-risk recurrence factors such as poor histological differentiation, T4 tumor classification, choroidal infiltration, preoperative intestinal obstruction or perforation, detection of fewer than 12 lymph nodes in the specimen, neural invasion, positive surgical margins, or indeterminate margins, as well as postoperative pathological staging of stage III; (II) physical status meeting the requirements for chemotherapy; (III) no contraindications to chemotherapy; and (IV) patients willing to receive chemotherapy. The patients were evaluated for the recurrence of colon cancer post-surgery through regular follow-up examinations every 3 months to monitor tumor progression. These evaluations included routine physical exams, serum carcinoembryonic antigen (CEA) testing, and thoracic, abdominal, and pelvic computed tomography (CT) and magnetic resonance imaging (MRI) scans. The diagnosis of colon cancer recurrence was made if new lesions were identified during imaging or confirmed through histological biopsy.

Laboratory testing

On postoperative, peripheral cubital venous blood (10 mL) was collected from the patients. The blood samples were centrifuged at 3,000 r/min for 20 min to obtain serum, which was then subjected to chemiluminescence immunoassay for CEA detection (reagent kit produced by Changsha Chuxiang Biotechnology Co., Ltd., Changsha, China). Serum albumin was detected using immunoturbidimetric assay (reagent kit produced by Jiangxi Huipeptide Biotechnology Co., Ltd., Nanchang, China). Reference ranges were based on the instructions provided with the respective kits.

Statistical analysis

The statistical analysis was conducted using SPSS 25.0 software, with count data presented as n (%) for the Chi-squared test and measure data expressed as mean ± standard deviation for the t-test with a significance level of 0.05. Logistic regression was employed to identify independent protective/risk factors. Prediction modeling and calculation of the consistency index (C-index) were performed using R 4.2.3 software, utilizing the regression modeling strategies (rms) program package for internal validation through the Bootstrap method and Caret program package. Additionally, receiver operating characteristic (ROC) curve analysis was conducted using the “ROCR” and “rms” program packages.

Results

Univariate analysis of colon cancer recurrence in postoperative patients

The findings indicated that out of the 209 postoperative colon cancer patients examined, there were 55 cases of colon cancer recurrence, resulting in a recurrence rate of 26.3%. Univariate analysis revealed that factors such as “tumor stage”, “tumor differentiation”, “lymph node metastasis”, “adjuvant chemotherapy”, “Invasion depth”, “C-reactive protein level”, “serum albumin level”, and “serum carcinoembryonic antigen level” were the most important factors affecting postoperative recurrence in colon cancer patients. “C-reactive protein level”, “serum albumin level”, and “serum carcinoembryonic antigen level” were identified as particularly influential factors (respectively: P=0.03, P=0.03, P=0.003) (Table 1).

Multifactorial logistic regression analysis of colon cancer recurrence in postoperative patients

A multifactorial logistic regression model was established by stepwise inclusion with “recurrence of colon cancer” as the dependent variable and the factors with significant differences in the above univariate analysis as independent variables. Utilizing odds ratios (ORs) and a 95% confidence interval (CI) to demonstrate the findings of the study. The results showed that “tumor stage (IV)” (OR =12.794; 95% CI: 5.163–31.706), “lymph node metastasis (presence)” (OR =1.952; 95% CI: 1.047–3.639), “C-reactive protein level” (OR =1.124; 95% CI: 1.014–1.245), and “serum carcinoembryonic antigen level” (OR =1.041; 95% CI: 1.013–1.071) were independent risk-factors for “colon cancer recurrence” in postoperative patients, whereas “tumor differentiation (middle/high differentiation)” (OR =0.472; 95% CI: 0.247–0.901) and “serum albumin level” (OR =0.949; 95% CI: 0.905–0.995) were protective factors for postoperative recurrence in colon cancer patients (Table 2).

Establishment and evaluation of the column-line diagram prediction model of colon cancer recurrence in postoperative patients

The study’s results were derived from an analysis of four distinct risk factors, including “Tumor stage (IV)”, “Presence of lymph node metastases (presence)”, “C-reactive protein level”, and “Serum carcinoembryonic antigen level”, as well as three protective factors, namely “Degree of tumor differentiation (moderately to highly differentiated)”, “Administration of adjuvant chemotherapy”, and “Serum albumin”. A predictive model utilizing column-line graphs was created to evaluate the influence of various factors on the recurrence rate of colon cancer in postoperative individuals. The findings indicated a positive correlation between the score of each independent risk factor and the total score of the model, leading to a gradual increase in the recurrence rate of colon cancer (Figure 1). The model underwent validation through 1,000 iterations using the Bootstrap self-sampling method, resulting in the generation of a calibration curve (Figure 2). The results of the analysis suggest that the column-line graph model effectively predicted the “recurrence rate of colon cancer in postoperative patients”, with a close alignment between predicted and observed values. These findings indicate a high level of consistency in the predictions made by the column-line graph model. The ROC curve was employed to evaluate the predictive accuracy of the column-line diagram model for the “recurrence rate of colon cancer in postoperative patients”, revealing an area under the curve of 0.834 (95% CI: 0.776–0.892), further supporting the reliability of the model (Figure 3).

Figure 1 Column line graph prediction model of colon cancer recurrence in postoperative patients. CRP, C-reactive protein; CEA, carcinoembryonic antigen.

Figure 2 Validation of the column-line diagram model for predicting colon cancer recurrence in postoperative patients.

Figure 3 ROC curves of column chart model for predicting recurrence of colon cancer in postoperative patients. AUC, area under the curve; CI, confidence interval; ROC, receiver operating characteristic.

Discussion

This study presents the development and validation of a predictive model for assessing the risk of postoperative recurrence in colon cancer. The model incorporates seven parameters including tumor stage, lymph node metastasis, C-reactive protein (CRP) level, carcinoembryonic antigen level, degree of differentiation, chemotherapy status, and serum albumin level. The outcomes of model assessment and internal validation suggest that our nomogram prediction model demonstrates robust predictive capabilities. Additionally, an escalation in the number of independent risk factors correlates with a higher cumulative score in the nomogram model, signifying an elevated risk of postoperative recurrence.

Surgical intervention is the primary treatment modality for patients with intermediate and advanced colon cancer, with adjuvant chemotherapy and targeted therapy playing a crucial role in achieving radical treatment. However, the unpredictable recurrence rate poses challenges in predicting the prognosis of postoperative colon cancer patients. Research indicates that tumor stage significantly influences the likelihood of recurrence, with higher stages correlating with increased recurrence rates (4,5). The Japanese Society for Colorectal Cancer (JSCCR) documented varying rates of recurrence based on disease stage, with 3.7% for stage I, 13.3% for stage II, and 30.8% for stage III (6). In our study, the postoperative recurrence rate of colon cancer in stages III–IV was 49.0%, compared to just 6.0% for stage II colon cancer. The results of other studies are consistent with the considerable difference in postoperative recurrence rates between colon cancer in stages II and III–IV (7,8). Multifactorial regression analysis further indicated that “tumor stage” was a significant predictor of recurrence (OR =12.794; 95% CI: 5.163–31.706). The etiology of postoperative recurrence in stage III–IV patients is believed to be associated with lymph node metastasis. Despite the removal of metastatic lymph nodes during surgery, the presence of residual metastases, such as tiny metastases or single cancer cells, in other lymph nodes or distant organs may contribute to the development of postoperative recurrence (9). In this research, a comparison was made between patients with and without lymph node metastasis, revealing postoperative recurrence rates of 34.1% and 21.0%, respectively. Although statistically different, the difference was not deemed significant. However, Sugiura et al.’s study illustrated that the 5-year relapse-free survival (RFS) rates were 42.7% for groups with lymph node metastases and 84.0% for those without (10), suggesting that lymph node metastatic instability may serve as a predictive factor for postoperative outcomes. Furthermore, the findings of this study indicated that a high degree of differentiation served as a protective factor against postoperative recurrence, as evidenced by a recurrence rate of 37.1% in poorly differentiated patients compared to 21.8% in highly differentiated patients. It is commonly observed that hypo-differentiated colon cancers exhibit a heightened risk of postoperative recurrence due to their aggressive and malignant characteristics.

The standard treatment for intermediate and advanced colon cancer has been adjuvant oxaliplatin in combination with fluorouracil and calcium folinic acid (FOLFOX) or capecitabine (CAPOX) for 6 months (11). Adjuvant chemotherapy has demonstrated a significant improvement in disease-free survival (DFS) and overall survival (OS) in patients (12). This study identified adjuvant chemotherapy as a protective factor against postoperative colon cancer recurrence, with a high OR (OR =3.633; 95% CI: 1.913–6.901). In this study, the postoperative recurrence rate among patients who did not receive adjuvant chemotherapy was approximately 42.3%, whereas patients who did receive adjuvant chemotherapy had a notably lower recurrence rate of approximately 16%.

CRP serves as a non-specific inflammatory marker, and its elevation post-surgery is correlated with reduced OS following colon cancer surgery (13). The present study demonstrates that high levels of CRP were identified as a risk factor for postoperative recurrence, indicative of an inflammatory response and tissue damage post-surgery that may contribute to tumor recurrence, metastasis, and progression. However, a meta-analysis showed that CRP has limited accuracy in predicting the risk of colon cancer recurrence, but has some value in predicting the prognosis of patients with colorectal cancer (14). A direct association between CRP and postoperative recurrence of colon cancer has also not been shown in most other studies (15-17). A comprehensive assessment in combination with other clinical indicators and imaging may be needed.

Low serum albumin levels have been linked to worse outcomes in colon cancer patients, especially those with advanced disease. Studies have shown that preoperative serum albumin levels can independently impact prognosis, with hypoalbuminemia associated with poorer clinicopathological characteristics and lower OS rates (18,19). The present study found a negative correlation between serum albumin levels and postoperative recurrence of colon cancer. It is important to note that a decrease in albumin levels does not always indicate cancer recurrence, as it can be influenced by other health conditions. The research also identified a relationship between postoperative recurrence and CEA, consistent with prior studies, where elevated post-surgical levels indicate the potential presence of residual or recurrent tumors. Monitoring CEA levels in postoperative colorectal cancer patients has been demonstrated to facilitate early detection of recurrence (20-22).

In summary, the predictive capacity of individual factors for postoperative recurrence in patients with middle and advanced colon cancer is constrained, emphasizing the imperative for the creation of a prognostic model. After the identification of seven autonomous factors, a column chart model was devised to anticipate postoperative recurrence in patients with middle- to late-stage colon cancer. The ROC curves demonstrated that the column chart model displayed a high level of discrimination, suggesting its potential usefulness in clinical customization. However, the absence of external validation in this study underscores the necessity for additional data collection, including from diverse cohorts, to substantiate the model’s relevance in future applications.

Conclusions

In conclusion, our study has successfully developed a nomogram prediction model that accurately forecasts the likelihood of recurrence in patients with colon cancer. This model aids clinicians in enhancing their clinical decision-making processes and offers valuable guidance for promptly assessing the risk of postoperative recurrence in colon cancer patients, as well as implementing timely and effective preventive measures.

Acknowledgments

Funding: This work was supported by grants from the Scientific Research Project of Higher Education Institutions in Anhui Province (No. 2022AH051464) and the Natural Science Key Projects of Bengbu Medical College (No. 2021byzd062).

Footnote

Reporting Checklist: The authors have completed the TRIPOD reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-948/rc

Data Sharing Statement: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-948/dss

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-948/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-948/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study received approval from The First Affiliated Hospital of Bengbu Medical University {No. [2023] 414}, and all participants provided informed consent.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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