Guan RY, Wu JW, Yuan ZY, Liu ZY, Liu ZZ, Xiao ZC, Li JH, Huang CZ, Wang JJ, Yao XQ. Poorly controlled type II diabetes mellitus significantly enhances postoperative chemoresistance in patients with stage III colon cancer. World J Gastroenterol 2025; 31(3): 98688 [DOI: 10.3748/wjg.v31.i3.98688]
Corresponding Author of This Article
Xue-Qing Yao, MD, PhD, Professor, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, No. 106 Zhongshan Er Road, Guangzhou 510080, Guangdong Province, China. syyaoxueqing@scut.edu.cn
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Retrospective Cohort Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Ruo-Yu Guan, Jia-Wei Wu, Jun-Jiang Wang, Xue-Qing Yao, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou 510080, Guangdong Province, China
Ruo-Yu Guan, Jia-Wei Wu, Zi-Yun Yuan, Zhi-Yuan Liu, Zi-Zhu Liu, Zhi-Cong Xiao, Jing-Hui Li, Cheng-Zhi Huang, Jun-Jiang Wang, Xue-Qing Yao, Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, Guangdong Province, China
Ruo-Yu Guan, Jia-Wei Wu, Zi-Yun Yuan, Zhi-Yuan Liu, Zi-Zhu Liu, Zhi-Cong Xiao, Jing-Hui Li, Xue-Qing Yao, Department of General Surgery, Guangdong Provincial People’s Hospital Ganzhou Hospital (Ganzhou Municipal Hospital), Ganzhou 341000, Jiangxi Province, China
Zhi-Yuan Liu, Jun-Jiang Wang, Xue-Qing Yao, Shantou University Medical College, Shantou 515041, Guangdong Province, China
Zi-Zhu Liu, Jun-Jiang Wang, Xue-Qing Yao, School of Medicine, South China University of Technology, Guangzhou 510006, Guangdong Province, China
Jing-Hui Li, Gannan Medical University, Ganzhou 341000, Jiangxi Province, China
Co-corresponding authors: Jun-Jiang Wang and Xue-Qing Yao.
Author contributions: Guan RY, Wu JW, and Yuan ZY contributed to the data acquisition; Guan RY and Wu JW contributed equally to this work as co-first authors; Liu ZY, Liu ZZ, and Xiao ZC participated in the quality control of data and algorithms; Guan RY, Liu ZY, and Li JH took part in the data analysis and interpretation; Guan RY and Liu ZZ contributed to the statistical analysis of this manuscript; Guan RY, Wu JW, Yuan ZY involved in the manuscript preparation; Guan RY and Yao XQ contributed to the manuscript review; Huang CZ, Wang JJ, and Yao XQ edited the manuscript; Yao XQ and Wang JJ contributed equally to this work as co-corresponding authors.
Supported by the Leading Innovation Specialist Support Program of Guangdong Province; the Science and Technology Planning Project of Ganzhou, No. 202101074816; and the National Natural Science Foundation of China, No. 82260501.
Institutional review board statement: The study received approval from the Clinical Research Ethics Committee of Guangdong Provincial People’s Hospital, No. S2024-629-01.
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: No additional data are available.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Xue-Qing Yao, MD, PhD, Professor, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, No. 106 Zhongshan Er Road, Guangzhou 510080, Guangdong Province, China. syyaoxueqing@scut.edu.cn
Received: July 8, 2024 Revised: October 3, 2024 Accepted: November 25, 2024 Published online: January 21, 2025 Processing time: 164 Days and 17.3 Hours
Abstract
BACKGROUND
Type II diabetes mellitus (T2DM) has been associated with increased risk of colon cancer (CC) and worse prognosis in patients with metastases. The effects of T2DM on postoperative chemoresistance rate (CRR) and long-term disease-free survival (DFS) and overall survival (OS) in patients with stage III CC who receive curative resection remain controversial.
AIM
To investigate whether T2DM or glycemic control is associated with worse postoperative survival outcomes in stage III CC.
METHODS
This retrospective cohort study included 278 patients aged 40-75 years who underwent surgery for stage III CC from 2018 to 2021. Based on preoperative T2DM history, the patients were categorized into non-DM (n = 160) and DM groups (n = 118). The latter was further divided into well-controlled (n = 73) and poorly controlled (n = 45) groups depending on the status of glycemic control. DFS, OS, and CRR were compared between the groups and Cox regression analysis was used to identify risk factors.
RESULTS
Patients in the DM and non-DM groups demonstrated similar DFS, OS, and CRR (DFS: 72.03% vs 78.75%, P = 0.178; OS: 81.36% vs 83.12%, P = 0.638; CRR: 14.41% vs 7.5%, P = 0.063). Poorly controlled DM was associated with a significantly worse prognosis and higher CRR than well-controlled DM (DFS: 62.22% vs 78.07%, P = 0.021; OS: 71.11% vs 87.67%, P = 0.011; CRR: 24.40% vs 8.22%, P = 0.015). High preoperative fasting plasma glucose [DFS: Hazard ratio (HR) = 2.684, P < 0.001; OS: HR = 2.105, P = 0.019; CRR: HR = 2.214, P = 0.005] and glycosylated hemoglobin levels (DFS: HR = 2.344, P = 0.006; OS: HR = 2.119, P = 0.021; CRR: HR = 2.449, P = 0.009) indicated significantly poor prognosis and high CRR, while T2DM history did not (DFS: HR = 1.178, P = 0.327; OS: HR = 0.933, P = 0.739; CRR: HR = 0.997, P = 0.581).
CONCLUSION
Increased preoperative fasting plasma glucose and glycosylated hemoglobin levels, but not T2DM history, were identified as risk factors associated with poor postoperative outcomes and high CRR in patients with stage III CC.
Core Tip: Type II diabetes mellitus (T2DM) has been consistently associated with high risk of carcinogenesis in gastrointestinal malignances. However, the relationship between T2DM and postoperative chemotherapy outcomes or long-term prognosis in patients with colon cancer remains unclear. This study emphasizes that preoperative poorly controlled hyperglycemia, but not T2DM history, is associated with enhanced chemoresistance and frustrating prognosis in patients who underwent surgery for stage III colon cancer. Our results also remind us of the importance of managing hyperglycemia in patients with T2DM, and that glycemic-related parameters such as fasting plasma glucose and glycosylated hemoglobin levels are potential predictive indicators for chemotherapy responses.
Citation: Guan RY, Wu JW, Yuan ZY, Liu ZY, Liu ZZ, Xiao ZC, Li JH, Huang CZ, Wang JJ, Yao XQ. Poorly controlled type II diabetes mellitus significantly enhances postoperative chemoresistance in patients with stage III colon cancer. World J Gastroenterol 2025; 31(3): 98688
Colon cancer (CC) is one of the most prevalent malignances worldwide and its incidence continues to increase in many countries[1]. Due to advances in diagnostic, surveillance, and surgical technologies, the incidence of CC per 100000 people decreased from 60.5 to 38.7[2], while the 5-year relative survival rate has improved from 50% to 65%[3] over the past decades. Despite these advances, approximately 20%-30% of patients experience tumor recurrence after surgery[4], which poses major challenges for CC treatment and limits therapeutic efficacy. Hence, decreasing disease recurrence and metastasis after curative resection merits further attention.
Adjuvant chemotherapy is the recommended treatment for patients with resected locally advanced, lymph node-positive (stage III) CC[5,6]. To date, chemotherapy regimens incorporating oxaliplatin and/or fluoropyrimidines are widely acknowledged for improving postoperative prognosis in patients with CC[7,8]. Capecitabine, a prodrug of 5-fluorouracil, is an oral fluoropyrimidine used for treating CC in both the early and advanced stages, either as monotherapy or in combination with other chemotherapeutic medications[9,10]. This drug provides a more convenient regimen than intravenous 5-fluorouracil, with significantly fewer toxic reactions such as diarrhea, nausea, and stomatitis[11]. However, the benefits of capecitabine-based therapy are frequently compromised by the development of chemoresistance, leading to tumor recurrence and metastasis[8,12]. These observations suggest that in-depth analyses are needed to explore effective ways to overcome or alleviate chemoresistance after surgical resection.
Type II diabetes mellitus (T2DM) is a metabolic disorder characterized by prolonged hyperglycemia. Research on T2DM-related carcinogenesis has expanded exponentially since T2DM was recognized as an important risk factor for gastrointestinal diseases[13] and various cancers, such as pancreatic[14], breast[15], and colorectal cancer (CRC)[16]. Persistent hyperglycemia promotes tumor progression[17,18], cancer cell proliferation[19], and metastasis[20]. Moreover, antidiabetic medications such as metformin have been shown to have anticancer activity and enhance chemotherapy sensitivity in ovarian cancer[21], lung cancer[22], and acute myeloid leukemia[23]. Metabolic disorders are hallmarks of cancer[24]. Notably, some genetic drivers of CC, such as P53, KRAS, and Wnt, have been recognized as regulators of cancer metabolism[25-27], which indicates the potential impact of metabolic disorders on carcinogenesis in CC. The effects of T2DM on CC have long been debated, and studies show that T2DM increases the risk of CC[28,29]. Additionally, metformin, administered as monotherapy or in combination with chemotherapy, is a potential therapeutic agent against cancer progression and for overcoming chemoresistance in vitro and animal studies[30,31]. Based on this evidence, it is reasonable to speculate that hyperglycemia may promote chemoresistance in patients with CC after surgical resection.
Due to the limited number of studies, the effects of hyperglycemia on postoperative chemoresistance in patients with CC remain unclear and warrant further exploration. To address this issue, in this study, we evaluated data from patients who underwent curative resection for stage III CC. By comparing preoperative glycemic characteristics and postoperative prognostic alongside chemotherapy-related data, we aimed to elucidate whether a preoperative T2DM history or hyperglycemia was more significantly associated with enhanced chemoresistance and poor prognosis.
MATERIALS AND METHODS
Study population
The population in this retrospective cohort study was selected from a cohort of 1932 consecutive patients who underwent surgical resection for CRC between January 2018 and December 2021 at the Department of Gastrointestinal Surgery, Guangdong Provincial People’s Hospital, Southern Medical University. The inclusion and exclusion criteria were formulated according to tumor-node-metastasis (TNM) stage, basic characteristics, and pathological and follow-up data. We excluded patients if they were diagnosed with non-CC (n = 732), non-TNM stage III, T2 or well-differentiated (n = 326), aged < 40 or > 75 years (n = 120), presented with other malignancies or non-malignant severe illnesses (n = 55), lacked follow-up or baseline data (n = 387), or had recurrence or died within 3 months or experienced severe complications after surgery (n = 34). Data from a final cohort of 278 patients were included in our analysis (Figure 1).
Figure 1 Study flow chart.1Defined as the American Society of Anesthesiologists classification > III or New York Heart Association classification> II. 2Defined as Clavien-Dindo classification > II. DM: Diabetes mellitus; TNM: Tumor-node-metastasis.
Information on demographics, morbidity, postoperative mortality, and histological results were obtained from the hospital’s medical system. Physical examination, chest computed tomography (CT), magnetic resonance imaging, and blood tests were performed routinely. Fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c) levels were tested before surgery. The plasma glucose levels were monitored in patients with T2DM history; the patients were switched to receive insulin based on their plasma glucose levels on admission, and continued taking their antidiabetic agents after discharge. For patients without T2DM history but with abnormal FPG or HbA1c levels, a T2DM diagnosis was ascertained by endocrinologists before surgery, and the insulin and plasma glucose levels were monitored once diagnosed perioperatively. All patients were followed up regularly in the Department of Endocrinology after surgery and received appropriate antidiabetic medications. The study was approved by the Clinical Research Ethics Committee of Guangdong Provincial People’s Hospital, and written informed consent was obtained from all study patients.
Follow-up protocol and postoperative chemotherapy strategy
After surgical resection, the patients were followed-up regularly at outpatient clinics, and follow-up results were obtained via telephone by an experienced researcher from the Department of Gastrointestinal Surgery. Tumor marker tests, chest and abdominal contrast-enhanced CT, colorectal endoscopy, and hepatic and renal function tests were conducted every 3-6 months during the first 2 years and every 6-12 years thereafter until the end of the study or patient loss to follow up. The patients indicated for postoperative chemotherapy started receiving capecitabine orally one month after surgery. The regimen consisted of twice-daily administration of 500 mg of capecitabine for 3 weeks, with 2 weeks of therapy followed by a 1-week rest period. All patients received six to eight courses of postoperative chemotherapy.
Definitions
The primary endpoints in this study were disease-free survival (DFS) and overall survival (OS). DFS was defined as survival from the date of initial surgical resection to the day of confirmed tumor recurrence or metastasis. OS was defined as survival from the date of initial resection to the date of patient death or last follow-up. Chemoresistance was defined as tumor recurrence or metastasis within 1 year of surgery[32,33]. Non-malignant severe illness was defined as an American Society of Anesthesiologists classification > III or a New York Heart Association classification > II. Severe postoperative complications were defined as Clavien-Dindo classification > II. Tumors originating from the splenic flexure, descending colon, or sigmoid colon were defined as left-sided CC (LCC) while right-sided CC (RCC) was defined as tumors originating from the cecum, ascending colon, or hepatic flexure.
The T2DM diagnoses were based on one of the diagnostic criteria by the Chinese Medical Society[34,35]: (1) FPG level ≥ 7 mmol/L (126 mg/dL); (2) Glycated albumin/HbA1c content ≥ 7%; and (3) 2 hour-postprandial plasma glucose or random plasma glucose level ≥ 11.1 mmol/L (199.8 mg/dL). Well-controlled T2DM was determined based on the Chinese Medical Society diagnostic criteria[34,35] and included: (1) FPG level < 7 mmol/L (126 mg/dL); (2) Glycated albumin/HbA1c content < 7%; and (3) 2 hour-postprandial plasma glucose or random plasma glucose level < 10.0 mmol/L (180 mg/dL).
Selection of covariates
Variables that may influence postoperative chemoresistance and prognosis and could be accessed from the hospital medical system as well as patient follow-up data were identified as covariates; these included demographic characteristics (age and sex), lifestyle factors [body mass index (BMI) and history of smoking and drinking], chronic disease except T2DM (hypertension and cardiovascular disease), glycemic traits (FPG and HbA1c levels), levels of tumor markers [carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA)], and TNM stage and oncological characteristics (location, size, vascular invasion, perineural invasion, and differentiation).
Statistical analysis
Continuous variables are presented as means ± SDs and categorical variables as numbers or percentages. Continuous variables were compared using the Student’s t-test or the Mann-Whitney nonparametric U-test. Categorical variables were assessed using the χ2 test. Cumulative recurrence and OS rates were calculated using the Kaplan-Meier method and compared using the log-rank test. The Cox proportional hazards model was used for univariate and multivariate analyses of chemoresistance and prognostic factors after surgery. For continuous variables, the upper limits of the normal values for CA19-9 (≥ 37/< 37 ng/mL), CEA (≥ 5/< 5 μg/mL), FPG (≥ 7/< 7 mmol/L), and HbA1c (≥ 7/< 7%), and the median for age (≥ 60/< 60 years) and tumor size (≥ 4.5/< 4.5 cm) were considered as cut-off values. Significant variables in the univariate analysis were included in the multivariate analysis. The statistical analyses were performed using IBM SPSS (Statistical Product and Service Solutions) Statistics version 26.0; two-sided P-values < 0.05 were considered to indicate statistical significance. The GraphPad Prism 8 software was used to generate survival curves.
RESULTS
Clinicopathological characteristics of the patients
Of the 1932 patients, 278 fulfilled the inclusion criteria for this study. All patients were diagnosed with stage III CC and received postoperative chemotherapy. All tumors were microsatellite-stable. Median age was 59.65 years (range: 40-75 years), and there were 159 men and 119 women. The median follow-up duration was 32.69 months (range: 6.50-64.90 months). The 1-, 3-, and 5-year DFS and OS rates were 89.57% and 76.98%, 76.90% and 99.82%, 83.45% and 82.37%, respectively.
Among the patients diagnosed with T2DM before admission, the most commonly administered antidiabetic medication was metformin, either as monotherapy or in combination with other agents (n = 77). Patients diagnosed with T2DM after hospitalization received insulin based on their plasma glucose levels. All patients were followed-up regularly in the endocrinology department after surgery and received antidiabetic medications.
Association between preoperative history of T2DM with postoperative DFS and OS rates
Based on whether they had been diagnosed with T2DM before or after admission, 160 patients (57.55%) were allocated to the non-DM group and 118 (32.45%) to the DM group. All patients in the DM group were diagnosed with T2DM. The characteristics of the two groups are summarized in Table 1. The patients in the DM group had higher HbA1c (P < 0.001) and FPG levels (P < 0.001) than those in the non-DM group. The age difference between the groups was also significant (P < 0.001), while no significant differences were observed regarding sex, BMI, lifestyle factors, presence of chronic disease, tumor markers, TNM stage, or pathological characteristics (all P > 0.05).
Table 1 Comparison of the clinical and pathological characteristics between the non-diabetes mellitus and diabetes mellitus groups.
The median follow-up duration was 33.28 months (range: 9.03-64.83 months) and 31.89 months (range: 6.50-64.90 months) in the non-DM and DM groups, respectively. The 1-, 3-, and 5-year recurrence-free survival rates were 92.50%, 79.37%, and 78.75%, and 85.59%, 73.73%, and 72.03% in the non-DM and DM groups, respectively. The 1-, 3-, and 5-year OS rates were 98.12%, 83.75%, and 83.12%, and 98.31%, 83.05%, and 81.36% in the non-DM and DM groups, respectively. No significant differences in DFS [hazard ratio (HR) = 1.388, 95% confidence interval (CI): 0.853-2.258, P = 0.178; Figure 2A] or OS (HR = 1.144, 95%CI: 0.648-2.020, P = 0.638; Figure 2B) rates were observed between the non-DM and DM groups.
Figure 2 Comparisons of the prognostic outcomes of patients in the non-diabetes mellitus, diabetes mellitus, well-controlled and poorly controlled groups.
A: Comparison of disease-free survival rates between the non-diabetes mellitus (DM) and DM groups (P = 0.178); B: Comparison of overall survival rates between the non-DM and DM groups (P = 0.638); C: Comparison of disease-free survival rates between the well-controlled and poorly controlled groups (P = 0.021); D: Comparison of overall survival rates between the well-controlled and poorly controlled groups (P = 0.011). DFS: Disease-free survival; OS: Overall survival.
Association between preoperative plasma glucose or HbA1c level and DFS and OS rates
Based on the status of T2DM control, the 118 patients in the DM group were further allocated to well-controlled (n = 73) and poorly controlled groups (n = 45; preoperative FPG level ≥ 7 mmol/L or HbA1c content ≥ 7%). The characteristics of the two groups are summarized in Table 2. The patients in the poorly controlled group exhibited significantly higher HbA1c (P < 0.001) and FPG levels (P = 0.001) than the patients in the well-controlled group. No significant differences were observed in terms of sex, BMI, lifestyle factors, presence of chronic disease, tumor markers, TNM stage, or pathological characteristics (all P > 0.05).
Table 2 Comparison of the clinical and pathological characteristics between the well-controlled and poorly controlled groups.
The median follow-up duration was 33.54 months (range: 6.72-64.90 months) and 29.22 months (range: 6.50-61.79 months) in the well-controlled and poorly controlled groups, respectively. The 1-, 3-, and 5-year DFS rates were 91.78%, 78.67%, and 78.67%, and 75.56%, 66.67% and 62.22% in the well-controlled and poorly controlled groups, respectively. The corresponding 1-, 3-, and 5-year OS rates were 98.63%, 89.33%, and 87.67%, and 97.78%, 73.33%, and 71.11%. Significant differences in the DFS (HR = 2.189, 95%CI: 1.508-4.530, P = 0.011; Figure 2C) and OS (HR = 2.856, 95%CI: 1.179-6.918, P = 0.011; Figure 2D) rates were observed between the well-controlled and poorly controlled groups.
Association between poorly controlled T2DM and postoperative chemoresistance rate in patients with stage III CC
We examined the chemoresistance rate (CRR) in the non-DM, DM, well-controlled, and poorly controlled groups. The CRRs were 7.50%, 14.41%, 8.22%, and 24.40% for the four groups, respectively. The poorly controlled group demonstrated the highest CRR compared to the non-DM (24.40% vs 7.50%, P = 0.001) and well-controlled groups (24.40% vs 8.22%, P = 0.015), whereas the latter two groups demonstrated similar CRRs (7.5% vs 8.22%, P = 0.849; Table 3).
Table 3 Comparison of disease-free survival, overall survival and chemoresistance rate in the non-diabetes mellitus, diabetes mellitus, well-controlled and poorly controlled groups, n (%).
All variables from the data of the 278 patients included in the present study were subjected to univariate Cox regression analysis. Risk factors with P < 0.05 were further subjected to multivariate analysis. Notably, multivariate analyses revealed that high preoperative FPG and HbA1c levels were independently associated with worse DFS (FPG, P < 0.001; HbA1c, P = 0.006) and OS (FPG, P = 0.019; HbA1c, P = 0.021), whereas a preoperative history of T2DM was not independently associated with poor postoperative prognosis (DFS, P = 0.327; OS, P = 0.739; Table 4).
Table 4 Univariate and multivariate cox regression analysis for disease-free survival and overall survival.
Other well-recognized risk factors, including CEA level ≥ 5 μg/mL (DFS, P = 0.014; OS, P = 0.06), CA19-9 level ≥ 37 ng/mL (DFS, P = 0.021; OS, P = 0.041), T4 (DFS, P = 0.044; OS, P = 0.029), N2 (DFS, P = 0.007; OS, P = 0.033), RCC (DFS, P = 0.038; OS, P = 0.040), tumor size > 4.5 cm (DFS, P = 0.023; OS, P = 0.024), poor tumor differentiation (DFS, P = 0.0013; OS, P = 0.018), presence of vascular invasion (DFS, P = 0.008; OS, P = 0.041), and presence of perineural invasion (DFS, P = 0.039; OS, P = 0.036) were also independently associated with poor DFS and OS rates (Table 4).
Univariate and multivariate Cox regression analyses revealed that high preoperative FPG and HbA1c levels were independently associated with higher CRR (FPG, P = 0.005; HbA1c, P = 0.009), whereas a preoperative history of T2DM was not an independent risk factor associated with CRR (P = 0.581; Table 5). N2 (P = 0.041), poor tumor differentiation (P = 0.028), and presence of vascular invasion (P = 0.009) were also independently associated with a higher CRR (Table 5).
Table 5 Univariate and multivariate cox regression analysis for chemoresistance rate.
Variables
Univariate analysis
Multivariate analysis
HR (95%CI)
P value
HR (95%CI)
P value
Age (≥ 60/< 60), years
0.872 (0.663-1.025)
0.843
Gender (male/female)
1.004 (0.593-1.118)
0.703
BMI > 24 kg/m2 (present/absent)
1.931 (1.658-2.405)
0.007
History of DM (present/absent)
0.997 (0.556-1.200)
0.581
History of smoke (present/absent)
1.074 (0.665-1.209)
0.648
History of drinking(present/absent)
0.837 (0.425-1.102)
0.431
Hypertension (present/absent)
0.915 (0.503-1.220)
0.549
Cardiovascular disease (present/absent)
1.025 (0.694-1.280)
0.331
CEA (≥ 5/< 5), μg/mL
1.231 (0.994-1.398)
0.223
CA19-9 (≥ 37/< 37), ng/mL
1.096 (0.603-1.222)
0.387
T stage (4/3)
1.331 (0.967-1.438)
0.198
N stage (2/1)
1.669 (1.408-2.015)
0.019
1.594 (1.335-1.891)
0.041
Tumor location (RCC/LCC)
1.330 (0.894-1.505)
0.097
Tumor size (≥ 4.5/< 4.5), cm
1.205 (0.983-1.483)
0.105
Tumor differentiation (PD/MD)
1.606 (1.493-1.994)
0.013
1.499 (1.308-1.837)
0.028
Vascular invasion (present/absent)
1.999 (1.784-2.391)
< 0.001
1.803 (1.647-2.089)
0.009
Perineural invasion (present/absent)
1.347 (1.033-1.688)
0.124
FPG (≥ 7/< 7), mmol/L
2.558 (2.147-3.669)
< 0.001
2.214 (1.980-3.014)
0.005
HbA1c (≥ 7/< 7), %
2.867 (2.504-3.771)
< 0.001
2.449 (2.101-3.338)
0.009
Subgroup analysis of the effect of initiation time of antidiabetic medications on RFS, OS, and CRR
The 118 patients in the DM group were further assigned to three groups based on the time of initiation of antidiabetic agents and preoperative status of T2DM control. A total of 92 patients were diagnosed with T2DM and received antidiabetic medications before admission for CC, of whom 73 presented with perioperative well-controlled T2DM (group 1) and 19 with poorly controlled T2DM (group 2). The remaining patients in the DM group were diagnosed with T2DM and received antidiabetic medications after admission for CC; moreover, they exhibited poorly controlled T2DM (group 3, n = 26).
The characteristics of the three groups are summarized in Supplementary Table 1. Groups 2 and 3 were associated with significantly higher preoperative FPG (group 1 vs 2, P < 0.001; group 1 vs 3, P = 0.001) and HbA1c (group 1 vs 2, P < 0.001; group 1 vs 3, P = 0.001) levels than group 1. Preoperative FPG and HbA1c levels were similar between groups 2 and 3. There were no significant differences in other variables between the three groups (all P > 0.05).
The 1-, 3-, and 5-year DFS rates in groups 1, 2, and 3 were 91.78%, 78.67%, and 78.67%; 73.68%, 63.16%, and 57.89%; and 76.92%, 69.23%, and 65.38%, respectively. The corresponding 1-, 3-, and 5-year OS rates were 98.63%, 89.33%, and 87.67%; 100%, 68.42%, and 68.42%; and 96.15%, 76.92%, and 73.08%. Compared to groups 2 and 3, group 1 showed significant better DFS (group 1 vs 2, HR = 2.225, 95%CI: 1.673-6.255, P = 0.024; group 1 vs 3, HR = 2.242, 95%CI: 1.843-5.966, P = 0.045; Supplementary Figure 1A) and OS (group 1 vs 2, HR = 2.875, 95%CI: 1.788-7.049, P = 0.036; group 1 vs 3, HR = 2.956, 95%CI: 1.885-6.870, P = 0.023; Supplementary Figure 1B). No significant differences were observed in DFS (HR = 0.992, 95%CI: 0.383-2.572, P = 0.987) or OS (HR = 0.972, 95%CI: 0.326-2.896, P = 0.959) between groups 2 and 3. The CRRs were 8.22% (6), 26.32% (5), and 23.08% (6) in groups 1, 2, and 3. Group 1 demonstrated the lowest CRR compared to groups 2 and 3 (8.22% vs 26.32%, P = 0.030; 8.22% vs 23.08%, P = 0.046), whereas the CRRs were similar for the latter two groups (26.32% vs 23.08%, P = 0.803).
DISCUSSION
In the present study, we found that elevated preoperative FPG and HbA1c levels rather than a history of T2DM were closely associated with a high CRR and poor postoperative prognosis in patients who underwent curative surgery for stage III CC and initiated capecitabin after surgery. These observations indicate that poorly controlled T2DM is a risk factor associated with worse postoperative outcomes. Previous studies have suggested that hyperglycemia is closely related to the occurrence and progression of CC[36,37], and our findings not only substantiate the conclusions of these studies but also confirm that poorly controlled T2DM is an independent risk factor associated with postoperative chemoresistance. It is generally accepted that reprogrammed metabolism is a hallmark of cancer and that T2DM is an endocrine disease characterized by metabolic dysfunction. Hence, our findings also underscore the significance of focusing on glucose metabolism in CC, which may help identify therapeutic targets for addressing chemoresistance.
T2DM has been consistently associated with a higher risk of developing CC in clinical cohort studies[28,29]. The main features of T2DM are hyperglycemia and dysfunction in glucose metabolism; moreover, the glycolytic rate of tumor cells is up to 200 times higher than that of normal cells[38]. The high plasma glucose levels in patients with DM provide sufficient energy for the growth of CC cells, which may enhance the progression, recurrence, metastasis, and even chemoresistance in patients with CC with T2DM. Recent in vivo experimental studies have suggested that the activity of hexokinase and pyruvate kinase in colonic tissues increases in diabetic rats[39]. These two key enzymes are reported to contribute to the synthesis of nucleic acids, amino acids, and phospholipids, which imparts a growth advantage to tumor cells[40]. Patients with T2DM, especially those in the early stage (without complications such as retinopathy, diabetic nephropathy, diabetic foot disease, cerebrovascular disease, or recurrent hypoglycemia), always feature a higher serum insulin level. Studies have demonstrated that insulin, by binding to the insulin-like growth factor receptor-1, further activates downstream signaling pathways, which in turn lead to cellular proliferation and protein synthesis in tumor cells[41,42]. Chemoresistance in CC is characterized by complex etiologies that are not yet completely understood, necessitating further experimental studies to explore the underlying mechanisms.
The relationship between T2DM and CC has long been debated. A study from Taiwan also indicated that blood sugar levels but not a DM history can enhance oxaliplatin chemoresistance, which is consistent with our results[32]. However, both patients with CC and rectal cancer were included in their study. Although CC and rectal cancer are classified as CRC, emerging evidence supports their distinction due to variations in anatomy, embryological origins, and metastatic patterns, resulting in differences in treatment, prognosis, and chemotherapy responses[43,44]. Only patients with stage III CC were included in the present study to avoid potential bias affecting the final conclusions. In addition, FPG levels reflect daily blood glucose levels, whereas HbA1c values reflect mean endogenous exposure to glucose over the preceding 2-3 months, including postprandial spikes, and show low intra-individual variability, particularly in individuals without diabetes[45,46]. Compared with previous studies, we comprehensively analyzed the effects of FPG and HbA1c content on postoperative prognosis and chemoresistance, which enhanced the reliability of our conclusions.
The effects of other chronic diseases, including hypertension and cardiovascular disease, on postoperative outcomes were also evaluated in our study, but no close association was observed. Similar with T2DM, they are all characterized by metabolic dysfunction, while hypertension and cardiovascular disease are more closely related to lipid metabolism and may influence postoperative chemoresistance[47] as well as long-term prognosis. Only approximately one third (33.09%) and one fifth (21.22%) of the patients were diagnosed with these diseases, respectively; due to the limited sample size and lack of sensitive indicators to evaluate lipid metabolism status in the present study, future studies are needed to further explore this issue.
Lifestyle factors such as BMI, smoking, and alcohol abuse are established risk factors of gastrointestinal carcinogenesis[48], and obesity as well as smoking are related to chemoresistance[49,50]. Obesity is defined as BMI > 28 kg/m2 in clinical practice; of the 87 patients with overweight (BMI > 24 kg/m2) in our study, only 17 (6.1%) were with obesity (BMI > 28 kg/m2). Similarly, patients seldom meet the criteria for alcohol abuse and patients who are preparing for surgery quit smoking during the perioperative period and after discharge. Hence, evaluation of the exact impact of these lifestyle behaviors on postoperative outcomes was challenging in the present study. Studies with elaborate designs are required to address these problems.
LCC and RCC are distinct CC subtypes that vary in cell origins, vasculature, as well as physiological function[51], and RCC is associated with poor differentiation, increased tumor size and lympho-vascular invasion, advanced tumor stage, and worse survival outcomes than LCC[52]. These results were partially confirmed in our study, as RCC was closely related to disappointing postoperative DFS and OS, while tumor location appeared to have a limited effect on postoperative chemoresistance. Microsatellite instability and stability also describe different CC subtypes and may influence the efficacy of chemoresistance. All tumors in this study were microsatellite-stable; therefore, more studies are demanded to analyze the effects of tumor subtypes on chemotherapy responses.
T2DM is a chronic disease that requires lifelong treatment. We found that administration of antidiabetic agents before or after hospitalization was not associated with significant differences in DFS, OS, or CRR. Our subgroup analysis suggests that the perioperative hyperglycemic status is related to worse postoperative outcomes and chemoresistance rather than the time of initiation of antidiabetic medication. The long-term prognosis of CC survivors may benefit from better control of FPG and HbA1c levels after surgery, and future studies should focus on the influence of pharmacological or lifestyle interventions on postoperative outcomes in these patients.
Some limitations of our study should be noted. First, it was a single-institution cohort study. Second, a large proportion of patients (83.70%) in the DM group received metformin before admission, while medication switching or a combination approach was applied at other instances, depending on the status of glycemic control after hospitalization. We did not investigate the influence of the use of different antidiabetic medications on postoperative chemoresistance owing to the limited sample size, which made effective statistical analysis challenging. Third, similar to the situation with the various types of antidiabetic agents, we did not analyze the effect of postoperative treatment duration of DM on survival outcomes. Fourth, other medications for hypertension and cardiovascular disease, such as nifedipine and atorvastatin, as well as detailed lifestyle factors, including diet and physical activity, may also influence postoperative outcomes. These factors were not considered in the present study due to difficulties in data acquisition.
CONCLUSION
In summary, our study suggests that in patients with T2DM who underwent surgical resection for stage III CC, poorly controlled preoperative hyperglycemia but not a history of T2DM significantly enhanced postoperative chemoresistance and was related to poor long-term prognosis. Additional large-scale prospective studies are necessary to verify our conclusions. Future studies should focus on the underlying mechanism linking hyperglycemia to postoperative chemoresistance in patients with CC.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Gastroenterology and hepatology
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade A, Grade C, Grade C, Grade D
Novelty: Grade B, Grade B, Grade B, Grade C
Creativity or Innovation: Grade B, Grade B, Grade B, Grade B
Scientific Significance: Grade A, Grade B, Grade B, Grade C
P-Reviewer: Jung MJ; Khazem FR; Raonic J S-Editor: Wang JJ L-Editor: A P-Editor: Wang WB
Grothey A, Sobrero AF, Shields AF, Yoshino T, Paul J, Taieb J, Souglakos J, Shi Q, Kerr R, Labianca R, Meyerhardt JA, Vernerey D, Yamanaka T, Boukovinas I, Meyers JP, Renfro LA, Niedzwiecki D, Watanabe T, Torri V, Saunders M, Sargent DJ, Andre T, Iveson T. Duration of Adjuvant Chemotherapy for Stage III Colon Cancer.N Engl J Med. 2018;378:1177-1188.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 639][Cited by in F6Publishing: 628][Article Influence: 104.7][Reference Citation Analysis (0)]
Schmoll HJ, Tabernero J, Maroun J, de Braud F, Price T, Van Cutsem E, Hill M, Hoersch S, Rittweger K, Haller DG. Capecitabine Plus Oxaliplatin Compared With Fluorouracil/Folinic Acid As Adjuvant Therapy for Stage III Colon Cancer: Final Results of the NO16968 Randomized Controlled Phase III Trial.J Clin Oncol. 2015;33:3733-3740.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 162][Cited by in F6Publishing: 185][Article Influence: 20.6][Reference Citation Analysis (0)]
Gallois C, Shi Q, Meyers JP, Iveson T, Alberts SR, de Gramont A, Sobrero AF, Haller DG, Oki E, Shields AF, Goldberg RM, Kerr R, Lonardi S, Yothers G, Kelly C, Boukovinas I, Labianca R, Sinicrope FA, Souglakos I, Yoshino T, Meyerhardt JA, André T, Papamichael D, Taieb J. Prognostic Impact of Early Treatment and Oxaliplatin Discontinuation in Patients With Stage III Colon Cancer: An ACCENT/IDEA Pooled Analysis of 11 Adjuvant Trials.J Clin Oncol. 2023;41:803-815.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 6][Cited by in F6Publishing: 14][Article Influence: 14.0][Reference Citation Analysis (0)]
Cervantes A, Adam R, Roselló S, Arnold D, Normanno N, Taïeb J, Seligmann J, De Baere T, Osterlund P, Yoshino T, Martinelli E; ESMO Guidelines Committee. Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up.Ann Oncol. 2023;34:10-32.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 186][Cited by in F6Publishing: 541][Article Influence: 541.0][Reference Citation Analysis (0)]
Yoshino T, Argilés G, Oki E, Martinelli E, Taniguchi H, Arnold D, Mishima S, Li Y, Smruti BK, Ahn JB, Faud I, Chee CE, Yeh KH, Lin PC, Chua C, Hasbullah HH, Lee MA, Sharma A, Sun Y, Curigliano G, Bando H, Lordick F, Yamanaka T, Tabernero J, Baba E, Cervantes A, Ohtsu A, Peters S, Ishioka C, Pentheroudakis G. Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis treatment and follow-up of patients with localised colon cancer.Ann Oncol. 2021;32:1496-1510.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 34][Cited by in F6Publishing: 37][Article Influence: 12.3][Reference Citation Analysis (0)]
Luo HY, Li YH, Wang W, Wang ZQ, Yuan X, Ma D, Wang FH, Zhang DS, Lin DR, Lin YC, Jia J, Hu XH, Peng JW, Xu RH. Single-agent capecitabine as maintenance therapy after induction of XELOX (or FOLFOX) in first-line treatment of metastatic colorectal cancer: randomized clinical trial of efficacy and safety.Ann Oncol. 2016;27:1074-1081.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 64][Cited by in F6Publishing: 61][Article Influence: 7.6][Reference Citation Analysis (0)]
Murphy N, Song M, Papadimitriou N, Carreras-Torres R, Langenberg C, Martin RM, Tsilidis KK, Barroso I, Chen J, Frayling TM, Bull CJ, Vincent EE, Cotterchio M, Gruber SB, Pai RK, Newcomb PA, Perez-Cornago A, van Duijnhoven FJB, Van Guelpen B, Vodicka P, Wolk A, Wu AH, Peters U, Chan AT, Gunter MJ. Associations Between Glycemic Traits and Colorectal Cancer: A Mendelian Randomization Analysis.J Natl Cancer Inst. 2022;114:740-752.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 35][Cited by in F6Publishing: 45][Article Influence: 22.5][Reference Citation Analysis (0)]
Goncalves MD, Lu C, Tutnauer J, Hartman TE, Hwang SK, Murphy CJ, Pauli C, Morris R, Taylor S, Bosch K, Yang S, Wang Y, Van Riper J, Lekaye HC, Roper J, Kim Y, Chen Q, Gross SS, Rhee KY, Cantley LC, Yun J. High-fructose corn syrup enhances intestinal tumor growth in mice.Science. 2019;363:1345-1349.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 161][Cited by in F6Publishing: 220][Article Influence: 44.0][Reference Citation Analysis (0)]
Xia P, Zhang H, Lu H, Xu K, Jiang X, Jiang Y, Gongye X, Chen Z, Liu J, Chen X, Ma W, Zhang Z, Yuan Y. METTL5 stabilizes c-Myc by facilitating USP5 translation to reprogram glucose metabolism and promote hepatocellular carcinoma progression.Cancer Commun (Lond). 2023;43:338-364.
[PubMed] [DOI][Cited in This Article: ][Cited by in F6Publishing: 42][Reference Citation Analysis (0)]
Cui Y, Liu H, Wang Z, Zhang H, Tian J, Wang Z, Song W, Guo H, Liu L, Tian R, Zuo X, Ren S, Zhang F, Niu R. Fructose promotes angiogenesis by improving vascular endothelial cell function and upregulating VEGF expression in cancer cells.J Exp Clin Cancer Res. 2023;42:184.
[PubMed] [DOI][Cited in This Article: ][Cited by in F6Publishing: 3][Reference Citation Analysis (0)]
Farrash WF, Aslam A, Almaimani R, Minshawi F, Almasmoum H, Alsaegh A, Iqbal MS, Tabassum A, Elzubier ME, El-Readi MZ, Mahbub AA, Idris S, Refaat B. Metformin and thymoquinone co-treatment enhance 5-fluorouracil cytotoxicity by suppressing the PI3K/mTOR/HIF1α pathway and increasing oxidative stress in colon cancer cells.Biofactors. 2023;49:831-848.
[PubMed] [DOI][Cited in This Article: ][Cited by in F6Publishing: 1][Reference Citation Analysis (0)]
Almaimani RA, Aslam A, Ahmad J, El-Readi MZ, El-Boshy ME, Abdelghany AH, Idris S, Alhadrami M, Althubiti M, Almasmoum HA, Ghaith MM, Elzubeir ME, Eid SY, Refaat B. In Vivo and In Vitro Enhanced Tumoricidal Effects of Metformin, Active Vitamin D(3), and 5-Fluorouracil Triple Therapy against Colon Cancer by Modulating the PI3K/Akt/PTEN/mTOR Network.Cancers (Basel). 2022;14:1538.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 16][Cited by in F6Publishing: 14][Article Influence: 7.0][Reference Citation Analysis (0)]
Yang IP, Miao ZF, Huang CW, Tsai HL, Yeh YS, Su WC, Chang TK, Chang SF, Wang JY. High blood sugar levels but not diabetes mellitus significantly enhance oxaliplatin chemoresistance in patients with stage III colorectal cancer receiving adjuvant FOLFOX6 chemotherapy.Ther Adv Med Oncol. 2019;11:1758835919866964.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 17][Cited by in F6Publishing: 18][Article Influence: 3.6][Reference Citation Analysis (0)]
Schmoll HJ, Twelves C, Sun W, O'Connell MJ, Cartwright T, McKenna E, Saif M, Lee S, Yothers G, Haller D. Effect of adjuvant capecitabine or fluorouracil, with or without oxaliplatin, on survival outcomes in stage III colon cancer and the effect of oxaliplatin on post-relapse survival: a pooled analysis of individual patient data from four randomised controlled trials.Lancet Oncol. 2014;15:1481-1492.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 113][Cited by in F6Publishing: 121][Article Influence: 12.1][Reference Citation Analysis (0)]
Chinese Elderly Type 2 Diabetes Prevention and Treatment of Clinical Guidelines Writing Group; Geriatric Endocrinology and Metabolism Branch of Chinese Geriatric Society; Geriatric Endocrinology and Metabolism Branch of Chinese Geriatric Health Care Society; Geriatric Professional Committee of Beijing Medical Award Foundation; National Clinical Medical Research Center for Geriatric Diseases (PLA General Hospital). [Clinical guidelines for prevention and treatment of type 2 diabetes mellitus in the elderly in China (2022 edition)].Zhonghua Nei Ke Za Zhi. 2022;61:12-50.
[PubMed] [DOI][Cited in This Article: ][Cited by in F6Publishing: 66][Reference Citation Analysis (0)]
Chen H, Zheng X, Zong X, Li Z, Li N, Hur J, Fritz CD, Chapman W Jr, Nickel KB, Tipping A, Colditz GA, Giovannucci EL, Olsen MA, Fields RC, Cao Y. Metabolic syndrome, metabolic comorbid conditions and risk of early-onset colorectal cancer.Gut. 2021;70:1147-1154.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 56][Cited by in F6Publishing: 117][Article Influence: 39.0][Reference Citation Analysis (0)]
Hwang S, Yang S, Park K, Kim B, Kim M, Shin S, Yoo A, Ahn J, Jang J, Yim YS, Seong RH, Jeong SM. Induction of Fatty Acid Oxidation Underlies DNA Damage-Induced Cell Death and Ameliorates Obesity-Driven Chemoresistance.Adv Sci (Weinh). 2024;11:e2304702.
[PubMed] [DOI][Cited in This Article: ][Reference Citation Analysis (0)]
Chen X, Zhang W, Liu R, Zhu Z, Gong M, Wang Q, Qian W, Wu Z, Ma Q, Wang Z. NNK from tobacco smoking enhances pancreatic cancer cell stemness and chemoresistance by creating a β2AR-Akt feedback loop that activates autophagy.Mol Oncol. 2022;16:2881-2895.
[PubMed] [DOI][Cited in This Article: ][Cited by in Crossref: 7][Cited by in F6Publishing: 11][Article Influence: 5.5][Reference Citation Analysis (0)]
Mao Y, Wang X, Xi L, Dong M, Song P, Miao J, Lu C, Sun S, Li Q, Yu C, Shen X. Prediction values of tertiary lymphoid structures in the prognosis of patients with left- and right-sided colon cancer: a multicenter propensity score-matched study.Int J Surg. 2023;109:2344-2358.
[PubMed] [DOI][Cited in This Article: ][Cited by in F6Publishing: 3][Reference Citation Analysis (0)]
