*Article* **Metabolic Effects of Gastrectomy and Duodenal Bypass in Early Gastric Cancer Patients with T2DM: A Prospective Single-Center Cohort Study**

**Young Ki Lee 1,†, Eun Kyung Lee 1,2,†, You Jin Lee 1,\*, Bang Wool Eom 3, Hong Man Yoon 2,3, Young-Il Kim 2,3, Soo Jeong Cho 3, Jong Yeul Lee 3, Chan Gyoo Kim 3, Sun-Young Kong 2,4, Min Kyong Yoo 5, Yul Hwangbo 1,6, Young-Woo Kim 3, Il Ju Choi 3,6, Hak Jin Kim 7, Mi Hyang Kwak <sup>7</sup> and Keun Won Ryu 3,\***

	- <sup>6</sup> Department of Cancer Control and Population Health, National Cancer Center Graduate School of Cancer Science and Policy, National Cancer Center, Goyang 10408, Korea
	- <sup>7</sup> Division of Cardiology, Department of Internal Medicine, National Cancer Center, Goyang 10408, Korea; drkhj@ncc.re.kr (H.J.K.); cardiokmh@ncc.re.kr (M.H.K.)
	- **\*** Correspondence: eulee@ncc.re.kr (Y.J.L.); docryu@ncc.re.kr (K.W.R.); Tel.: +82-31-920-1644 (Y.J.L.); +82-31-920-1628 (K.W.R.)
	- † Young Ki Lee and Eun Kyung Lee contributed equally to this work.

**Abstract:** We evaluated the metabolic effects of gastrectomies and endoscopic submucosal dissections (ESDs) in early gastric cancer (EGC) patients with type 2 diabetes mellitus (T2DM). Forty-one EGC patients with T2DM undergoing gastrectomy or ESD were prospectively evaluated. Metabolic parameters in the patients who underwent gastrectomy with and without a duodenal bypass (groups 1 and 2, *n* = 24 and *n* = 5, respectively) were compared with those in patients who underwent ESD (control, *n* = 12). After 1 year, the proportions of improved/equivocal/worsened glycemic control were 62.5%/29.2%/8.3% in group 1, 40.0%/60.0%/0.0% in group 2, and 16.7%/50.0%/33.3% in the controls, respectively (*p* = 0.046). The multivariable ordered logistic regression analysis results showed that both groups had better 1-year glycemic control. Groups 1 and 2 showed a significant reduction in postprandial glucose (−97.9 and <sup>−</sup>67.8 mg/dL), body mass index (−2.1 and <sup>−</sup>2.3 kg/m2), and glycosylated hemoglobin (group 1 only, −0.5% point) (all *p* < 0.05). Furthermore, improvements in group 1 were more prominent when preoperative leptin levels were high (*p* for interaction < 0.05). Metabolic improvements in both groups were also observed for insulin resistance, leptin, plasminogen activator inhibitor-1, and resistin. Gastrectomy improved glycemic control and various metabolic parameters in EGC patients with T2DM. Patients with high leptin levels may experience greater metabolic benefits from gastrectomy with duodenal bypass.

**Keywords:** gastrectomy; endoscopic submucosal dissection; early gastric cancer; type 2 diabetes mellitus; glycemic control; insulin resistance

#### **1. Introduction**

Gastric cancer is the most frequently diagnosed cancer in Korea and has the fifthhighest incidence among newly diagnosed cancer cases worldwide [1,2]. While the incidence of gastric cancer has steadily decreased, the number of gastric cancer survivors has

**Citation:** Lee, Y.K.; Lee, E.K.; Lee, Y.J.; Eom, B.W.; Yoon, H.M.; Kim, Y.-I.; Cho, S.J.; Lee, J.Y.; Kim, C.G.; Kong, S.-Y.; et al. Metabolic Effects of Gastrectomy and Duodenal Bypass in Early Gastric Cancer Patients with T2DM: A Prospective Single-Center Cohort Study. *J. Clin. Med.* **2021**, *10*, 4008. https://doi.org/10.3390/ jcm10174008

Academic Editor: Matthias Biebl

Received: 14 July 2021 Accepted: 30 August 2021 Published: 4 September 2021

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**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

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increased due to early diagnosis and improved treatment techniques [1–3]. In Korea, the 5-year survival rate of gastric cancer has dramatically improved from 43.9% in 1993–1995 to 76.5% in 2013–2017, and the number of gastric cancer survivors reached about 300,000 in 2017 [1].

Type 2 diabetes mellitus (T2DM) is one of the most common comorbidities that determine overall mortality, non-cancer mortality, and quality of life in cancer survivors [4–6]. The prevalence of T2DM has been increasing worldwide, and it reached 13.8% in 2018 in Korea [7,8]. Patients with T2DM are at a higher risk for gastric cancer development, and the incidence of T2DM increases after gastric cancer development [9,10]. Therefore, proper management of T2DM is an important issue in many gastric cancer patients.

Gastrectomy and endoscopic submucosal dissection (ESD) are two curative treatment modalities for early gastric cancer (EGC) that show comparable overall and disease-specific survival [11]. Interestingly, gastrectomy performed as bariatric surgery improves glycemic control in morbidly obese patients with T2DM [12–14]. Moreover, studies have reported improvement in T2DM in gastric cancer patients after gastrectomy [15–18]. This evidence suggests that gastrectomy may have additional benefits over ESD in improving glycemic control in EGC patients with T2DM. However, to date, no study has compared the effects of gastrectomy with those of ESD on glycemic control in gastric cancer patients with T2DM using laboratory results.

This study aimed to prospectively examine the metabolic effects of gastrectomy with or without the duodenal bypass and compare the findings with those for ESD in EGC patients with T2DM. We also aimed to explore preoperative conditions in which the metabolic advantage of gastrectomy over ESD increases to identify patients who would benefit the most from gastrectomy.

#### **2. Materials and Methods**

#### *2.1. Study Subjects and Protocols*

This nonrandomized, controlled, prospective cohort study initially recruited 62 eligible EGC patients with T2DM who were scheduled to undergo ESD or gastrectomy between April 2012 and December 2014 at the National Cancer Center in Korea (clinicaltrials.gov accesed on 14 July 2014, identifier: NCT01643811). The enrollment criteria were as follows: (1) histologically proven primary gastric adenocarcinoma; (2) in clinical stage Ia or Ib examined with endoscopy, endoscopic ultrasound, and computed tomography; (3) aged 20–80 years; (4) performance status of 0 or 1 on the Eastern Cooperative Oncology Group scale; (5) diagnosis of T2DM; (6) plan to undergo gastrectomy or ESD; and (7) provision of written informed consent. The exclusion criteria were as follows: (1) having a high risk regarding the operation, such as severe heart disease or respiratory disease; (2) being pregnant or planning for pregnancy; (3) having experienced previous abdominal surgery or radiation therapy; or (4) having a proven more advanced disease than pathological stage II requiring adjuvant chemotherapy.

All treatment options were chosen at the discretion of each surgeon. We categorized all patients into three groups according to the intervention: (1) gastrectomy with duodenal bypass group (total and subtotal gastrectomy with Roux-en-Y gastrojejunostomy, and subtotal gastrectomy with loop gastrojejunostomy), (2) gastrectomy without bypass group (subtotal gastrectomy with gastroduodenostomy), and (3) ESD group (the control). Each preoperative and follow-up (3 and 12 months after treatment) examination included measurements of the patient's height and body weight, along with blood tests (glycosylated hemoglobin (HbA1c), fasting blood glucose (FBG), 2-hour postprandial glucose (PP2), metabolic hormones, and adipokines). After the follow-up examination at 12 months, the patients were followed up regularly in a routine care setting. The protocol and data were approved by the institutional review board of the National Cancer Center (IRB No. NCCNCS-12-563) and all patients provided written informed consent.

#### *2.2. Identification and Management Protocols for T2DM*

Patients who had previously received antidiabetic drugs were classified as having diabetes. Among patients with no previous history of diabetes, DM was defined based on the result of preoperative evaluation according to the American Diabetes Association criteria: FBG ≥ 126 mg/dL, random glucose ≥ 200 mg/dL, or HbA1c ≥ 6.5% [19]. During a follow-up after 1 year, the diabetes medications were titrated by endocrinologists to achieve HbA1c < 7.0%.

#### *2.3. Metabolic Hormones and Adipokines Measurement*

Patient blood samples (fasting and postprandial) were stored in a −70 ◦C deep freezer and used for the measurement of metabolic hormones and adipokines using Bio-Plex Pro™ Diabetes Assay Panels (Luminex, Austin, TX, USA). Insulin, glucagon, ghrelin, gastric inhibitory polypeptide (GIP), glucagon-like peptide-1 (GLP-1), leptin, plasminogen activator inhibitor-1 (PAI-1), resistin, and visfatin levels were assessed. The homeostasis model of insulin resistance (HOMA-IR) was calculated using the following formula: fasting insulin (IU/mL) × FBG (mg/dL)/405.

#### *2.4. Glycemic Control Status Assessment*

Glycemic control status was assessed at the 1-year visit. Glycemic control status was considered to be "improved" if patients had lower HbA1c with medication with a dose equal to or lower than the baseline and "worsened" if patients had higher HbA1c with medication with a dose equal to or higher than the baseline. Other cases excluded from the "improved" and "worsened" categories were defined as "equivocal".

#### *2.5. Long-Term Outcomes*

The composite event was recorded until 3 February 2021, and it included the recurrence of gastric cancer, myocardial infarction, stroke, coronary revascularization, and all-cause death.

#### *2.6. Statistical Analysis*

Continuous values were presented as means with standard deviations or medians with interquartile ranges. Categorical values were presented as frequencies and percentages. Baseline characteristics, according to intervention groups, were compared via an analysis of variance followed by a Bonferroni post hoc test, a Kruskal–Wallis test followed by Dunn's post hoc test, or Fisher's exact test, according to the variable type.

The association between the types of the intervention and glycemic control status (the order of "improved", "equivocal", and "worsened") at the 1-year visit was assessed using the ordered logistic regression analysis. Demographic characteristics and baseline metabolic parameters were considered as potential confounders, and the final multivariable model was adjusted for statistically significant potential confounders through a stepwise selection method. The associations are presented as odds ratios (ORs) with 95% confidence intervals (CIs).

Each metabolic parameter (HbA1c, FBG, PP2, BMI, and HOMA-IR) and levels of metabolic hormones and adipokines during the 1-year follow-up period were compared between the groups of gastrectomy with duodenal bypass patients, gastrectomy without duodenal bypass patients, and ESD patients using the linear mixed model. HOMA-IR, metabolic hormones, and adipokines levels were log-transformed to improve the normality. The differences between groups were adjusted for age, sex, time from the baseline, and the baseline measurements of each assessed variable. The difference between the groups in logtransformed levels of metabolic hormones and adipokines was exponentially transformed and interpreted as a ratio of hormone levels between the groups on the basis of the following equation:

#### *difference between groups in log(measurements) = log(measurements in the gastrectomy group)* − *log(measurements in the ESD group) = log(measurements in the gastrectomy group/measurements in the ESD group) = log(a ratio of measurements between groups).*

Additionally, the changes in each measurement at the 3-month and 1-year visits, relative to the baseline levels, were assessed using a paired *t*-test, and *p*-values were adjusted using Dunnett's method for multiple comparisons between two visit points and the baseline.

For long-term outcomes, the Kaplan–Meier method was used to generate survival curves, while the log-rank test was performed to evaluate differences in composite eventfree survival according to the types of the interventions.

#### *2.7. Assessment of Effect Modification*

Whether the effects of gastrectomy on the 1-year glycemic control status (with ESD as the control) were altered by the baseline metabolic characteristics was explored using the interaction terms, which were defined as the product of the type of interventions and the levels of each parameter. The significance of the effect modification was tested by entering each interaction term into the multivariable ordered logistic regression model for the 1-year glycemic control status.

Patient subgroups were classified based on the median values of the significant effect modifiers detected in the preceding test. Stratified analyses for changes in metabolic parameters were performed according to the subgroups using the linear mixed models. The significance of the heterogeneity according to the subgroups was tested by entering the product of the type of interventions and subgroups into the linear mixed models.

All statistical analyses were performed using SAS 9.4 (SAS Institute Inc., Cary, NC, USA). Analysis items with *p* < 0.05 were considered to be statistically significant.

#### **3. Results**

#### *3.1. Patient Baseline Characteristics*

A total of 62 EGC patients with T2DM were initially enrolled and underwent either gastrectomy or ESD (Figure 1). Among them, 21 patients were excluded due to withdrawal of agreement (*n* = 18), failure to follow-up (*n* = 2), and advancement of the disease beyond pathological stage II (*n* = 1). Finally, a total of 41 patients were included in the 1-year outcome analysis. The number of patients was 24, 5, and 12 in the gastrectomy with duodenal bypass, gastrectomy without duodenal bypass, and ESD groups, respectively. The gastrectomy with duodenal bypass group consisted of patients who underwent a total (*n* = 5) and subtotal (*n* = 9) gastrectomy with Roux-en-Y gastrojejunostomy and patients who underwent subtotal gastrectomy with loop gastrojejunostomy (*n* = 10).

The patient baseline characteristics are presented in Table 1. There were no significant differences in age, sex, duration of diabetes, HbA1c, FBG, PP2, and HOMA-IR between the groups. The mean BMI values were different between the groups (24.1, 21.9, and 26.1 kg/m<sup>2</sup> in gastrectomy with duodenal bypass, without bypass, and ESD groups, respectively, *p* = 0.022), and the gastrectomy without duodenal bypass group had a lower BMI than did the ESD group (adjusted *p* = 0.024). The levels of metabolic hormones and adipokines were similar between the groups, except for fasting and postprandial PAI-1 levels; the postprandial PAI-1 levels were lower in the gastrectomy without duodenal bypass group than in the ESD group (adjusted *p* = 0.015). Most patients (40 of 41) did not use insulin; the gastrectomy with duodenal bypass group included one patient who took insulin.

**Figure 1.** Flow chart of the study.


Data are presented as mean ± standard deviation, median (interquartile range), or frequency (%). Significant *p*-values (*p* < 0.05) are in boldface type. \* Significant difference from the ESD group in the post hoc analysis (adjusted *p* < 0.05). DM, diabetes mellitus; BMI, body mass index; HbA1c, hemoglobin A1c; HOMA-IR, homeostasis model assessment of insulin resistance; ESD, endoscopic submucosal dissection; GIP, gastric inhibitory polypeptide; GLP-1, glucagon-like peptide-1; PAI-1, plasminogen activator inhibitor-1.

#### *3.2. Glycemic Control Status at the 1-Year Visit*

After 1 year of follow-up, the glycemic control status was different according to the type of intervention (Supplementary Figure S1 online); the proportions of improved/ equivocal/worsened glycemic control were 62.5%/29.2%/8.3% in the gastrectomy with

duodenal bypass group, 40.0%/60.0%/0.0% in the gastrectomy without duodenal bypass group, and 16.7%/50.0%/33.3% in the ESD group, respectively (*p* = 0.046).

The independent effect of each type of surgery on the 1-year glycemic control status was assessed using ordered logistic regression analysis (Table 2). In the univariable analysis, gastrectomy with duodenal bypass was associated with a better glycemic control status than was an ESD (OR = 7.93, 95% CI = 1.81–34.70). In the final multivariable model, the effects of gastrectomy were adjusted for the baseline HOMA-IR, which was the only significant variable among potential confounders, including age, sex, DM duration, BMI, and HbA1c. In this final model, both gastrectomy with duodenal bypass (OR = 8.68, 95% CI = 1.81–41.63) and gastrectomy without duodenal bypass (OR = 10.60, 95% CI = 1.10–102.35) were associated with a better glycemic control status than was ESD. These estimates for ORs were similar in the full multivariable model that included all potential confounding variables.

**Table 2.** The effects of gastrectomy with or without duodenal bypass on the probability of better glycemic control at the 1-year visit.


The association between each baseline characteristic, including the type of the intervention and better glycemic control (the order of "improved", "equivocal", and "worsened") at the 1-year visit is presented as an OR and its CI estimated using ordered logistic regression analysis. <sup>1</sup> Variables included in the final multivariable model were selected through a stepwise selection method. This model, including only significant variables, was chosen as the final model for parsimoniousness. Significant values (*p* < 0.05) are in boldface type. OR, odds ratio; CI, confidence interval; ESD, endoscopic submucosal dissection; DM, diabetes mellitus; BMI, body mass index; HbA1c, hemoglobin A1c; HOMA-IR, homeostasis model assessment of insulin resistance.

#### *3.3. Changes in Metabolic Parameters after Gastrectomy*

To investigate the effect of surgery on the metabolic parameters (HbA1c, FBG, PP2, BMI, and HOMA-IR), we compared each measurement during the follow-up period between the groups (Table 3). Compared with the ESD group, the gastrectomy with duodenal bypass group showed significantly lower HbA1c (−0.5% point), PP2 (−97.9 mg/dL), BMI (−2.1 kg/m2), and log10-transformed HOMA-IR (−0.21) (all *<sup>p</sup>* < 0.05). The gastrectomy without duodenal bypass group showed similar patterns of metabolic improvements in PP2 (−67.8 mg/dL), BMI (−2.3 kg/m2), and log10-transformed HOMA-IR (−0.31) (all *p* < 0.05), but the improvement in HbA1c was not significant (−0.5% point, *p* = 0.184). The improvement in FBG was not significant in either of the gastrectomy groups, with or without duodenal bypass.

Metabolic parameters at the 3-month and 1-year visits were also compared with the baseline levels (Table 3 and Supplementary Figure S2 online). Compared with the preoperative levels, HbA1c, PP2, and BMI showed significant improvements in the gastrectomy with duodenal bypass group, while only BMI showed a significant improvement in the gastrectomy without duodenal bypass group. In contrast, the ESD group showed significant worsening in the FBG levels (+23.8 mg/dL at the 1-year visit, *p* = 0.024).



<sup>1</sup> During the 1-year follow-up period, each metabolic parameter in the gastrectomy with duodenal bypass group (group 1) and the gastrectomy without duodenal bypass group (group 2) was compared with each respective parameter in the control group using a linear mixed model. The estimates and *p*-values were adjusted for age, sex, time from the baseline, and the baseline measurements of each assessed variable. <sup>2</sup> Statistical significance of the change in each variable at each visit, relative to the baseline value, was assessed using a paired *t*-test. The *p*-values were adjusted using Dunnett's method for multiple comparisons between two visit points and the baseline. Significant values (*p* < 0.05) are in boldface type. SD, standard deviation; HbA1c, hemoglobin A1c; ESD, endoscopic submucosal dissection; Ref, reference value; BMI, body mass index; Log, log10-transformed; HOMA-IR, homeostasis model assessment of insulin resistance.

#### *3.4. Changes in Metabolic Hormones and Adipokines after Gastrectomy*

Metabolic hormone and adipokine levels in the gastrectomy groups during the followup period were compared with those in the ESD group (Figure 2 and Supplementary Table S1 online). The gastrectomy with duodenal bypass group showed a significant reduction in fasting leptin, postprandial leptin, and fasting PAI-1 levels (reduced to 61.1%, 67.5%, and 60.1% of those in the ESD group, respectively, all *p* < 0.05). The gastrectomy without duodenal bypass group showed a similar magnitude of reduction in fasting leptin, postprandial leptin, and fasting PAI-1 levels (reduced to 60.5%, 54.4%, and 53.3% of those in the ESD group, respectively), but the reduction in leptin levels was not statistically significant. Fasting resistin levels were reduced only in the gastrectomy without duodenal bypass group (reduced to 63.8% of those in the ESD group, *p* = 0.040). Ghrelin, GIP, GLP-1, glucagon, visfatin, postprandial PAI-1, and postprandial resistin levels after gastrectomy were not different from those in the ESD groups.

#### *3.5. Factors Influencing the Metabolic Effects of Gastrectomy with Duodenal Bypass*

We explored the influence of preoperative metabolic characteristics on the improvement of the 1-year glycemic control status in patients treated using gastrectomy with duodenal bypass (Supplementary Table S2 online). Due to a small number of cases, potential effect modifiers for gastrectomy without duodenal bypass were not explored. In this exploratory analysis, the beneficial effect of gastrectomy with duodenal bypass was more prominent in patients with higher preoperative fasting or postprandial leptin levels (*p* for interaction = 0.011 and 0.009, respectively) but was attenuated in those with higher preoperative fasting PAI-1 levels (*p* for interaction = 0.013). The effect of gastrectomy with duodenal bypass on the 1-year glycemic control status was not changed by the preoperative BMI, HbA1c, FBG, PP2, HOMA-IR, other metabolic hormones, or adipokines levels.

**Figure 2.** The ratios of metabolic hormone and adipokine levels after gastrectomy and after ESD (the reference). (**a**) Fasting leptin, (**b**) postprandial leptin, (**c**) fasting PAI-1, and (**d**) fasting resistin. The ratios and 95% confidence intervals were estimated using linear mixed models for log-transformed hormone levels, with adjustments for age, sex, time from the baseline, and the baseline measurements of each assessed variable. ESD, endoscopic submucosal dissection; PAI-1, plasminogen activator inhibitor-1.

Next, patient subgroups were classified according to the median values of the preoperative fasting leptin (2.1 ng/mL), postprandial leptin (1.8 ng/mL), and fasting PAI-1 (47.6 ng/mL) levels (Table 4). In the stratified analyses, those with high fasting leptin levels showed a greater decrease in PP2 (−127.1 vs. −72.3 mg/dL, *p* for interaction = 0.017) and BMI (−3.1 vs. −1.2 kg/m2, *<sup>p</sup>* for interaction = 0.018) than did those with lower fasting leptin levels, after gastrectomy with duodenal bypass. Similarly, patients with high postprandial leptin levels showed a greater decrease in PP2 (−133.5 vs. −72.4 mg/dL, *p* for interaction = 0.017) and BMI (−3.0 vs. −1.2 kg/m2, *<sup>p</sup>* for interaction = 0.010) than did those with lower postprandial leptin levels. However, the metabolic improvement after gastrectomy with duodenal bypass was not different, according to fasting PAI-1 levels.

#### *3.6. Long-Term Outcomes*

During the postoperative follow-up period (median, 5.7 years; interquartile range, 4.9–6.9), one case each of recurrence (ESD group), stroke (gastrectomy without duodenal bypass group), and coronary revascularization (ESD group), and three cases of death from other malignancies (gastrectomy with duodenal bypass group; one biliary cancer and two hematologic malignancies) were recorded (Supplementary Figure S3 online). There was no difference in the composite event-free survival rate between groups (*p* = 0.647).



duodenal bypass, age, sex, time from the baseline, and the baseline

duodenal bypass according to the subgroups was tested by entering the product of "gastrectomy values (*<sup>p</sup>* < 0.05 and *p* for interaction <0.05) are in boldface type. ESD, endoscopic submucosal dissection; PAI-1, plasminogen

mass index; Log,

log10-transformed;

 HOMA-IR, homeostasis

 model assessment of insulin resistance.

measurements

 of each assessed metabolic parameter. 1

 with duodenal bypass" and the subgroups into the linear mixed models. Significant

Significance of the differences in the effects of gastrectomy with

 activator inhibitor-1; HbA1c, hemoglobin A1c; BMI, body

#### **4. Discussion**

This single-center prospective controlled cohort study compared standard curative treatment modalities for EGC in patients with T2DM in terms of metabolic effects. EGC patients with T2DM who underwent gastrectomy, with or without duodenal bypass, showed improvement in glycemic control status more frequently than did those who underwent ESD at 1 year postoperatively. The metabolic improvement by gastrectomy was significant in terms of the PP2, HbA1c, and BMI, as well as some metabolic hormones and adipokines, such as leptin and PAI-1. In particular, the patients with higher preoperative leptin levels experienced a greater metabolic benefit from gastrectomy with duodenal bypass versus ESD than did those with lower leptin levels; in this subgroup, the probability for better 1-year glycemic control status was much higher and the degree of improvement in PP2 and BMI was more pronounced.

It is well established in meta-analyses of randomized controlled trials (RCTs) that gastrectomy, performed as bariatric surgery, is excellent at improving or alleviating serum glucose in obese T2DM patients compared to medical therapy [20,21]. In the meta-analysis by Pack et al., both Roux-en-Y gastric bypass and sleeve gastrectomy showed higher remission rates than did standard medical therapy at 1 to 2 years post operation (risk ratios for remission = 9.13 and 11.15, respectively), and this superiority was maintained until 5 years post operation [21]. Bariatric surgery reduced the microvascular and macrovascular diabetic complications and improved the related mortality [22–24]. Although most studies included patients with BMI > 35 kg/m2, meta-analyses of selected RCTs and nonrandomized studies showed that bariatric surgery was similarly effective in T2DM patients with BMI < 30~35 kg/m2 [25–27].

Gastrectomy to treat gastric cancer is technically similar to bariatric surgery; therefore, it was expected to have metabolic benefits in gastric cancer patients with T2DM. Several studies have discussed improvement in glycemic control and weight reduction after gastrectomy in gastric cancer patients [15–18,28,29]. However, no studies have compared gastrectomy to non-surgical treatment in gastric cancer patients, except for our previous epidemiological study [18]. This absence of an appropriate control group is an important limitation that can distort the estimate of the effect of gastrectomy in existing observational studies. Previously, we analyzed the Korean National Health Insurance System claims database and showed that, compared with endoscopic resection, total gastrectomy decreased the requirement for antidiabetic medications in gastric cancer patients [18]. However, due to the lack of biochemical data, the improvement of disease control could only be assessed with drug discontinuation [18]. In the current study, we regularly evaluated antidiabetic medications; biochemical data, including serum glucose and HbA1c levels; and anthropometric parameters. Consequently, we showed that the glycemic control status and BMI in EGC patients with T2DM who underwent gastrectomy were significantly improved relative to those in patients who underwent ESD.

In this study, patients who underwent gastrectomy with duodenal bypass had lower leptin and PAI-1 levels than did those who underwent ESD. The improvement in metabolic hormones and adipokines levels after gastrectomy has been demonstrated in studies on bariatric surgery, and Askarpour et al. reported in their recent meta-analysis that bariatric surgery reduced serum leptin, PAI-1, and chemerin levels [30]. A decrease in leptin levels after gastrectomy was also reported in gastric cancer patients, although the control group with non-surgical treatment was limited [15]. Leptin is a satiety hormone that is secreted mainly by the adipocytes [31]. It decreases body weight by suppressing appetite and promoting energy expenditure in physiologic conditions, but hyperleptinemia is observed in patients with obesity and T2DM due to leptin resistance [31,32]. Hyperleptinemia is associated with insulin resistance and micro- and macrovascular diabetic complications, and leptin-mediated hypertension was suggested as one of the mechanisms of developing cardiovascular diseases [32–34]. PAI-1 is an inflammatory adipokine that is associated with T2DM, diabetic nephropathy, and cardiovascular diseases [35,36]. Thus, reductions

in leptin and PAI-1 levels after gastrectomy in ECG patients with T2DM might predict or mediate a reduction in risk for diabetic complications.

Another notable finding in this study was that higher preoperative leptin levels played a predictive role for a greater metabolic benefit from gastrectomy with duodenal bypass versus ESD. Such a predictive role has not been widely investigated, but there are a few recent studies on this topic [15,37]. In an RCT that included 40 patients that compared the glycemic control effects of gastric cancer surgery according to surgery type, patients who experienced improvement or remission of diabetes at 12 months after surgery had higher preoperative leptin levels than those who did not [15]. In contrast, in a cohort study on 38 obese patients (mean BMI = 47.3 kg/m2) with diabetes who underwent bariatric surgery, those with higher than mean preoperative leptin levels (27.3 ng/mL) had higher glucose levels at 3 months post operation [37]. However, this leptin level was approximately 13 times higher than that measured in our study (2.1 ng/mL) due to differences in study populations (obesity vs. EGC) [37]. Since an improvement in hyperleptinemia is one of the remarkable effects of gastrectomy [30], the metabolic benefit from gastrectomy might be less prominent in those without hyperleptinemia. Our results suggest that choosing gastrectomy with duodenal bypass over ESD might be particularly advantageous in EGC patients with T2DM with high leptin levels.

This study had some limitations. The small sample size of this study led to underpowered results, and results on gastrectomy without duodenal bypass may not be reliable due to the small number of patients included. In addition, given the exploratory nature of the study, statistical adjustment for multiplicity was not conducted for multiple outcomes. Therefore, the possibility cannot be excluded that some of the statistically significant results in this study appeared by chance and, thus, they should be interpreted with caution based on the existing scientific knowledge. Because this was a nonrandomized observational study, the results may have been influenced by unmeasured confounders, although most of the measured potential confounders did not differ significantly between groups and were additionally controlled in multivariable analyses. The high dropout rate (33.9%) might serve as a source of bias via differential dropout, although the dropout rates were similar between groups, and the most common reason for dropout was the withdrawal of consent rather than medical problems or failure to follow-up. Furthermore, we could not confirm the difference in the long-term cardiovascular outcome, which could be dependent on diabetes control, due to the small number of events. Studies with a larger sample size are warranted to overcome these limitations and to validate our results.

In summary, our study suggests that gastrectomy has an advantage over ESD in terms of better diabetes management and weight reduction in EGC patients with T2DM and that this advantage can be more prominent in those with higher leptin levels. Metabolic benefits from gastrectomy should be considered in treatment decisions in these patients.

**Supplementary Materials:** The following are available online at https://www.mdpi.com/article/10 .3390/jcm10174008/s1: Supplementary Table S1. Changes in the metabolic hormone levels (log10 transformed); Supplementary Table S2. Changes in the effects of gastrectomy with duodenal bypass according to the candidate effect modifiers on the probability of better 1-year glycemic control at the 1-year visit; Supplementary Figure S1. Glycemic control status at the 1-year visit according to the type of intervention. ESD, endoscopic submucosal dissection; Supplementary Figure S2. Changes in the metabolic parameters from the baseline values; Supplementary Figure S3. Kaplan–Meier curves for composite events (recurrence of gastric cancer, myocardial infarction, stroke, coronary revascularization, and all-cause death) according to the type of intervention.

**Author Contributions:** Writing—original draft, formal analysis, Y.K.L.; conceptualization, methodology, formal analysis, E.K.L. and Y.J.L.; data curation, writing—review and editing, B.W.E., H.M.Y., Y.-I.K., S.J.C., J.Y.L., C.G.K., M.K.Y., Y.-W.K. and I.J.C.; writing—review and editing, S.-Y.K., Y.H., H.J.K. and M.H.K.; conceptualization, methodology, data curation, supervision, K.W.R. All authors read and agreed to the published version of the manuscript.

**Funding:** This work was supported by research grants NCC1210552-3 (PI: Keun Won Ryu), NCC1510 740-1 (PI: Mi Hyang Kwak), and NCC1410650-1 (PI: Eun Kyung Lee) from the National Cancer Center, Republic of Korea.

**Institutional Review Board Statement:** The study was conducted according to the guidelines of the Declaration of Helsinki, and the protocol and data were approved by the institutional review board of the National Cancer Center (IRB No. NCCNCS-12-563).

**Informed Consent Statement:** Informed consent was obtained from all subjects involved in the study.

**Data Availability Statement:** The datasets generated for this study are available on reasonable request to the corresponding author. The data are not publicly available due to privacy reasons.

**Conflicts of Interest:** The authors declare that there are no conflict of interest. The funding sources were not involved in study design, data collection, analysis, interpretation of data, or the decision to submit the paper for publication.

#### **References**


## *Article* **Prevalence and Clinical Implications of Ascites in Gastric Cancer Patients after Curative Surgery**

**Ju-Hee Lee 1,\*, Sung-Joon Kwon 1, Mimi Kim <sup>2</sup> and Bo-Kyeong Kang <sup>2</sup>**


**Abstract:** We aimed to determine the frequency and clinical significance of ascites that developed during the follow-up period in patients who underwent curative resection for gastric cancer. The study included 577 patients with gastric cancer who underwent curative gastrectomy. Among them, 184 showed ascites in postoperative follow-up images. Benign ascites was observed in 131 of 490 patients without recurrence, 48 patients (of 87) with recurrence had malignancy-related ascites, and the remaining 5 patients had ascites only prior to recurrence. In most patients without recurrence (97.7%) and in 50% of patients with malignancy-related ascites, the ascites was small in volume and located in the pelvic cavity at the time that it was first identified. However, with the exception of nine patients, malignancy-related pelvic ascites occurred simultaneously or after obvious recurrence. Of those nine patients who had minimal pelvic ascites before obvious recurrence, only one had a clear association with a malignancy-related ascites. In the multivariate analysis, an age of ≤45 was the only independent risk factor for the occurrence of benign ascites. A small volume of pelvic ascites fluid is common in young gastric cancer patients who do not have recurrence after gastrectomy, regardless of sex. It is rare for ascites to be the first manifestation of recurrence.

**Keywords:** gastric cancer; ascites; postoperative follow-up

#### **1. Introduction**

Gastric cancer is one of the leading causes of cancer-related deaths worldwide [1] and most gastric cancer-related deaths are due to recurrence [2]. The peritoneal region is the most common site of gastric cancer recurrence and is associated with a poor prognosis [3–5]. Diagnosis of peritoneal metastasis is typically determined by a computed tomography [CT] scan. Ascites is one of the most common findings suggestive of peritoneal carcinomatosis; others include peritoneal thickening, nodularity, and contrast enhancement in CT [6–9]. Although there is little convincing evidence that intense surveillance improves survival, routine follow-up after curative resection for the early detection of recurrence in gastric cancer is considered general practice, as some research findings indicate that asymptomatic patients had longer post-recurrence and overall survival than symptomatic patients [10–12]. Physicians often encounter ascites in abdominal imaging during the post-gastrectomy follow-up period and there are concerns that this finding may indicate early peritoneal recurrence, especially in men, despite a lack of evidence otherwise. Preoperatively detected ascites in CT strongly suggests the presence of peritoneal metastasis and free cancer cells in patients with advanced gastric cancer [13,14]. However, the clinical significance of ascites detected by postoperative CT or other abdominal imaging during the follow-up period is not well-studied. In this study, we evaluated the frequency and clinical implications of ascites in patients who underwent curative surgery for gastric cancer.

**Citation:** Lee, J.-H.; Kwon, S.-J.; Kim, M.; Kang, B.-K. Prevalence and Clinical Implications of Ascites in Gastric Cancer Patients after Curative Surgery. *J. Clin. Med.* **2021**, *10*, 3557. https://doi.org/10.3390/ jcm10163557

Academic Editor: Matthias Biebl

Received: 30 June 2021 Accepted: 11 August 2021 Published: 13 August 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

#### **2. Materials and Methods**

A total of 634 patients with gastric cancer who underwent curative gastrectomy at the Hanyang University Seoul Hospital between January 2008 and December 2015 were selected from a prospective gastric cancer database. Fifty-seven patients were excluded for the following reasons: (1) mortality after surgery (*n* = 3); (2) synchronous or metachronous cancers (*n* = 14); (3) recurrent ascites due to liver cirrhosis or chronic kidney disease (*n* = 3); (4) ascites due to ileus (*n* = 1); and (5) follow-up loss or a short follow-up time of <12 months due to unknown causes (in patients without recurrence) after surgery (*n* = 35). A postoperative follow-up was conducted every 3–6 months for up to 5 years and annually thereafter. Standard clinical practice included evaluation by physical examination, laboratory tests including the measurement of tumor markers, radiologic imaging, and endoscopy. Imaging was conducted alternatively by abdominopelvic and chest CT and abdominal sonography. Medical records of the remaining 577 patients were retrospectively reviewed. The median period of follow-up was 61.0 months (range of 4.0–146.0 months).

Ascites was primarily detected in CT imaging, having been initially identified by abdominal sonography in only one patient. Images were reviewed by at least two experienced radiologists and ascites was considered present when a low radiologic density of ≤10 Hounsfield units was found within the abdominal cavity outside the intra-abdominal or pelvic organs. Intraperitoneal fluid collection that occurred within 3 months after surgery was excluded to distinguish from postoperative changes in benign ascites. The volume of ascites fluid was estimated using ruler grids applied to CT images using the method described by Chang et al. [15]. A small degree of ascites was defined as a volume of <50 mL, moderate as 50–500 mL, and large as >500 mL (Figure 1).

**Figure 1.** *Cont*.

**Figure 1.** Typical ascites imaging in CT: (**A**) benign small pelvic ascites; (**B**) malignant small pelvic ascites with peritoneal thickening; (**C**) benign moderate ascites in perisplenic area (left abdomen); (**D**) malignant moderate ascites; and (**E**,**F**) alignant large ascites. Yellow stars indicate ascites.

Cases of benign ascites were those in which patients developed ascites without recurrence during the follow-up period. None of the patients had an interval of <12 months from identification of ascites to the follow-up conclusion, excluding eight patients whose follow-up period exceeded to 5 years without recurrence. If only ascites was present without symptoms or other findings suggesting intra-abdominal recurrence, the ascites was considered benign at that time and routine radiologic follow-up was performed according to the gastric cancer follow-up protocol of our hospital. Short-term radiologic tests including positron emission tomography and/or abdominopelvic CT were performed within 3 months in 40 patients with benign ascites for the following reasons: (1) an advanced-stage disease with newly detected ascites (*n* = 13); (2) a remaining or increased infiltration around the surgical site (*n* = 11); (3) combined intra-abdominal lymphadenopathy, ultimately confirmed as reactive lymph node enlargement by repeat tests (*n* = 7); (4) combined abnormal laboratory findings (*n* = 2) or levels of tumor markers (*n* = 1); (5) complaints of abdominal symptoms (*n* = 1); (6) the presence of portal vein thrombosis; (7) moderate volume of ascites fluid (*n* = 1); (8) an increased volume of ascites fluid compared to the findings immediately after surgery (*n* = 2); and (9) a liver cyst of increasing size (*n* = 1). The phrase "malignancy-related ascites" is used as a more appropriate descriptor than "malignant ascites" considering malignant cells were confirmed by ascites cytology in only some patients with recurrence. Intra-abdominal recurrence or peritoneal metastasis was diagnosed by serial changes in the CT and/or positron emission tomography performed when recurrence was suspected based on the CT. A histological examination of biopsy specimens or ascites cytology for patients with recurrence was performed whenever possible. Death due to disease progression was confirmed in all patients classified as having recurrence.

Statistical analyses were performed using SPSS version 22.0 (SPSS Inc., Chicago, IL, USA). Chi-squared tests and independent Student's *t*-tests were used for comparisons between groups. A binary logistic regression model was used for multivariate analysis. The threshold for statistical significance was set at *p* ≤ 0.05.

#### **3. Results**

Of the 577 eligible patients, ascites was identified in 184 patients during the follow-up period. Among them, 131 patients had benign ascites, accounting for 26.7% of the 490 patients without recurrence. Of the 131 patients with benign ascites, 78 were male (78/328; 23.8% of all males without recurrence) and 53 were female (53/162; 32.7% of all females without recurrence). Ascites was observed in 53 (60.7%) of the 87 patients with recurrence. Patients fell into three groups: (1) 40 patients with malignancy-related ascites at the same time as the findings of peritoneal seeding or intra-abdominal recurrence, including one patient who on initial recurrence had ascites only; (2) eight patients with ascites presumed to be benign before obvious recurrence and considered to have malignancy-related ascites after the obvious recurrence; and (3) five patients with ascites before recurrence but no evidence of malignancyrelated ascites upon recurrence. Groups (1) and (2) were classified as patients with malignancyrelated ascites. Among 48 patients with malignancy-related ascites, ascites appeared prior to recurrence in eight patients (16.7%, Group (2)), simultaneous with the recurrence detection in 25 (48.1%) and following recurrence in 15 (31.3%) (Figure 2).

**Figure 2.** Study population.: +, presence; −, absence.

Comparisons between patients with and without recurrence are shown in Table 1. The T and N stages, type of resection, mean albumin and hemoglobin level, and history of adjuvant chemotherapy were significantly different between patients with and without recurrence. The most common location of ascites at first appearance was the pelvic cavity both in patients with (29/53, 54.7%) and without (128/131, 97.7%) recurrence, followed by the whole abdominal region (16/53, 30.2%), perihepatic area (6/53, 11.3%), and paracolic gutter (2/53, 3.8%) in patients with recurrence. In the remaining patients without recurrence, ascites was located in the perihepatic area (2/131, 1.5%) and the left abdominal cavity (1/131, 0.8%). Ascites fluid was small in volume and located in the pelvic cavity in most patients without recurrence (128/131, 97.7%). In the majority of patients with malignancy-related ascites, the volume of ascites fluid at first detection was small (33/48, 68.8%). Among 131 patients with benign ascites, repeatability was observed in 79 (60.3%). With the exception of one case, there was no difference in the amount and location of ascites after the initial detection in patients with recurrent benign ascites. The one exceptional case had a moderate amount of benign ascites in the perisplenic area (Figure 1C) and a small volume of pelvic ascites fluid on later examination. Median time for the first appearance of ascites was 10.5 months post-surgery (range of 3.0–108.0) in all patients with ascites, 9.0 months (range of 3.0–108.0) in those with benign ascites, and 11.5 months (range of 3.0–71.0) in those with recurrence. There was a significant difference in the mean age of males and females at the detection of benign ascites (58.8 ± 11.5 vs. 51.6 ± 12.4, *p* = 0.001). Repeatability (45 (57.0%) vs. 34 (65.4%), *p* = 0.366) and the history of adjuvant chemotherapy (32 (41.8%) vs. 18 (34.6%), *p* = 0.466) were not significantly different between males and females with benign ascites.


#### **Table 1.** Clinicopathologic features.

"Ascites with recurrence" includes patients with malignancy-related ascites (*n* = 40), patients in whom ascites before recurrence were reclassified as malignancy-related ascites at a later stage (*n* = 8), and patients with benign ascites before recurrence but with no evidence of malignancy-related ascites after recurrence (*n* = 5). Abbreviations: SD, standard deviation. † In the case of ascites without recurrence.

> According to the presence or absence of ascites, sensitivity, specificity, accuracy, and positive and negative predictive values for intra-abdominal recurrence were 60.9%, 73.3%, 71.4%, 28.8%, and 91.3%, respectively. Positive and negative likelihood ratios were 2.28 and 0.53, respectively. Values for intra-abdominal recurrence were then calculated according to location of ascites (pelvic vs. other). Sensitivity, specificity, and positive and negative predictive values for the pelvic location were 54.7%, 2.3%, 18.5%, and 1.1%, respectively, and for other locations, 45.3%, 97.7%, 88.9%, and 81.5%, respectively. The positive and negative likelihood ratios for the pelvic location were 0.56 and 19.7, respectively, and 19.7 and 0.56 for other locations, respectively.

> Risk factors for the occurrence of benign ascites were evaluated in recurrence-free patients (Table 2). Univariate analyses showed that younger age (≤45), a pN2–3 stage, and a history of adjuvant chemotherapy were associated with the occurrence of benign ascites. Patient sex (*p* = 0.065) and pT stage (*p* = 0.054), significant at the 0.1 level, were included with these factors in a multivariate analysis to evaluate the risk for benign ascites. Younger

#### age (≤45) was the only independent risk factor associated with the occurrence of benign ascites post-surgery.


**Table 2.** Risk factors related to the occurrence of benign ascites in disease-free patients.

+, presence; −, absence. Abbreviation: CI, confidence interval.

Table 3 shows the characteristics of the nine patients with undefined ascites at the first discovery. This group includes eight patients with ascites presumed to be benign before definitive recurrence and one patient with eventual recurrence who developed ascites without other evidence of peritoneal and/or intra-abdominal recurrence. Shortterm follow-up abdominopelvic CT and ascites cytology examinations were conducted one month later due to increased ascites, and peritoneal recurrence was eventually confirmed in the latter patient mentioned previously (Figure 3). All of these patients were in an advanced stage of pathology and the ascites fluid was small in volume and located in the pelvic cavity at first appearance.

**Figure 3.** CT images of a patient on initial recurrence of malignant ascites without other CT findings related to peritoneal seeding, later confirmed by cytology. A small volume of pelvic ascites fluid was observed at first appearance (**A**). Follow-up CT (**B**) showed an increased volume of ascites fluid. Yellow stars indicate ascites.


Abbreviations: PG, partial gastrectomy; TG, total gastrectomy; and CT, computed tomography.

**Table 3.**

Characteristics

 of patients with temporarily

 undefined ascites.

#### **4. Discussion**

In gastric cancer patients, the most common cause of ascites after surgery is thought to be intra-abdominal recurrence but this is not supported by our study. In this study, a small volume of pelvic ascites fluid that had no identified pathological cause was noted in a substantial number of patients, notably an incidental finding during regular follow-ups. Malignancy-related ascites was observed in only 28.8% of patients with a history of ascites.

Normal peritoneal fluid that keeps the peritoneum moist and smooth may accumulate in the deep region of the pelvis in both males and females [16]. It is more frequently observed in premenopausal females than in males or postmenopausal females. In premenopausal females, the fluid that accumulates in the pelvis is thought to originate from ovarian exudation and decreased absorption of peritoneal fluid due to adhesions caused by various factors including endometriosis [17,18]. In a board sense, this fluid is called "physiologic ascites". The precise incidence of physiologic ascites has rarely been studied. According to Yoshikawa et al., a small amount of physiologic pelvic ascites was observed in 3.8% of healthy males and 16.8% of healthy postmenopausal females in pelvic magnetic resonance imaging conducted during health screenings [17]. In our study, benign ascites was identified in 23.8% of all male patients and 32.7% of all female patients without recurrence. There was no statistically significant difference in ascites detection between the sexes on either univariate or multivariate analyses. Peritoneal fluid accumulation seems to occur more often after gastric cancer surgery regardless of sex. A possible explanation for this is that the absorption capacity of the peritoneum decreases when it is infected or injured [19]. It is assumed that ascites accumulation increases after surgery due to peritoneal injury and adhesion. This reaction may be stronger in younger patients because an age of ≤45 was the only independent factor significantly linked to the occurrence of benign ascites in our study. In addition, young female patients are more likely to have ascites due to gynecological causes but those were not investigated in this study because of insufficient medical records. Therefore, the level of concern regarding recurrence is lower if the patient's ascites has a gynecological cause.

Cheon et al. reported that a small amount of pelvic fluid was detected in follow-up CT after curative surgery for gastric cancer in 3.9% of male patients [20]. This incidence is quite low when compared with our study. The authors obtained data only from radiology reports without a review of all CT images, whereas in our study, all images were independently reviewed by two radiologists. In addition, their definition of a "small" volume of ascites fluid was less than 20 mL, while in our study, it was defined as less than 50 mL. These reasons may explain the discrepancy between the results of the two studies. Further prospective observation is required for clarification.

According to reports from South Korea as well as western countries, malignant tumors are the second most common pathologic cause of ascites, following portal hypertension due to cirrhosis [21,22]. Malignancy-related ascites typically develops in the setting of recurrent and/or advanced cancer. The primary pathophysiological mechanism of malignancy-related ascites is peritoneal carcinomatosis, which blocks the drainage of lymphatic channels and increases vascular permeability [23]. Along with peritoneal carcinomatosis, some tumors may metastasize in the liver, which can cause ascites because of the obstruction/compression of the portal veins, further leading to portal hypertension or liver failure. Other types of tumors such as lymphomas can cause lymph node obstruction with accumulation of chylous ascites [24]. In gastric cancer, multiple pathophysiological mechanisms of ascites formation can occur but the primary mechanism is peritoneal carcinomatosis. There are few reports considering ascites as the first manifestation of gastric cancer despite its being the first detected sign of intra-abdominal malignancy in 50% of patients with peritoneal carcinomatosis [23,25]. To date, there are no reports considering ascites as the first manifestation of recurrence in postgastrectomy gastric cancer patients. In our study, most cases of malignancy-related ascites were accompanied by other findings of recurrence or were discovered during disease progression. Malignancy-related ascites is indicated as a late manifestation of intra-abdominal metastasis after gastrectomy for

gastric cancer, as in the first diagnosis of gastric cancer [26]. Therefore, a small amount of pelvic ascites cannot be excluded from consideration as an early indicator of peritoneal carcinomatosis. This judgment requires caution. In our study, ascites was the only initially detected sign of intra-abdominal recurrence in one patient (Table 3; Figure 3). Furthermore, among patients with ascites presumed to be benign before obvious recurrence, the possibility of malignancy-related ascites due to peritoneal recurrence cannot be excluded because of the relatively short time between the first occurrence of ascites and the recurrence in some cases (Pt. 1, 5, 6, and 8 in Table 3). All patients mentioned above were in far-advanced stages of the disease (Table 3). The possibility of recurrence should be suspected in all gastric cancer patients with advanced disease who develop ascites even when the characteristics of the ascites are similar to those of benign ascites and there are no definitive findings suggesting peritoneal metastasis.

CT is frequently used for the postoperative surveillance of patients with gastric carcinoma. CT allows for the detection of even small amounts of ascites and provides information that is difficult to obtain in ultrasonography [16]. It would be desirable if intra-abdominal recurrence could be predicted with CT-detected ascites; however, this does not seem to be possible. The likelihood ratios were not at appropriate levels in our study. According to previous reports, malignancy-related ascites is often loculated or septated, or may be absent in typical or dependent areas such as the pelvis [8,27]. Similarly, in our study, the specificity and positive and negative predictive values for intra-abdominal recurrence were improved when calculated for ascites at locations other than the pelvis. In terms of the volume of the ascites fluid, that of >50 mL in a preoperative CT was found to be related to peritoneal metastasis in gastric cancer patients in a recently published study [13]. Additionally, in our study, malignancy-related ascites fluid volumes were larger (>50 mL are considered moderate and large amounts) than benign ascites at the time of initial detection. However, except for some patients with undefined ascites, all patients with malignancy-related ascites exhibited definitive peritoneal metastasis or intra-abdominal recurrence in the CT when ascites was first detected. Ascites alone therefore seems to be inappropriate as a diagnostic marker for intra-abdominal or peritoneal recurrence in postgastrectomy gastric cancer patients.

#### **5. Conclusions**

The presence of small-volume pelvic ascites fluid in follow-up images has minimal clinical significance in the majority of patients who undergo gastrectomy for gastric cancer. This phenomenon is more common in younger patients, regardless of sex. Although the presence of malignant ascites alone in the pelvic cavity can precede obvious intraabdominal recurrence involving peritoneal seeding, ascites is more likely to be an indicator of disease progression in patients with recurrent gastric cancer.

**Author Contributions:** Conceptualization, J.-H.L. and S.-J.K.; methodology, M.K., J.-H.L. and S.-J.K.; software, J.-H.L.; validation, J.-H.L., S.-J.K., M.K. and B.-K.K.; formal analysis, J.-H.L.; investigation, J.-H.L., M.K. and B.-K.K.; resources, S.-J.K. and B.-K.K.; data curation, J.-H.L.; writing—original draft preparation, J.-H.L.; writing—review and editing, J.-H.L., S.-J.K., M.K. and B.-K.K.; visualization, J.-H.L.; supervision, S.-J.K.; project administration, J.-H.L.; funding acquisition, J.-H.L. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work was supported by the research fund of Hanyang University (HY-202100000000767).

**Institutional Review Board Statement:** The study was conducted according to the guidelines of the Declaration of Helsinki and was approved by the Institutional Review Board (or Ethics Committee) of the Hanyang University hospital (protocol code 2021-03-050-004 and date of approval 23 April 2021).

**Informed Consent Statement:** Patient consent was waived due to the minimal risk of a retrospective study.

**Data Availability Statement:** The data presented in this study are available on request from the corresponding author.

#### **Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


## *Article* **Colorectal Cancer Risk in Women with Gynecologic Cancers—A Population Retrospective Cohort Study**

**Szu-Chia Liao 1,2, Hong-Zen Yeh 1,3, Chi-Sen Chang 1, Wei-Chih Chen 4, Chih-Hsin Muo <sup>5</sup> and Fung-Chang Sung 5,6,7,\***


**Abstract:** We conducted a retrospective cohort study to evaluate the subsequent colorectal cancer (CRC) risk for women with gynecologic malignancy using insurance claims data of Taiwan. We identified patients who survived cervical cancer (N = 25,370), endometrial cancer (N = 8149) and ovarian cancer (N = 7933) newly diagnosed from 1998 to 2010, and randomly selected comparisons (N = 165,808) without cancer, matched by age and diagnosis date. By the end of 2011, the incidence and hazard ratio (HR) of CRC were estimated. We found that CRC incidence rates were 1.26-, 2.20-, and 1.61-fold higher in women with cervical, endometrial and ovarian cancers, respectively, than in comparisons (1.09/1000 person–years). The CRC incidence increased with age. Higher adjusted HRs of CRC appeared within 3 years for women with endometrial and ovarian cancers, but not until the 4th to 7th years of follow up for cervical cancer survivals. Cancer treatments could reduce CRC risks, but not significantly. However, ovarian cancer patients receiving surgery alone had an incidence of 3.33/1000 person–years for CRC with an adjusted HR of 3.79 (95% CI 1.11–12.9) compared to patients without any treatment. In conclusion, gynecologic cancer patients are at an increased risk of developing CRC, sooner for those with endometrial or ovarian cancer than those with cervical cancer.

**Keywords:** colorectal cancer; gynecologic cancer; retrospective cohort study; colonoscopy screening

#### **1. Introduction**

Cervical, endometrial and ovarian cancers are gynecologic (GYN) cancers among the ten leading causes of deaths from cancer for women. Cervical cancer is the most common female cancer in developing countries and the eighth most common in the US women [1–3]. The prevalence of endometrial cancer is on the rise in developed countries, with the incidence higher than that of cervical cancer. Ovarian cancer is the second-most common cancer in women, with a higher incidence in developed countries. The 5-year survival rates of GYN cancers have improved over the past few decades due to the improved treatments [1]. GYN cancer survivors are at risk for a second cancer [4–10]. Human papillomavirus infection, smoking, obesity, hormone replacement therapy, radiotherapy and hereditary nonpolyposis colorectal cancer (HNPCC) are associated with a secondary malignancy [6,10,11]. A meta-analysis found that the standardized incidence ratios (SIRs) on all types of second cancer risk ranged from 1.0 to 1.4 for women with primary breast

**Citation:** Liao, S.-C.; Yeh, H.-Z.; Chang, C.-S.; Chen, W.-C.; Muo, C.-H.; Sung, F.-C. Colorectal Cancer Risk in Women with Gynecologic Cancers—A Population Retrospective Cohort Study. *J. Clin. Med.* **2021**, *10*, 3127. https://doi.org/10.3390/ jcm10143127

Academic Editor: Sun-Young Lee

Received: 29 May 2021 Accepted: 11 July 2021 Published: 15 July 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

cancer, with the risk greater for women of less than 50 years than those who were older (SIR 1.51 vs. 1.11) [11].

Colorectal cancer (CRC) has become the second or third leading cause in cancer-related deaths in women [12–15]. GYN cancers and CRC share some common risk factors, such as obesity, lifestyle and socioeconomic status [10–12,14,16]. Thus, the risk of CRC development is an important concern for women with GYN cancer. Previous epidemiologic studies have shown conflicting results about the CRC risk in women with prior cervical or endometrial cancers [4,17–22]. Studies on the risk of subsequent CRC after radiotherapy for cervical cancer have conflicting results. Women with previous endometrial or ovarian cancer with or without radiotherapy have been found to be at increased risk for CRC [14,22].

Using cancer registries in European countries and the United States, Chaturvedi et al. followed 104,760 one-year survivors of cervical cancer for 40 years [19]. Patients treated with heavy radiotherapy have a higher SIR for second cancers, including colorectal cancer and other GYN cancers. Limited data are available on the risk of CRC for Asian women with GYN. A retrospective study followed 52,972 women with cervical cancer for 9 years using the Taiwan Cancer Registry and found the second cancer risk was greater for rectal cancer than for colon cancer (SIR = 1.31 vs. 1.13) [5]. The effects of treatment for cervical cancer on the risk of CRC have not been clarified in the study.

No study has compared the CRC risk for women with GYN cancers by treatment modality other than with or without radiotherapy. In the present study, we established cohorts of survivors with major GYN cancers, including cervical, endometrial and ovarian cancers, to evaluate the risk of subsequent CRC. Risks of the second CRC cancers were also assessed for patients with GYN treatment methods.

#### **2. Methods and Materials**

#### *2.1. Study Design, Data Source and Study Subjects*

We performed a population-based retrospective cohort study using data obtained from Taiwan National Health Insurance, which is a universal health insurance system with over 99% of the population covered. We used 1998–2011 claims data, which included inpatient and outpatient records for cancer care and a registry for catastrophic illnesses. The International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) and A-code was applied to retrieve information on diagnosis.

From the registry for catastrophic illnesses, we identified 41,452 cases of GYN cancers with at least one-year survival from 1998 to 2010, for the study cohorts. Patients with the history of CRC at the baseline were excluded. The GYN cancer cohort included 25,370 cases of cervical cancer (ICD-9-CM code 180), 8149 cases of endometrial cancer (ICD-9-CM code 182) and 7933 cases of ovarian cancer (ICD-9-CM code 183). The diagnosis date was designated as index date. Using a ratio of 1:4, 165,808 women free from any cancer were randomly selected as the reference cohort, and frequency matched with all GYN cases by age and index date. Follow up began 1 year after the subject was included in the cohort until the date of CRC diagnosis or the end of 2011, whichever occurred first. Subjects lost to follow up were censored. Subsequent CRC cases were identified by linkage within the respective cancer registry files and confirmed by the registry for catastrophic illnesses.

#### *2.2. Statistical Analysis*

Data analysis first displayed sociodemographic characteristics (age and occupation) and comorbidities among cohorts. Comorbidities included diabetes mellitus (ICD-9-CM 250), hypertension (ICD-9-CM 401–405,997.91), hyperlipidemia (ICD-9-CM 272), noninfectious enteritis and colitis (ICD-9-CM 555–558), anal and rectal polyp (ICD-9-CM 560.9), benign neoplasm of the colon (ICD-9-CM 211.3), and cholecystectomy (ICD-9-CM 51.22–51.23) [23]. Distributions of age (30–39, 40–49, 50–64, and >60 years), occupation and comorbidities were compared between the GYN cohorts and reference cohort and examined using a Chi-square test for categorical variables and a *t*-test for continuous variables. We calculated the incidence rates of subsequent CRC for each cohort during

the follow-up period. The Cox proportional hazards regression analysis was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of CRC associated with GYN cancers and treatment modalities. The multivariable Cox model was used to calculate adjusted HR (aHR) controlling for demographic factors and comorbidities. To assess the effect of cancer therapy, GYN cohorts were stratified into five groups by therapeutic modalities: radiation therapy (RT) only, chemotherapy (CT) only, combination of RT and CT (RT/CT), surgery only and no treatment (non-RT/CT/surgery). We used the no treatment group as a reference to examine whether RT, CT, surgery, and RT/CT were associated the CRC risk. We also calculated the HRs of CRC by the follow-up duration, <1, 2–3, 4–5, 6–7, 8–9 and ≥10 years for the GYN cohorts. In order to evaluate the competing risk of death, we also used the sub-distribution model to estimate the overall sub-hazard ratio (SHR) of CRC cancer associated with each of the 3 GYN cancers. All data analyses were performed using the SAS 9.3 statistical package (SAS Institute Inc., Cary, NC, USA). The study was approved by Research Ethics Committee at China Medical University and Hospital (CMUH104-REC2-115).

#### **3. Results**

All GYN cancer cases and the reference cohort were similar in distributions of age, with the mean age of 54.9 years (Table 1). Patients with cervical cancer were older than patients with endometrial and ovarian cancers (means 56.2, 53.2 and 52.0 years, respectively). Women with endometrial cancer and ovarian cancer were more likely to work in white collar jobs. Overall, GYN cancer patients were more prevalent than the reference cohort with diabetes mellitus, hypertension, non-infectious enteritis and colitis, anal and rectal polyps, and benign neoplasm of the colon. The prevalence rates of hyperlipidemia and cholecystectomy were similar.

**Cancer Cohorts Reference** *p* **Value Cervical Endometrial Ovarian Total** Total population, n (%) 25,370 (61.2) 8149 (19.7) 7933 (19.1) 41,452 (100) 165,808 (100) Age, n (%) 30–39 2905 (11.5) 770 (9.45) 1284 (16.2) 4959 (12.0) 19,836 (12.0) 0.95 40–49 6727 (26.5) 2293 (28.1) 2514 (31.7) 11,534 (27.8) 46,136 (27.8) 50–64 8513 (33.6) 3914 (48.0) 2845 (35.9) 15,272 (36.8) 61,088 (36.8) ≥65 7225 (28.5) 1172 (14.4) 1290 (16.3) 9687 (23.4) 38,748 (23.4) Mean (SD) 56.2 (13.5) 53.6 (10.7) 52.0 (12.1) 54.9 (12.8) 54.8 (12.9) 0.36 Occupation n, (%) White collar 11,034 (43.5) 4495 (55.2) 4421 (55.7) 19,950 (48.1) 81,365 (49.1) <0.0001 Blue collar 11,902 (46.9) 2963 (36.4) 2805 (35.4) 17,670 (42.6) 71,622 (43.2) Others 2405 (9.48) 651 (8.36) 693 (8.74) 3779 (9.12) 12,634 (7.62) Missing 29 (0.11) 10 (0.12) 14 (0.18) 53 (0.13) 187 (0.11) Comorbidity, n (%) Diabetes 3139 (12.4) 1325 (16.3) 794 (10.0) 5258 (12.7) 18,894 (11.4) <0.0001 Hypertension 2938 (11.6) 1180 (14.5) 848 (10.7) 4966 (12.0) 12,275 (7.40) <0.0001 Hyperlipidemia 520 (2.05) 187 (2.29) 143 (1.80) 850 (2.05) 3366 (2.03) 0.79 Non-infectious enteritis and colitis 419 (1.65) 70 (0.86) 86 (1.08) 575 (1.39) 1944 (1.17) 0.0004 Anal and rectal polyp 25 (0.10) 0 (0.00) 6 (0.08) 31 (0.07) 56 (0.03) 0.0003 Benign neoplasm of colon 94 (0.37) 18 (0.22) 42 (0.53) 154 (0.37) 153 (0.09) <0.0001 Cholecystectomy 267 (1.05) 104 (1.28) 104 (1.31) 475 (1.15) 1911 (1.15) 0.91

**Table 1.** Distributions of gender, age, and comorbidity among gynecologic cancer cohorts and reference cohort identified from 1998 to 2010.

*p* value: reference vs. total cases.

The overall CRC incidence rate was the highest in the endometrial cohort, followed by the ovarian cohort and cervical cohort (2.20, 1.76 and 1.37 per 1000 person–years, respectively) with aHRs of 2.26 (95% confidence interval (CI): 1.77–2.90), 2.09 (95% CI: 1.59–2.76) and 1.20 (95% CI: 1.03–1.40), compared to the reference cohort (1.09 per 10,000 person– years) (Table 2). The age-specific CRC cancer incidence increased with age in each cohort. However, the age-specific HR of CRC, relative to the reference cohort, decreased with age, particularly for patients with endometrial and ovarian cancer. We further used the sub-distribution model to estimate the adjusted hazard ratio (aSHR) of CRC associated with the competing risk of death in women with these GYN cancers. The overall aSHRs of developing CRC were 1.04 (95% CI: 0.89–1.21), 1.97 (95% CI: 1.54–2.52) and 1.53 (95% CI: 1.16–2.01), respectively, in women with cervical, endometrial and ovarian cancers.

**Table 2.** Incidence of colorectal cancer and gynecologic cancer cohorts to reference cohort adjusted hazard ratio by age.


Incidence rate: per 1000 person–years, aHR: adjusted for age, diabetes, hypertension, benign neoplasm of colon, anal and rectal polyp and cholecystectomy. CRC, colorectal cancer. \* *p* < 0.05; \*\* *p* < 0.01; \*\*\* *p* < 0.001.

> Table 3 shows the CRC risk associated with treatment modalities. The incidence rates were higher in patients with cervical cancer and endometrial cancer receiving no treatment (1.90 and 3.84 per 1000 person–years, respectively) than those with treatment. The aHR was significant for those with endometrial cancer (aHR = 3.38, 95% CI: 1.61–7.11), compared to the reference cohort, but not significant for those with cervical cancer. Treatments reduced the CRC incidence rates in both cohorts, with significant aHRs in the endometrial cancer cohort but not significant in the cervical cancer cohort. However, all reduced aHRs were not significant for patients with treatments, compared to those with no treatment. On the other hand, the CRC incidence rate in ovarian cancer patients was 4.6-fold greater in those undergoing surgery than those receiving no treatment (3.33 vs. 0.73 per 1000 person–years), with an aHR of 3.56 (95% CI: 2.23–5.68) compared with controls. Most ovarian cancer patients received chemotherapy (5069/7933) and had an adjusted HR of 1.95 (95% CI: 1.35–2.80).

**Table 3.** Incidence and adjusted hazard ratio of colorectal cancer by type of treatment for patients with gynecologic cancers and reference cohort.


aHR: Adjusted for age, diabetes, hypertension, benign neoplasm of colon, anal and rectal polyp and cholecystectomy. RT, radiation therapy; CT, chemotherapy. Incidence rate ++: per 1000 person-years. \* *p* < 0.05; \*\* *p* < 0.01; \*\*\* *p* < 0.001.

Figure 1 shows the Cox model-estimated aHRs of CRC for GYN cohorts in a 10-year follow-up period, compared with the reference cohort. The incident CRC developed earlier in women with the endometrial cohort and the ovarian cohort than in women with cervical cancer. Elevated aHRs were significant within the first 3 years of follow up for women with endometrial cancer and ovarian cancer, but not until 4th to 7th years for women with cervical cancer.

**Figure 1.** Cox proportional hazards regression analysis estimated adjusted hazard ratio of colorectal cancer for patients with gynecologic cancers compared to reference cohort by follow-up year.

Figure 2 shows the Cox model estimated age-specific aHRs of CRC during the followup period. The hazards of developing CRC were all greater for younger GYN patients, particularly during the first 3 years of follow up for women <50 years old with endometrial cancer and ovarian cancer.

**Figure 2.** Cox proportional hazards regression analysis estimated adjusted hazard ratios of colorectal cancer for patients with gynecologic cancers relative to comparison cohort by follow-up year and age group. (**A**) Age: <50 years, (**B**) Age: 50–64 years, (**C**) Age: ≥65 years.

#### **4. Discussion**

This population-based retrospective cohort study showed that women with major GYN cancers are at an elevated risk of developing CRC. The CRC risk is the highest for women with endometrial cancer, followed by ovarian cancer and cervical cancer. The CRC risk varied not only by GYN cancer type, but also by the follow-up period, cancer treatment modality and age. Previous studies on relationships between a second CRC and GYN cancers are inconsistent [4,17–22]. In general, the CRC risks found were stronger for patients with ovarian cancer and endometrial cancer than for patients with cervical cancer. Weaker relationships between CRC and cervical cancer in these studies are consistent with our findings. We failed to identify the CRC risk in association with treatment modality in cervical cancer.

A retrospective cohort study using the US cancer registry data of the Surveillance, Epidemiology, and End Results (SEER) program found women with GYN cancer tended to have a higher CRC incidence in the first 6 months after the diagnosis of the cancer; the estimated SIR of subsequent CRC is significant for those with ovarian cancer (SIR: 2.20, 95% CI: 1.06–2.58), but not for endometrial cancer [22]. Another study using SEER data found the risk of CRC was the highest in 12–24 months after the diagnosis of endometrial cancer [14]. The Swedish record-linkage study also found a significant SIR of 1.64 (95% CI: 1.24–2.11) for CRC within 2 years for women with ovarian cancer [4].

The exact mechanisms associated with CRC risk among women with GYN cancers remain unclear. GYN cancers shared the same risk factors with CRC, including hormone modulation, lifestyle and hereditary diseases. Decreased exposure to estrogen may protect against colorectal, endometrial, and ovarian cancer [24]. Nulliparous women and women using hormone replacement therapy are at a high risk [16]. Dietary factors and obesity are the shared risk factors in colorectal and ovarian or endometrial cancer [14]. Estrogen levels are elevated in obese persons [25]. In addition, the familial CRC syndrome of HNPCC can appear in the early development of colorectal, endometrial and ovarian cancer [26]. However, HNPCC is not prevalent in our population. HNPCC may do little to explain the association between GYN cancers and CRC.

GYN cancer detection and treatment may in part explain the CRC risk variations among GYN cancers. The latent periods of subsequent CRC for women with cervical cancer is longer than that for women with endometrial cancer and ovarian cancer. The pap test helps to detect cervical cancer in the early stages. The detection and treatment of carcinoma in situ of the cervix may prevent not only the development of an invasive carcinoma of the cervix but also other cancer. On the other hand, ovarian cancer and endometrial cancer are more likely not detected until they are in more advanced stages. This may also explain in part why the incidence of CRC in cervical cancer patients was lower than that in ovarian cancer and endometrial cancer patients.

Some women may have developed CRC by the time they are diagnosed with ovarian cancer and endometrial cancer. In our study, the CRC incidence was the highest in women receiving surgery alone for ovarian cancer treatment. These patients might have received more screening modalities. A higher CRC incidence is thus identified in a shorter follow-up time for ovarian cancer patients than for cervical cancer patients. Most patients with endometrial cancer received surgery alone, but they had the lowest CRC incidence. These patients might have the disease diagnosed at an advanced stage. This is probably why CRC incidence was the highest in endometrial cancer patients receiving no treatment. On the other hand, the incidence among ovarian cancer patients was the lowest for those receiving no treatment. However, there were few ovarian cases receiving no treatment. A further investigation with a more ovarian cases is needed to address the finding.

Evidence from previous studies has shown the risk of CRC is elevated for cervical cancer patients after receiving RT [18,19]. Brown et al. found the RT treatment increased colon cancer risk after endometrial cancer [18]. In the present study, the CRC risk increased after RT for endometrial cancer and ovarian cancer, but not for cervical cancer. The relationship between CRC risk and endometrial cancers treated with RT in our study is compatible with findings in two studies using the US Survival, Epidemiology, and End Results database [18,20].

In our study, 70.7% patients with ovarian cancer, 10.1% patients with endometrial cancer and 6.09% patients with cervical cancer received CT. The subsequent CRC risk after CT was significant for those with endometrial cancer and ovarian cancer. No previous study has observed the CRC risk for GYN cancers after CT. Further data analysis showed that the age-specific GYN cancer cohort to the reference cohort risk of CRC was greater for younger patients than older patients after CT. As for 30–49 years old patients, the adjusted HRs of CRC were 5.44 (95% CI: 2.23–13.3) for those with endometrial cancer and 3.29 (95% CI: 1.86–5.84) for those with ovarian cancer. In general, younger women might have these cancers diagnosed at an earlier stage and have longer survival than older women have. Longer survival increases the detection of CRC cancer. The greater impact of CT for young GYN patients than older patients could be true, because of low CRC incidence in younger general population [27]. A further investigation for the impact of CT regimens needs to be addressed. Routine gynecologic examination and cancer screening are also recommended for these younger women.

Boice et al. found the risk of secondary cancer was greater for young GYN patients after RT [28]. A previous study on testicular cancer patients noted that platinumbased chemotherapy had induced leukemia and solid organ tumors, including colon cancer [15,29–31]. Travis et al. found a higher risk of leukemia in ovarian cancer patients after receiving CT [32], but no report on the risk of CRC. No other report has addressed the carcinogenic effect after CT for endometrial and ovarian cancers. We suspect that harder follow-up checks for GYN cancer patients may also explain in part the increased identification of CRC.

Our study results should be interpreted with caution because of limitations. First, data on patient lifestyles and family history of diseases were not adjusted in data analyses because the information is not available from the NHRI records. Second, the NHRI records also provide no information on cancer stage and dosages of CT and RT, and we are unable to measure the dose–response association between treatment and CRC risk. Third, cancer patients covered in the insurance system are registered in the catastrophic illnesses group eligible for treatment benefit with discounted treatment costs. The insurance system provides no guides on which treatment modalities are usually used on treatment by the cancer stage. Our study could not differentiate whether the health insurance policies affect the development of CRC. However, further study is needed to investigate factors associated with increased CRC risk in women receiving surgery for ovarian cancer. Information on images of colonoscopy screening is also unavailable, and we are unable to prove whether hard follow-up checkups increase the diagnosis of CRC for GYN patients. However, all cancer patients have been registered as catastrophic illnesses, and the misdiagnosis of GYN cancer and CRC is unlikely in this study.

#### **5. Conclusions**

In this study, the number of patients with cervical cancer was much greater than that of endometrial and ovarian cancers. The risk of developing a second CRC was higher for patients with endometrial and ovarian cancers than for those with cervical cancer. The younger patients were at a higher impact after treatment. The risk of developing CRC after GYN cancer therapy is an important concern, because the CRC risk varied by the cancer treatment method among GYN cancers. The elevated incidence of CRC associated with surgery in patients with endometrial and ovarian cancers, but not cervical cancer should prompt the mechanism investigation. Colonoscopy screening for the subsequent development of CRC in these GYN cancer patients should be performed as soon as possible, especially for patients below 50 years old, in the early years after cancer diagnosis and after ever receiving chemotherapy or radiotherapy.

**Author Contributions:** Conceived and designed the study: S.-C.L., H.-Z.Y., C.-S.C., W.-C.C., C.-H.M. and F.-C.S. Data analysis and interpretation: C.-H.M., S.-C.L., F.-C.S. Data evaluation: H.-Z.Y., C.-S.C., W.-C.C., F.-C.S. Manuscript preparation: S.-C.L. and F.-C.S. Manuscript editing: F.-C.S. Manuscript review: All authors. All authors have read and agreed to the published version of the manuscript.

**Funding:** This study was supported in part by the Ministry of Health and Welfare, Taiwan (MOHW109- TDU-B-212-114004), MOST Clinical Trial Consortium for Stroke (MOST 109-2321-B-039-002), the Ministry of Science and Technology, Taiwan (Grant no. MOST108-2410-H-039-001 and MOST109-2410-H-039-001), the China Medical University, Taiwan (Grant no. CMU109-MF-119), and Tseng-Lien Lin Foundation, Taichung, Taiwan.

**Institutional Review Board Statement:** This study was approved by the Research Ethics Committee of China Medical University and Hospital (CMUH104-REC2-115). Surrogate identification numbers were used for data linkage to protect the privacy. No consents are required.

**Data Availability Statement:** Data are available from the Ministry of Health and Welfare of Taiwan by request after IRB approval. Authors are not allowed to duplicate data files.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**

