The prognostic significance of metabolic syndrome and weight loss in esophageal squamous cell carcinoma

Our study aimed to investigate the association between metabolic syndrome and postoperative survival in patients with esophageal squamous cell carcinoma, and evaluate whether metabolic syndrome can predict the prognosis in esophageal cancer patients. The retrospective study reviewed 519 patients with esophageal squamous cell carcinoma who had received esophagetomy and lymphnode dissections in the Department of Thoracic Surgery, Qilu Hospital of Shandong University between January 2007 and December 2011. All patients were followed up until December 2016. The median follow-up time was 39.59 months (range 0.25–72 months). The 3-year and 5-year survival rate was 51.4% and 37.0%, respectively. Kaplan–Meier survival analysis revealed a significant correlation between OS and obesity (P = 0.000), weight loss (P = 0.000), diabetes (P = 0.001) and dyslipidemia (P = 0.030). Multivariate analysis indicated that advanced TNM staging (P = 0.007, HR: 1.760, 95% CI: 1.167–2.654) and more weight loss (P = 0.000, HR: 1.961, 95% CI: 1.697–2.267) were independent factors for adverse prognosis of esophageal squamous carcinoma patients. In contrast, diabetes was a protective factor in the prognosis of patients with esophageal cancer (P = 0.018, HR: 0.668, 95% CI: 0.478–0.933). Our findings suggest that TNM staging, weight changes and diabetes were independent predictors for the prognosis of esophageal cancer patients.

The evidence for the positive correlation between lipid metabolism and risk of esophageal cancer was presented 16 . There is now accumulating evidence that the MS may be not only risk factor for tumors but also cancer mortality marker 10 . However, the relationship between MS factor and prognosis of esophageal cancer is controversial. Some studies suggested that MS was associated with better prognosis of esophageal cancer 17 , while others failed to establish a connection 18 . Accordingly, the effects of MS and its related factors on overall survival (OS) and progression-free survival (PFS) of esophageal cancer need to be further discussed.  Therefore, we conducted this retrospective study to investigate the relationship between MS, weight loss and postoperative survival in patients with ESCC, and evaluate whether MS or weight loss can predict the prognosis in esophageal cancer patients.

Results
Patient characteristics. According Table 2. Clinicopathological characteristics of 519 esophageal squamous cell carcinoma patients grouped by BMI, weight loss, hypertension, diabetes, dyslipidemia and metabolic syndrome.
In addition, hypertension, diabetes, dyslipidemia and MS had no significant relationship with clinicopathological characteristics. A correlation analysis between patients with esophageal cancer who are accompanied with obesity, diabetes, dyslipidemia, and hypertension and weight loss can be found as Supplementary Table S1.
The relationship between BMI, weight loss, diabetes, dyslipidemia and OS, PFS of ESCC. In our research, Kaplan-Meier survival analysis revealed a correlation between BMI, weight loss, diabetes, dyslipidemia and OS, PFS of esophageal cancer. As shown in Fig. 1, Kaplan-Meier curves showed that ESCC patients with obesity had significantly longer OS (P < 0.001) and PFS (P < 0.001). Furthermore, patients with middle or more weight loss, regardless of OS or PFS, were significantly shorter than patients with little body weight changes during treatment (OS, P < 0.001; PFS, P < 0.001). Compared with people in normal blood glucose level, esophageal cancer patients with diabetes showed a better prognosis in OS (P = 0.001), and PFS (P = 0.002). In the same way, dyslipidemia patients had longer survival in OS (P = 0.030) than those in normal blood lipids, although there was no statistical difference in PFS (P = 0.050). However, hypertension had no relationship with the prognosis of patients with esophageal squamous cell carcinoma. Univariate and multivariate analyses. The univariate analysis of suvival was exhibited in Table 3. There was a significant correlation between OS and gender (P = 0.019), tumor length (P = 0.008), tumor differentiation (P = 0.002), T stage (P = 0.000), LNM (P = 0.000), N stage (P = 0.000), TNM stage (N = 0.000), obesity (P = 0.000), weight loss (P = 0.000), diabetes (P = 0.001) and dyslipidemia (P = 0.032). The tumor location, treatment, hypertension, HDL, TG, MS and other factors did not have statistical significance with OS. In addition, univaviate analysis revealed a relationship between tumor length (P = 0.003), tumor differentiation (P = 0.002), T stage (P = 0.000), LNM (P = 0.000), N stage (P = 0.000), TNM stage (N = 0.000), treatment (P = 0.009), obesity (P = 0.000), weight loss (P = 0.000), diabetes (P = 0.002) and PFS time.
In male subgroup, obesity (P = 0.000), little weight loss (P = 0.000) and diabetes (P = 0.002) showed better survival compared with normal group in Fig. 4. Dislipidemia in female group showed better OS than normal patients (P = 0.035). Conversely, there were no significance in OS between patients accompanied by obesity (P = 0.052), little weight loss (P = 0.060), diabetes (P = 0.249) and ESCC patients with normal metabolic state in female subgroup. MS group showed better survival compared with normal group (P = 0.041) in males, while there was no significance between MS patients and normal ESCC patients in female subgroup (P = 0.846).

Discussion
In this study, we investigated the prognostic value of MS in patients with resectable esophageal squamous cell carcinoma, and found significant correlation between OS and gender, tumor length, tumor differentiation, T stage, LNM, N stage, TNM stage, obesity, weight loss, diabetes and dyslipidemia. In addition, analysis revealed a relationship between tumor length, tumor differentiation, T stage, LNM, N stage, TNM stage, treatment, obesity, weight loss, diabetes and PFS time. The results indicated that advanced TNM staging and more weight loss were independent indicators for adverse prognosis of esophageal squamous carcinoma patients. In contrast, diabetes was a protective factor in the prognosis of patients with ESCC. It was also shown that TNM stage, weight loss and diabetes were independently associated with PFS time.
The metabolic syndrome, comprising obesity, dyslipidemia, hypertension, and hyperglycaemia, is a cluster of risk factors for cardiovascular disease and type 2 diabetes 6,19 . There is some evidence that MS may be associated with the risk of some common cancers [7][8][9] , including liver, colorectal, bladder, pancreatic, breast and esophageal cancer [10][11][12] . Some prospective cohort studies investigated the association between MS and the risk of the two dominating types of esophageal cancer, EAC and ESCC. Study found that obesity was associated with an increased risk of EAC 12 and a decreased risk of ESCC 13 . In accordance with above study, Corley et al. detected that increasing abdominal diameter was strongly associated with an increased risk of esophageal adenocarcinoma but not esophageal squamous cell carcinoma 20 . The Me-Can project in Sweden conducted a prospective study and revealed an association between high blood pressure and risk of ESCC without adjusting alcohol consumption 21 . They also observed that MS was associated with EAC but not ESCC 21    between lipid metabolism and risk of esophageal cancer was presented 16 . Several studies indicated an association between high blood glucose and an increased risk of cancer overall 22,23 .
Although the relationship between MS and tumor risk was well studied, there is little research on the asscioation of metabolic factors and tumor mortality. It was indicated that MS might be an important prognostic factor for colorectal cancer. Patrizia et al. showed that metabolic syndrome at baseline emerged as an important prognostic factor for breast cancer recurrences 24 . However, there were different conclusions regarding the prediction value of MS in tumor prognosis. An analysis revealed no association between MS and prostate cancer risk. Moreover, it was proposed that the metabolic syndrome be considered as a high-risk state for certain types of cancer, such as colon cancer, and this relationship should be systematically explored across cancer types 25,26 .
Studies linking the metabolic syndrome to esophageal cancer are scarce. However, several studies had investigated the association between metabolic biomarkers and overall survival of esophageal cancer patients. A retrospective review was performed to show that MS was a significant and independent predictor for better survival in patients with resectable ESCC 27 . There was no apparent influence of any single component of MetS on OS 27 . Another study reported that low BMI and low fasting blood glucose were related to poor survival and BMI came to be stronger prognostic factors on lymph node-negative patients 28 . Our results were consistent with the above two researches. In our study, survival analysis revealed a correlation between BMI (P < 0.001), weight loss (P < 0.001), diabetes (P = 0.001), dyslipidemia (P = 0.030) and OS of esophageal cancer. In addition, our research also found that ESCC patients with obesity or little weight loss or diabetes had significantly longer PFS (obesity, P˂0.001; weight loss, P < 0.001; diabetes, P = 0.002). The multivariate analysis indicated that advanced TNM staging (P = 0.007, HR: 1.760, 95% CI: 1.167-2.654) and more weight loss (P = 0.000, HR: 1.961, 95% CI: 1.697-2.267) were independent factors for adverse prognosis of patients with ESCC. In contrast, diabetes was a protective factor in the prognosis of patients with esophageal cancer (P = 0.018, HR: 0.668, 95% CI: 0.478-0.933). It was also shown that TNM stage (P = 0.008, HR: 1.643, 95% CI: 1.140-2.369), weight loss (P = 0.000, HR: 1.674, 95% CI: 1.462-1.917) and dibetes (P = 0.027, HR: 0.691, 95% CI: 0.499-0.958) were independently associated with PFS. Nevertheless, there were conflicting results in the studies that had investigated whether MS influenced survival among esophageal cancer patients 13,17,18,29,30 . It was reported that BMI one year prior to diagnosis was not associated with esophageal adenocarcinoma survival in a study conducted in Australia 31 . Besides, a nationwide study in Sweden found that obese patients had a favourable prognosis in EAC, while lean patients had a better prognosis in ESCC, compared with normal weight patients 32 . The underlying mechanisms of the inverse relationship between MS and ESCC remained unclear.
In order to analyze the relationship between MS-related composition and survival at different levels, we carried out the subgroup analysis based on gender, lymph node metastasis and TNM stage. A study showed that HR of metabolic syndrome for ESCC mortality was statistically significant in male (HR: 1.45, 95% CI: 1.14-1.83, P:0.002), but not in female (HR: 1.46, 95% CI: 0.92-2.31, P: 0.107) 33 . Likewise, our research found that MS group showed better survival compared with normal group (P = 0.041) in males, while there was no significance between MS patients and normal ESCC patients in female subgroup (P = 0.846). In addition, we conducted subgroup analysis in accordance with lymph node metastasis and TNM staging. It was indicated that obesity (P = 0.000), little weight loss (P = 0.000) and diabetes (P = 0.034) showed association with survival time in N0 subgroup, while BMI (P = 0.003), weight loss (P = 0.000), diabetes (P = 0.012) and dyslipidemia (P = 0.030) were all associated with survival in N1-3 subgroup. In TNM II-III subgroup, it was revealed that BMI (P = 0.000), weight loss (P = 0.000) and diabetes (P = 0.000) showed association with longer OS, while weight loss (P = 0.000) was related to survival time in subgroup TNM I stage. To our knowledge, this is the first time that a study has grouped the clinicopathological characteristics to further investigate the effect of MS on ESCC survival.
All in all, our study confirmed that MS patients had a better prognosis in male esophageal cancer patients, not in female. In addition, TNM staging, weight changes and diabetes were also independent predictors for the prognosis of ESCC. The biological mechanisms that could explain the inverse association remain unclear. In the early stage of esophageal cancer, the good control of the blood glucose, lipids, weight and other factors of metabolic sydrome will greatly affect the prognosis.

Patients.
A retrospective study was carried out, which included 519 patients with esophageal squamous cell carcinoma who had received esophagetomy and lymphnode dissections in the Department of Thoracic Surgery, Qilu Hospital of Shandong University between January 2007 and December 2011. The study was approved by the Ethical Committee of Qilu Hospital of Shandong University. Informed consent was obtained from all the patients. All data had been anonymized and deidentified. Moreover, the patient data collection methods were carried out in accordance with the Declaration of Helsinki. The patient's exclusion criteria were as follows: non-primary esophageal cancer, non-first-time diagnosed esophageal cancer, non-squamous cell carcinoma, combined with other malignancies, incomplete clinical pathological information, received neoadjuvant chemoradiotherapy, palliative or R1/R2 resections, lost to follow-up.

Metabolic syndrome evaluation.
There is no consensus on the diagnostic criteria of metabolic syndrome in various groups. In this study, we conducted the diagnosis of MS by the CDS standard proposed by the Chinese medical association diabetes branch.
MS is defined as including three or four of the following criteria: overweight and/or obesity, BMI (Body Mass Index) is greater than 25.0 kg/m 2 ; high blood glucose, FPG is greater than 6.1 mmol/L(110 mg/dl) and (or) 2hPG is greater than 7.8 mmol/L (140 mg/dl), and/or has been diagnosed with diabetes; hypertension, SBP/ DBP >140/90 mmHg, and/or has been diagnosed with hypertension; dyslipidemia, blood TG is more than 1.7 mmol/L(110 mg/dl), and (or) fasting blood HDL-C <0.9 mmol/L(35 mg/dl) in males, <1.0 mmol/L (39 mg/dl) in females. Little weight loss refers to weight loss within 5%, middle weight loss is 5% to 10%, much weight loss is greater than 10%.
Follow up. All patients were followed up, including postoperative recovery, general health, necessary psychological support and rehabilitation guidance through telephone, SMS, email, outpatient visit, etc. The information were obtained every 3 months in the first two years, followed by every 6 months. Recurrent, metastatic, lost and dead patients were noted during the follow-up. The time was cut-off until December 2016.
Statistical analysis. SPSS Version 19.0 software (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. The relationship between MS and various clinical pathological characteristics was tested by the Pearson's chi square test. OS was the endpoint of the clinical trial, which was defined as the time from the date of the operation to the end of the patient's death or follow-up. PFS was also one of the endpoints of this study, which was defined as the time from the date of surgery to the progression of the tumor or the end of the patient's death or follow-up. Kaplan-meier was used to draw the survival curve and the log-rank method was used to test its significance. COX regression included univariate and multivariate analyses. Univariate analysis detected the element related to esophageal cancer survival time, while the independent prognostic factors affecting OS and PFS were determined by multivariate analysis. P < 0.05 was considered statistically significant.