DOI 10.1007/s11605-015-3059-x ORIGINAL ARTICLE Feasibility of Total Gastrectomy with D2 Lymphadenectomy for Gastric Cancer and Predictive Factors for Its Short- and Long-Term Outcomes Fan-Feng Chen 1 & Dong-Dong Huang 1 & Jin-Xiao Lu 1 & Chong-Jun Zhou 1 & Cheng-Le Zhuang 1 & Su-Lin Wang 1 & Xian Shen 1 & Zhen Yu 1,2 & Xiao-Lei Chen 1 Received: 11 August 2015 /Accepted: 10 December 2015 # 2015 The Society for Surgery of the Alimentary Tract Abstract Background The aim of this study was to evaluate the short- and long-term outcomes after total gastrectomy (TG) with D2 lymphadenectomy. Methods Patients undergoing TG with D2 lymphadenectomy for gastric cancer between December 2008 and December 2011 were enrolled. Univariate and multivariate analyses were performed to evaluate the risk factors for the short- and long-term outcomes. Results A total of 229 patients were analyzed, and 22.3 % developed complications within 30 days of surgery. No patient died within 30 days, while 2.6 % died within 90 days of the operation. In the multivariate analysis, age 65 years and cardiopulmonary comorbidities were associated with morbidity, whereas hypoproteinemia and tumor node metastasis (TNM) stage III were associated with the disease-free survival (DFS) and overall survival (OS). The number of preoperative risk factors stratified the morbidity from 10.3 % in those without any risk factors to 40.5 % in patients with both risk factors. Similarly, 5-year survival rates decreased from 68.9 % (DFS) and 71.1 % (OS) in those without risk factors to 20.2 % (DFS) and 22.9 % (OS) in patients with both risk factors. Conclusion TG with D2 lymphadenectomy has acceptable short- and long-term outcomes. Patient risk stratification may allow for more rational selection of patients and therapeutic strategies for gastric resection. Keywords Total gastrectomy. D2 lymphadenectomy. Morbidity. Mortality. Survival Fan-Feng Chen and Dong-Dong Huang contributed equally to this work. * Zhen Yu yuzhen0577@gmail.com * Xiao-Lei Chen chenxiaolei0577@126.com 1 2 Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, 2 Fuxue Lane, Wenzhou 325000, Zhejiang, China Department of Surgery, Shanghai Tenth People s Hospital Affiliated to TongJi University, Shanghai 200072, China Introduction Despite a decrease in its incidence, gastric cancer is still the fifth most common malignancy and the third leading cause of cancer-related death worldwide. 1 In Eastern Asia, including Japan, Korea, and China, gastric cancer is one of the most prevalent types of cancer. 2 Surgical resection has remained the mainstay of treatment for gastric cancer for decades and currently provides the only hope for long-term survival. 3 According to the Japanese treatment guidelines for gastric cancer, 4 total gastrectomy (TG) with a proper extent of lymphadenectomy should be adopted for upper and middle-third gastric carcinoma, advanced esophagogastric junction tumor, or huge gastric tumors. Compared with subtotal gastrectomy, TG is considered to result in a higher occurrence of postoperative morbidity and mortality. 5,6 Radical gastrectomy with D2 lymphadenectomy is the standard surgical procedure for the treatment of resectable advanced gastric cancer in Eastern countries. However, Western surgeons usually perform D1
or modified D2 (D1+) lymphadenectomy. 7 Several previous studies reported acceptable ranges of postoperative morbidity, mortality, and long-term survival rates after gastrectomy with D2 lymphadenectomy. However, there have been limited data about these surgical outcomes, specifically for TG with D2 lymphadenectomy, and the risk factors associated with these outcomes were unclear. In this study, we determined the postoperative morbidity, mortality, and long-term survival rates in patients who underwent TG with D2 lymphadenectomy. We further tried to identify the risk factors associated with these outcomes. This study would clarify whether the TG with D2 lymphadenectomy for gastric cancer is feasible and would help to riskstratify the patients undergoing TG with D2 lymphadenectomy for gastric cancer. Patients and Methods Patient Selection A total of 915 consecutive patients underwent gastrectomy for gastric cancer at the Gastrointestinal Surgical Department, The First Affiliated Hospital of Wenzhou Medical University between December 2008 and December 2011. Patients were excluded owing to subtotal gastrectomy (n = 566), TG but not D2 lymphadenectomy (n = 41), palliative surgery (n =73),and incomplete clinical data (n = 6). Therefore, the remaining 229 patients who underwent TG with D2 lymphadenectomy were included in this study. The surgeries were performed by nine surgeons whose operation quality was considered to be satisfactory after assessment by two professors in our department. No operations were performed laparoscopically. TG with D2 lymphadenectomy for gastric cancer was performed in accordance with the Japanese Gastric Cancer Treatment Guidelines. 4, 8 D2 Lymphadenectomy Procedure The lymph node stations included in D2 lymphadenectomy during total gastrectomy were nos. 1 7, 8a, 9, 10, 11p, 11d, and 12a. We performed spleen-preserved lymphadenectomy for no. 10 and no. 11d lymph nodes. The procedure is briefly described as follows. First, we mobilized the spleen and pancreatic tail by dissecting all the ligamentous attachments. The spleen and pancreatic tail were mobilized to the level where inferior mesenteric vein confluences to splenic vein. Then, the spleen and pancreatic tail were moved outside from the abdominal cavity, and all the lymphatic fatty tissues at splenic hilum were carefully removed under direct vision. The splenic artery sheath was then opened close to the upper edge of the pancreas. The splenic vessels were denuded from distal to proximal. The lymphatic fatty tissues around splenic vessels were carefully dissected and removed. After the dissection, the spleen and pancreas were fixed to the original position. Splenectomy is performed when the tumor invades the spleen or the fatty and connective tissue of splenic hilum. Pancreatectomy is performed when the tumor invades or adheres to the pancreas. Data Collection Referring to our prospectively maintained computer database, the following data were analyzed retrospectively: (1) clinicopathological features, including age, gender, body mass index (BMI), the American Society of Anesthesiology (ASA) score, plasma albumin concentration, hemoglobin concentration, comorbidities, previous abdominal surgery, Lauren s histology type, tumor location, tumor size, tumor node metastasis (TNM) stage, lymphovascular invasion, and combined resection; (2) postoperative outcomes, including the postoperative complications, surgical mortality, length of hospital stay, disease-free survival (DFS), and overall survival (OS). All participants provided their written informed consent and the protocol for this study was approved by the ethics committee of The First Affiliated Hospital of Wenzhou Medical University. Definition A plasma albumin concentration <35 g/l was defined as hypoproteinemia. A hemoglobin concentration <120 g/l in men and <110 g/l in women was defined as anemia. Cardiopulmonary comorbidities were defined as the presence of cardiopulmonary disease(s) before surgery, including hypertension, cardiac disease (myocardial infarction or stenocardia), pneumonia, bronchitis, tuberculosis, chronic obstructive pulmonary disease (COPD), pleural effusion, and asthma. Postoperative complications were defined as morbidities that occurred within 30 days of the operation, and those classified as grade II or above according to the Clavien-Dindo classification 9 were included in the univariate and multivariate analyses. Surgical mortality was defined as death within 30 or 90 days after surgical resection. The DFS was defined as the time between 90 days after surgery and the date of local/ distant recurrence or the date of last follow-up. The OS was defined as the time from the date of surgery to the date of death or the date of last follow-up. Follow-Up Strategies All patients were followed-up within the first month after surgery,every3monthsfor2years,every6monthsforup to 5 years, and every 1 year until the end of the study period or death. The follow-up program consisted of a physical examination, laboratory tests, and endoscopy, and/or
ultrasonography, and/or computed tomography. The last follow-up date was March 2015. Statistical Analysis Continuous variables were presented as the mean and standard deviation (normally distributed variables) or median and interquartile range (non-normally distributed variables). Categorical variables were presented as numbers and percentages. Clinical variables were compared using the Student t test (normally distributed data), the Pearson chi square test or Fisher exact test (categorical data), and the Mann-Whitney U test (ranked data) as appropriate. The survival analysis was undertaken using the Kaplan-Meier method, and the comparison of curves was performed using a log-rank test. Variables with a value of P < 0.10 in the univariate analyses were included in the subsequent multivariate (logistic regression or Cox proportional hazards regression) analyses. All tests were twosided, and differences were considered to be statistically significant at P < 0.05. The statistical analyses were performed using the SPSS statistics version 22.0 (IBM, Armonk, NY, USA) and GraphPad Prism 5.0 (GraphPad Software Inc., CA, USA) software programs. Results Patient Population The clinicopathological characteristics are summarized in Table 1. A total of 229 patients were included in this study. The present patient cohort had an average age of 65.0 years old, and 85.2 % of them were male. The mean BMI of the study population was 21.7 kg/m 2. The distribution of the TNM stages in the patients was 28 (12.2 %), 44 (19.2 %), and 157 (68.6 %) for TNM stages I, II, and III, respectively. The most common comorbidities were cardiopulmonary comorbidities (25.3 %, n = 58), obesity (10.9 %, n = 25), and diabetes (7.4 %, n =17). Short-Term Surgical Outcomes As shown in Table 2, the incidence of any complications was 22.3 %, and complications classified as grade II or above were observed in 20.0 % of the patients. The median postoperative hospital stay was 12 days (range, 9.5 16.0 days). The most common complications were pneumonia (7.4 %, n = 17) and wound infection (7.0 %, n = 16). None of the patients died within 30 days, while six patients (2.6 %) died within 90 days of the operation. The causes of death were respiratory failure induced by pneumonia (two patients), anastomotic leakage (two patients), intra-abdominal hemorrhage (one patient), Table 1 Patient demographic and clinical characteristics Factors Frequency, n Patients, % Age, mean (SD), years 65.0 (11.0) Gender Female 34 14.8 Male 195 85.2 BMI, mean (SD), kg/m 2 21.7 (2.8) Albumin, mean (SD), g/l 38.64 (5.23) Hemoglobin, median (IQR), g/l 118.0 (92.5 134.0) 11.8 Median no. of retrieved lymph 26 (18 57) nodes, range BMI <18.5 27 11.8 18.5 25 177 77.3 >25 25 10.1 ASA grade I 8 3.5 II 203 88.6 III 18 7.9 Diabetes No 212 92.6 Yes 17 7.4 Cardiopulmonary comorbidities No 171 74.7 Yes 58 25.3 Previous abdominal surgery No 205 89.5 Yes 24 10.5 Histologic type Differentiated a 59 17.1 Undifferentiated b 190 82.9 Tumor size (diameter) <5 cm 117 51.1 5 cm 112 48.9 T category T1 19 8.3 T2 16 7.0 T3 60 26.3 T4 134 58.4 Ncategory N0 66 28.8 N1 44 19.2 N2 50 21.8 N3 69 30.2 Tumor location Not upper 122 53.3 Upper c 107 46.7 TNM stage I 28 12.2 II 44 19.2 III 157 68.6
Table 1 (continued) Table 2 Short- and long-term outcomes Factors Frequency, n Patients, % Lymphovascular invasion No 155 67.7 Yes 74 32.3 Any additional organ resection d No 212 92.6 Yes 17 7.4 R0 resection No 2 0.9 Yes 227 99.1 BMI body mass index, ASA American Society of Anesthesiologists, SD standard deviation, IQR interquartile range a Undifferentiated carcinomas include poorly differentiated adenocarcinomas, signet ring cell carcinomas, and mucinous carcinomas b Differentiated carcinomas include well or moderately differentiated, tubular, or papillary adenocarcinomas c Tumor located in the upper of the stomach d Splenectomy and/or pancreatectomy and septic shock induced by intra-abdominal abscess from other causes (one patient). The results of the univariate and multivariate analyses of factors associated with postoperative complications (grade II or above) are shown in Table 3. The results of the multivariate analysis revealed that the independent risk factors for postoperative complications (grade II or above) were age 65 years (OR = 3.638, P = 0.001) and cardiopulmonary comorbidities (OR = 2.189, P =0.036). Long-Term Survival Outcomes As shown in Table 2, among the 229 patients, survival data were available for 224 patients. Five patients were lost to follow-up, giving a follow-up rate of 97.8 % (224/229) for the evaluation. The median follow-up period was 34.96 months (range 0.3 74.8 months). One hundred twenty-four patients (54.1 %) died during the follow-up period. The median DFS was 35.7 months (95 % CI 17.4 53.9 months), with a 1-, 3-, and 5-year DFS rates of 69.6, 49.1, and 43.0 %, respectively (Fig. 1a). The median OS was 41.1 months (95 % CI 28.7 53.5 months), with a 1-, 3-, and 5-year OS rates of 79.8, 51.8, and 43.2 %, respectively (Fig. 1b). The results of the univariate and multivariate analyses of factors associated with the DFS and OS are shown in Table 4. The multivariate analysis revealed that hypoproteinemia (HR = 1.625, P = 0.021) and TNM stage III (HR = 3.291, P < 0.001) were independent risk factors for a poorer DFS. Similarly, hypoproteinemia (HR = 1.901, P = 0.002) and Factors Frequency, n Patients, % Total complications 51 22.3 Grade II or above 46 20.0 Grade III or above 7 3.0 Grade I 5 2.0 Grade II 39 17.0 Grade III 4 1.7 Grade IV 3 1.3 Grade V 0 0 Detail of complications Wound infection 16 7.0 Bleeding 3 1.3 Intra-abdominal abscess 5 2.0 Anastomotic leakage 4 1.7 Bowel obstruction or ileus 6 2.6 Pancreatic fistula 2 0.9 Pneumonia 17 7.4 Respiratory failure 2 0.9 Thoracic cavity fluid collection 8 3.5 or abscess Cardiac 2 0.9 Others 2 0.9 30-mortality 0 0.0 90-mortality 6 2.6 Postoperative hospital stays, median 12 (9.5 16.0) (IQR), days Median DFS time, (95 % CI), months 35.7 (17.4 53.9) DFS rate (%) 1-year 69.6 3-year 49.1 5-year 43.0 Median OS time, (95 % CI), months 41.1 (28.7 53.5) OS rate (%) 1-year 79.8 3-year 51.8 5-year 43.2 TNM stage III (HR = 3.019, P < 0.001) were also independent risk factors for a worse OS. Patient Risk Stratification As shown in Table 5, the identified preoperative risk factors for postoperative complications (age 65 years and cardiopulmonary comorbidities) were used to risk-stratify patients. In patients who had no risk factors for postoperative complications, the complication rate was 10.3 % (95 % CI 3.8 16.7 %). The complication rate increased to 20.2 % (95 % CI 13.2 28.1 %) in those with one risk factor (age 65 years or cardiopulmonary comorbidities) and to 40.5 % (95 % CI 24.3
Table 3 Univariate and multivariate logistic regression analysis of risk factors for complications Factors Univariable analysis Multivariate analysis Complication a cases (%) P OR (95 % CI) Age 0.003 * <65 11 (11.1) 65 35 (26.9) 3.638 (1.635 8.098) Gender 0.189 Male 42 (21.5) Female 4 (11.8) BMI 0.330 <18.5 8 (29.6) 18.5 25 32 (18.1) >25 6 (24.0) Hypoproteinemia 0.703 No 35 (19.6) Yes 11 (22.0) Anemia 0.378 No 18 (15.9) Yes 28 (24.1) ASA grade 0.943 I II 43 (19.8) III 3 (16.7) Diabetes 0.052 No 39 (19.4) Yes 7 (41.2) Cardiopulmonary 0.016 * comorbidities No 28 (16.4) Yes 18 (31.0) 2.189 (1.053 4.550) Previous abdominal 0.715 surgery No 40 (19.5) Yes 6 (25.0) Histologic type 0.235 Differentiated b 15 (25.4) Undifferentiated c 31 (18.2) Tumor location 0.069 Not upper 19 (15.6) Upper d 27 (25.2) TNM stage 0.427 I 5 (17.9) II 6 (13.6) III 35 (22.3) Lymphovascular 0.070 invasion No 26 (16.8) Yes 20 (27.0) P 0.001 * 0.036 * Table 3 (continued) Factors Univariable analysis Multivariate analysis 56.8 %) in those with both risk factors (age 65 years and cardiopulmonary comorbidities). Regarding the long-term survival rates, the identified preoperative risk factors for the DFS and OS (hypoproteinemia and TNM stage III) were used to risk-stratify patients. In patients without risk factors, the 5-year survival rates were 68.9 % (95 % CI 62.5 75.3%)fortheDFSand71.1% (95 % CI 57.7 79.4 %) for the OS. When one risk factor was present (hypoproteinemia or TNM stage III), the 5-year survival rates decreased to 36.5 % (95 % CI 30.7 40.3 %) for the DFS and 36.7 % (95 % CI 32.4 41.0 %) for the OS. When both risk factors were present (hypoproteinemia and TNM stage III), the 5-year survival rates further decreased to 20.2%(95%CI11.9 27.7 %) for the DFS and 22.9 % (95 % CI 14.7 31.1 %) for the OS (Fig. 1c, d). Discussion Complication a cases (%) Any additional organ resection e No 42 (19.8) 0.957 Yes 4 (23.5) P OR (95 % CI) Values in parentheses are percentages unless indicated otherwise BMI body mass index, ASA American Society of Anesthesiologists, SD standard deviation, IQR interquartile range *Statistically significant (P < 0.05) a Grade II or above b Undifferentiated carcinomas include poorly differentiated adenocarcinomas, signet ring cell carcinomas, and mucinous carcinomas c Differentiated carcinomas include well or moderately differentiated, tubular, or papillary adenocarcinomas d Tumor located in the upper of the stomach e Splenectomy and/or pancreatectomy According to the Japanese treatment guideline for gastric cancer issued by the Japanese Gastric Cancer Association (JGCA), TG with a proper extent of lymphadenectomy should be adopted for tumors located in the upper third of the stomach or advanced gastric cancer extending to the cardia. In several previous studies specifically analyzing TG, the short-term morbidity and mortality rates ranged from 13 to 38 % and 2 to 8.5 %, respectively, and many studies have reported a higher complication rate after TG compared with subtotal gastrectomy, 5, 6, 10 12 leading to TG being considered a more invasive surgical procedure. With regard to lymph node dissection, a previously published Dutch trial indicated that D2 P
Fig. 1 Kaplan-Meier survival curves for disease-free survival (a) and overall survival (b). Comparison of disease-free survival rates (c) and comparison of overall survival rates (d) according to the presence or absence of risk factors (2 risk factors, 1 risk factor, 0 risk factor) lymphadenectomy was associated with lower locoregional recurrence and gastric cancer-related death rates than D1 lymphadenectomy after a median follow-up of 15 years. 13 However, two randomized clinical trials from Europe indicated that D2 lymphadenectomy did not lead to any long-term survival benefit compared with D1 lymphadenectomy. 14, 15 In addition, a recent study demonstrated that modified D2 (D1+) lymphadenectomy confers the same oncological adequacy as standard D2 lymphadenectomy, with a significant reduction of the postoperative morbidity. 7 Currently, D2 lymphadenectomy is widely accepted as the standard procedure for advanced gastric cancer in Eastern countries. On the contrary, Western surgeons usually perform D1 or modified D2 (D1+) lymphadenectomy due to fears about increasing the short-term morbidity and mortality by D2 lymphadenectomy. 16, 17 Therefore, it remains to be proven whether TG with D2 lymphadenectomy, a procedure comprising two factors that are both generally considered to be more invasive, is feasible. Although numerous studies have reported the postoperative morbidity, mortality, and long-term survival rates for TG in general, few have described these postoperative outcomes specifically for TG with D2 lymphadenectomy, and the risk factors associated with these outcomes were also unclear. In this study, we observed that 22.3 % of the patients developed postoperative complications within 30 days of the operation, but none of the patients died within 30 days, and six patients (2.6 %) died within 90 days of the operation. Cuschieri et al. reported morbidity and mortality rates of 46 and 13 %, respectively. 17 The Dutch trial conducted at 80 different centers in the Netherlands reported a morbidity rate of 43 % and a mortality rate of 10 %. 16 In view of the similar age range, the higher proportion of males, and the more advanced tumor stages of our study compared with these previous studies, we considered that our postoperative morbidity and mortality rates were satisfactory. The difference in the morbidity and mortality rates can be partially explained by the fact that our study is based on the data from a single large center that specializes in gastric cancer surgery. Numerous studies have demonstrated that the postoperative surgical outcomes may vary according to the volume of surgery and surgical specialization. 18 20 Therefore, we considered that the postoperative morbidity and mortality rates and the results of the univariate and multivariate analyses in this study were reliable. Based on these morbidity and mortality rates, we believe that TG with D2 lymphadenectomy is feasible for the treatment of gastric cancer. However, due to the retrospective design of this study, further prospective studies are needed to demonstrate the feasibility of TG with D2 lymphadenectomy in the future. Both the 30-day and 90-day mortality rates were reported in this study because surgery-related mortality after major abdominal surgery has been found to occur up to 90 days postoperatively. 21, 22 Our results showed that none of the patients died within 30 days, whereas six patients (2.6 %) died within 90 days of the operation. Thus, our results indicated that using the 30-day mortality rate may lead to an underestimation of the true postoperative mortality rate. Unfortunately, none of the previous studies specifically reported the 90-day mortality, so we were unable to compare the 90-day mortality rates directly. We propose that both the 30-day and 90-day mortality rates should be reported to better reflect the surgical mortality in the future studies. Age 65 years was found to be an independent risk factor associated with increased morbidity in the present study,
Table 4 Univariate and multivariate analysis of risk factors for disease-free and overall survival Factors Disease-free survival Overall survival Univariable analysis Multivariate analysis Univariable analysis Multivariate analysis 5-year DFS (%) P HR (95 % CI) P 5-year OS (%) P HR (95 % CI) P Age 0.045 * 0.027 * <65 54.5 51.2 65 34.5 35.1 Gender 0.135 0.377 Male 40.2 39.8 Female 60.7 41.4 BMI 0.327 0.280 18.5 25 40.2 39.5 <18.5 46.2 44.4 >25 58.8 58.5 Hypoproteinemia 0.014 * 0.001 * No 46.0 46.2 Yes 32.5 1.625 (1.076 2.452) 0.021 * 19.8 1.901 (1.271 2.843) 0.002 * Anemia 0.009 * 0.027 * No 53.8 49.7 Yes 32.0 42.0 ASA grade 0.401 0.115 I, II 44.0 43.6 III 29.7 22.2 Diabetes 0.463 0.510 No 43.2 42.3 Yes 41.2 41.2 Cardiopulmonary comorbidities 0.610 0.702 No 42.8 41.2 Yes 43.6 45.1 Previous abdominal surgery 0.966 0.875 No 42.8 41.2 Yes 43.5 45.8 Histologic type 0.044 0.021 * Differentiated a 50.3 54.3 Undifferentiated b 40.4 37.8 Tumor location 0.226 0.319 Not upper 38.6 37.6 Upper c 47.8 47.2 TNM stage 0.000 * 0.000 * I/II 61.1 60.0 III 30.8 3.291 (2.051 5.280) 0.000* 33.0 3.019 (1.897 4.803) 0.000* Lymphovascular invasion 0.011 * 0.004 * No 46.9 45.1 Yes 33.5 33.8 Any additional organ resection b 0.598 0.708 No 44.4 42.9 Yes 29.5 34.3 Values in parentheses are percentages unless indicated otherwise BMI body mass index, ASA American Society of Anesthesiologists, SD standard deviation, IQR interquartile range *Statistically significant (P < 0.05) a Undifferentiated carcinomas include poorly differentiated adenocarcinomas, signet ring cell carcinomas, and mucinous carcinomas b Differentiated carcinomas include well or moderately differentiated, tubular, or papillary adenocarcinomas c Tumor located in the upper of the stomach d Splenectomy and/or pancreatectomy
Table 5 Morbidity and survival by preoperative risk factors Frequency, n Morbidity rate, % 5-year survival rate, % Patient morbidity risk factors <0.001 0 8/78 10.3 1 23/114 20.2 2 15/37 40.5 Patient DFS risk factors <0.001 0 58 68.9 1 131 36.5 2 34 20.2 Patient OS risk factors <0.001 0 58 71.1 1 135 36.7 2 36 22.9 which is similar to the findings of the Dutch trial. 23 In general, elderly patients are more likely to have a functional diminution of their reserve capacity. Two previous studies have reported that elderly patients tended to experience more postoperative complications than younger patients due to their poorer physical function. 24, 25 In addition, another identified risk factor associated with morbidity in this study was cardiopulmonary comorbidities, which was also consistent with previous reports showing that cardiopulmonary comorbidities are one of the risk factors for the occurrence of complications after gastrectomy. 26 28 Therefore, careful patient selection for TG with D2 lymphadenectomy is warranted in elderly patients, particularly in those with cardiopulmonary comorbidities. Forpatientswithbothriskfactors(age 65 years and cardiopulmonary comorbidities), we further investigated whether changing to subtotal gastrectomy (STG) could decrease complication rate. Therefore, for the elderly patients with cardiopulmonary comorbidities, we compared the complication rate between those who underwent TG with D2 lymphadenectomy and those who underwent STG with D2 lymphadenectomy (data not shown). There were no significant differences in the postoperative complication rate between the patients who underwent STG and those who underwent TG. We speculate that these two factors are likely to be the risk factors for complications after STG as well. Considering the adverse nutritional consequences and poor quality of life of TG, 29, 30 we suggest that STG should still be recommended for elderly patients with cardiopulmonary comorbidities instead of TG, with the prerequisite of obtaining a negative margin. In the present study, the median DFS and OS were 35.7 and 41.1 months, respectively, with a 5-year DFS rate of 43.0 % and an OS rate of 43.2 %, while 5-year OS rates were reported ranging between 23.4 % and 35.6 % in Western studies 31 33 and were more than 60 % in Japan and Korea. 34 36 These differences in the prognosis after curative gastrectomy can P be attributed mainly to the tumor stage at the time of diagnosis. The diagnosis of gastric cancer in China and Western countries tends to be delayed, with patients being diagnosed at a more advanced TNM stage. In contrast, in Japan and Korea, early screening for gastric cancer using barium studies or upper endoscopy is recommended for individuals aged 40 years old and older, 37 leading to an earlier diagnosis of gastric cancer. Supporting this hypothesis, the proportion of TNM stage III was 68.6 % in this study and was 34.9 49.0 % in the above Western studies, 31 33 while it was 9.2 23.4 % in the above Japanese and Korean studies. 34 36 Considering the more advanced TNM stage in this study, we considered our 5- year survival rates to be satisfactory. Therefore, we have further proven the feasibility of TG with D2 lymphadenectomy in terms of long-term survivals. We also investigated the risk factors for long-term survival. As shown by the multivariate analysis, hypoproteinemia and TNM stage III were independent risk factors for the DFS and OS. Hypoproteinemic patients have a poor nutritional status with a reduced reserve capacity due to the cancer growth and the degeneration of their physical function. A previous study reported that the albumin level is significantly correlated with the 5-year overall and relapse-free survival rates after curative surgery for colon cancer. 38 Moreover, another study demonstrated that nutritional support can provide a survival benefit to gastric cancer patients with Nutritional Risk Screening (NRS) score 3. 39 Similar to previous studies, 40, 41 we also identified an advanced TNM stage as an independent prognostic factor for the long-term survival in this study. The TNM stage is a factor that has long been known to influence the long-term prognosis of almost all types of malignant diseases. For the malnourished patients (patients with hypoproteinemia), we further investigated whether changing to STG could improve the survival rates. Therefore, for the patients with hypoproteinemia, we compared the survival rates adjusted by TNM stage between those who underwent TG with D2 lymphadenectomy and those who underwent STG with D2 lymphadenectomy (data not shown). We found that the patients who underwent STG generally tend to have better DFS or OS than those who underwent TG. This could be attributed to the adverse nutritional consequences of TG. Therefore, we suggest that STG, with the prerequisite of obtaining a negative margin, should be adopted instead of TG to achieve a better longterm survival for the patients with hypoproteinemia. The identified preoperative risk factors for postoperative complications (age 65 years and cardiopulmonary comorbidities) were then used to risk-stratify patients. The complication rate rose from 10.3 % in those without either risk factor to 40.5 % in patients with both risk factors. Similarly, we also used the identified risk factors for the long-term survival (hypoproteinemia and TNM stage III) to risk-stratify patients. The 5-year survival rates
decreased from 68.9 % (DFS) and 71.1 % (OS) in those withouteitherriskfactorto20.2%(dfs)and22.9%(os) in patients with both risk factors. Thus, patients with multiple risk factors had significantly higher morbidity rates and lower long-term survival rates, which would contribute to the patient selection for this surgical procedure. Furthermore, based on the identified risk factors, several measures could be adopted to reduce the postoperative morbidity and improve the long-term survival of patients undergoing this surgery. Because cardiopulmonary comorbidity was identified as an independent risk factor for postoperative complications, preoperative evaluation of the cardiopulmonary function is necessary for each patient. For those who have a reduced cardiopulmonary function, preoperative optimization measures such as smoking cessation, preoperative physiotherapy, and preoperative pulmonary rehabilitation should be recommended to reduce the risk of postoperative pulmonary complications. 42 Second, as hypoproteinemia was independently associated with DFS and OS, preoperative enteral/parenteral nutrition should be administered to patients who have a poor nutritional status, 39 which might be helpful to prolong the long-term survival rates. Third, although the tumor stage is not a controllable factor, an intensive follow-up strategy may allow for the early detection and timely treatment of cancer recurrence, which may contribute to improvements in the long-term survivals. 43 There are several limitations associated with the present study. First, this study had a retrospective design and was conducted in a single center, which may limit the generalization of its conclusions. However, our department is one of the largest gastric cancer centers in China, so our data remain representative. Second, the sample size of this study was relatively small. Therefore, a large prospective and multicenter study is essential to overcome these limitations. Conclusion In summary, this study demonstrated that TG with D2 lymphadenectomy for gastric cancer is a feasible procedure with acceptable postoperative morbidity and mortality rates and long-term survival rates. Age 65 years and cardiopulmonary comorbidities were the independent risk factors for postoperative complications, whereas hypoproteinemia and TNM stage III were independently associated with a poorer DFS and OS. These risk factors were used to risk-stratify the patients undergoing TG with D2 lymphadenectomy. Patients with multiple risk factors had significantly higher complication rates and lower long-term survival rates, which would contribute to the patient selection and improvement of the quality of this surgical procedure. Compliance with Ethical Standards All participants provided their written informed consent, and the protocol for this study was approved by the ethics committee of The First Affiliated Hospital of Wenzhou Medical University. Conflict of Interest interests. References The authors declare that they have no competing 1. Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin. 2015; 65(2):87-108. 2. Bray F, Ren JS, Masuyer E, et al. Global estimates of cancer prevalence for 27 sites in the adult population in 2008. Int J Cancer. 2013; 132(5):1133-1145. 3. Kim JP. Current status of surgical treatment of gastric cancer. J Surg Oncol. 2002; 79(2):79-80. 4. Japanese Gastric Cancer Association. 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