Long-term survival outcomes of laparoscopyassisted gastrectomy with D2 lymph node dissection for gastric cancer at 103 Military Hospital

Although laparoscopy-assisted gastrectomy for gastric cancer has been applied in the world since 1991, it was not until 2007 that this technique was used widely at large medical centers in Vietnam. However, there have been no studies to evaluate the long-term survival of method so far. Subjects and methods: To study 165 gastric cancer patients undergoing laparoscopy-assisted gastrectomy with D2 lymph node dissection at 103 Military Hospital from April 2009 to August 2013. Surgical procedures according to instructions of Ministry of Health. Lymph node dissection and postoperative stage according to 3rd JGCA were diagnosed. Patients were followed at least 5 years after surgery, intra-and-postoperative complications, recurrence and metastases were recorded and managed.

Journal of military pharmaco-medicine n02-2019 LONG-TERM SURVIVAL OUTCOMES OF LAPAROSCOPYASSISTED GASTRECTOMY WITH D2 LYMPH NODE DISSECTION FOR GASTRIC CANCER AT 103 MILITARY HOSPITAL Ho Chi Thanh1; Hoang Manh An1; Dang Viet Dung1; Nguyen Van Xuyen1 Nguyen Trong Hoe1; Le Thanh Son1; Phan Hung Phuc2; Nguyen Van Tiep1 SUMMARY Background: Although laparoscopy-assisted gastrectomy for gastric cancer has been applied in the world since 1991, it was not until 2007 that this technique was used widely at large medical centers in Vietnam However, there have been no studies to evaluate the long-term survival of method so far Subjects and methods: To study 165 gastric cancer patients undergoing laparoscopy-assisted gastrectomy with D2 lymph node dissection at 103 Military Hospital from April 2009 to August 2013 Surgical procedures according to instructions of rd Ministry of Health Lymph node dissection and postoperative stage according to JGCA were diagnosed Patients were followed at least years after surgery, intra-and-postoperative complications, recurrence and metastases were recorded and managed Analysis and processing of data were performed by using SPSS software version 15.0 Results: Mean operative time was 205.7 ± 51.8 minutes, mean number of lymph nodes dissection per one patient was 21.5 ± 6.09 The incident in surgery was 1.81%, complications after surgery was 4.2%, postoperative mortality rate was 0.6%, cancer recurrence and metastasis was 44.8% Survival outcomes of postoperative five-year follow-up were 50.3%; with 93.3% in the stage Ia, 89.7% in the stage Ib; 61.7% in the stage IIa; 70.0% in the stage IIb; 25% in the stage IIIa; 7.7% in the stage IIIb and 0% in the stage IIIc Conclusions: Our study found that the long-term outcome of laparoscopy-assisted gastrectomy with D2 lymph node dissection for gastric cancer was promising and acceptable Survival outcomes after surgery depends on the stage and lymph node metastasis status * Keywords: Gastric cancer; Laparoscopy-assisted gastrectomy; D2 lymph node dissection; Long-term survival outcomes INTRODUCTION Gastric cancer is the most malignant disease in gastrointestinal cancer, according to Global Cancer Statistics in 2018, with mortality rate of 8.2%, which comes the second, just after lung cancer, common in both men and women [1] Radical gastrectomy with lymphadenectomy is the most effective treatment, increasing the survival rate 103 Military Hospital Vietnam Military Medical University Corresponding author: Ho Chi Thanh (hochithanh103@gmail.com) Date received: 20/11/2018 Date accepted: 14/01/2019 220 Journal of military pharmaco-medicine n02-2019 Laparoscopic gastrectomy for early gastric cancer was first performed by Kitano in 1991, so far many surgeons in the world have done this technique For advanced gastric cancer, gastrectomy with D2 lymph node dissection is considered standard surgery, however, with laparoscopy assisted, surgeons suspect the radicalization of the method [2, 3] In Vietnam, laparoscopyassisted gastrectomy (LAG) with D2 lymph node dissection for gastric cancer has been performed in big hospitals, but short follow-up time and there have been no studies of evaluating the long-term survival outcome Therefore, we studied this study: To evaluate long-term survival outcome of LAG with D2 lymph node dissection for gastric cancer - Patient was followed up after surgery with rd JGCA, follow-up time at least 60 months All cases of recurrence, metastases and causes of death were recorded and confirmed [5] * Handling of the resected specimen and description of histological findings: - The specimens are opened along the greater curvature, cleaned, fixed and examination of macroscopic type, location, size, invasion of tumor Measurement of tumor size along the margin of mucosal lesion, and the length of the proximal and distal resection margins were measured - After dissection of lymph nodes from the specimen, station to number according SUBJECTS AND METHODS Research subjects to 3rd JGCA, examples of macroscopic type, number of lymph nodes, and fixed 165 patients were diagnosed with gastric adenocarcinoma, who was LAG with D2 lymphadenectomy from April 2009 to October 2013, at Abdominal Surgery Department, 103 Military Hospital in 15 - 20% formalin solution, sent to - The procedure of LAG was uniform under the treatment guidelines of Ministry of Health issued in 2013 for laparoscopic gastrectomy with D2 lymphadenectomy [4] - Data were processed by the Kaplan- - The patients were the first people to undergo laparoscopic gastrectomy, afterwards, they conversed to open surgery Methods - Descriptive study, tracking down uncontrolled histopathology department - The results of postoperation stage according to 3rd JGCA [5] * Statistical analysis: Meier method using SPSS software, version 15.0 RESULTS Characteristics of patients - Mean age: 56.1 ± 11.38 (range, 26 - 81 years) - Male: 113 patients (68.5%); female: 52 patients (31.5%) 221 Journal of military pharmaco-medicine n02-2019 Pathological characteristics Surgical outcomes Table 2: Mean operative time: 205.7 ± 51.8 mins n % Upper 4.2 Middle 15 9.0 Lower 143 86.7 Tumor location Average lymph 21.5 ± 6.09 node dissection: Table 3: n % Type of gastrectomy Macroscopic type Polypoid 16 9.7 Distal gastrectomy 140 84.8 Ulcerated 79 47.9 Subtotal gastrectomy 11 6.7 Infiltrative ulcerated 63 38.2 Total gastrectomy 5.5 Infiltrative 4.2 Proximal gastrectomy 3.0 T1 21 12.7 3.03 T2 67 40.6 Bleeding 1.81 T3 63 38.2 Injured colon 1.21 T4a 14 8.4 Papillary 24 14.5 Respiratory failure 4.8 Tubular 38 23.0 Bronchopneumonia 0.6 Mucinous 13 7.8 Duodenal stump leak 0.6 Signet-ring cell 17 10.3 Poorly differentiated 72 43.6 Anastomosis leak 0.6 Residual abscess 1.2 Squamous cell 0.6 Wound infection 0.6 pN0 59 35.7 0.6 pN1 29 17.6 pN2 36 21.8 pN3 41 24.8 Ia 15 9.1 Ib 39 23.6 patients (4.2 %); hepatic lymph node: IIa 36 21.8 patients (3.6%); colon: patients (1.8%); IIb 20 12.1 lung: patients (1.2%); brain: patient IIIa 28 16.9 (0.6%); rectum: patient (0.6%); troiser: IIIb 26 15.8 patients (1.2%); ovary: patient (0.6%); IIIc 11 6.6 spine: patient (0.6%) T stage Histological type Incidents Complications Lymph node stage TNM stage 222 Mortality (because of respiratory failure) * Recurrence and metastasis (n = 74; 44.8%): Peritoneum: 50 patients (30.3%); liver: Journal of military pharmaco-medicine n02-2019 Table 4: Results of follow-up survival n % Survival rate 83 50.3% Disease-free alive 80 48.4% Disease alive 1.81% Mortality rate 77 46.7% Recurrenceinduced death 71 43.0% Non-recurrenceinduced death 3.63% Contact loss 3.03% Figure 1: Follow-up overall survival Overall 5-year survival rate was 50.3% Figure 2: Follow-up overall survival of sex Overall 5-year survival rates of male and female were 54.9% and 50.0%, test Log Rank χ2 = 0.389, p = 0.533 Figure 3: Follow-up overall survival of macroscopy Overall 5-year survival rates of polypoid, ulcerated, infiltrative ulcerated and infiltrative were 68.8%, 74.7%, 25.4% and 28.6%, test Log Rank χ2 = 49.220, p = 0.000 Figure 4: Follow up overall survival of T stage Overall 5-year survival rates of T1, T2, T3 and T4a were 90.5%, 70.1%, 33.3% and 7.1%, test Log Rank; χ2 = 56.538, p = 0.000 Figure 5: Overall survival rates of lymph node stage Overall 5-year survival rates of pN0, pN1, pN2 and pN3 were 86.4%, 72.4%, 38.9% 223 Journal of military pharmaco-medicine n02-2019 and 4.9%, test Log Rank χ2 = 148.978, p = 0.000 Overall 5-year survival rates of distal, subtotal, total and proximal gastrectomy were 54.3%, 36.4%, 44.4% and 80%, test Log Rank χ2 = 5.152, p = 0.161 DISCUSSION Patients’ characteristics Figure 6: Overall survival rates of TNM stage Overall 5-year survival rates of Ia, Ib, IIa, IIb, IIIa, IIIb and IIIc were 93.3%, 89.7%, 61.53%, 70.0%, 25.0%, 7.7% and 0.00%, test Log Rank χ2 = 148.978, p = 0.000 Figure 7: Overall survival rates of histological Overall 5-year survival rates of papillary, tubular, mucinous, signet-ring cell and poorly differentiated carcinoma were 87.5%, 63.2%, 53.8%, 47.1% and 38.9%, test Log Rank χ2 = 28.073, p = 0.000 Figure 8: Overall survival rates of type gastrectomy 224 The mean age was 56.1 ± 11.38 years, males occupied 68.5% and females accounted for 31.5% (table 1) These results were consistent with domestic and foreign studies, according to Global Cancer Statistics report in 2018, rates were 2-fold higher in men than in women [1, 6, 7] Tumor location with lower third was 86.7%, middle third was 9.09% and upper third was 4.24% (table 2) Pathological classifications were the most of ulcerated carcinomas (47.9%) and infiltrative ulcerated carcinomas were 38.2%, polypoid tumors was 9.7% and diffuse infiltrative carcinoma was 4.24% Depth of tumor invasion with T1, T2, T3 and T4a were 12.7%; 40.6%, 38.2% and 8.48% This result was consistent with the characteristics of gastric cancer in domestic studies: mostly in the lower third, macroscopic type was usually ulcerated and was advanced stages, surgery and prognosis was poor Park et al: T2, T3 and T4 were 25.7%; 58.7% and 15.6%; tumor location with upper, middle and lower third were 16.1%; 11.3% and 69.0%, respectively [6] Kim et al reported: tumor location with upper, middle and lower third were 5.8%; 23.8% and 70.0%; T1a, T1b, T2, T3 and T4 were 47.1%; 30.4%; 10.4%, 6.6% and 4.4%, respectively [7] Histological characteristics: Papillary, tubular, mucinous adenocarcinomas were Journal of military pharmaco-medicine n02-2019 14.5%; 23.0% and 7.87% Signet-ring cell and poorly differentiated adenocarcinoma were 10.3% and 43.6% One case of squamous cell carcinoma was 0.6% According to Kitano et al, tubular, signetring cell adenocarcinoma and others were 78.7%, 19.7% and 2.4%, respectively [2] Kim et al reported, signet-ring cell was 7.8% and poorly differentiated adenocarcinoma was 33.9% [7] Characteristics of lympho node metastasis: pN0, pN1, pN2 and pN3 were 35.7%, 17.6%, 21.8% and 24.8% Park et al [6]: pN0, pN1, pN2, pN3 were 44.0%, 16.5%, 13.5% and 25.7% Fang et al: pN0 was 43.7%, pN1 was 24.1%, pN2 was 19.5% and pN3 was 12.6% [8] Pathological stages according to 3rd JGCA: Ia and Ib were 9.09% and 23.6%; IIa and IIb were 21.8% and 12.1%; IIIa, IIIb and IIIc were 16.9%, 15.8% and 6.67% (table 2) This result was also consistent with our domestic research, the early gastric cancer was diagnosed in Vietnam is much lower than that in Japan and Korea Kitano et al showed that the rate of stage disease for Ia, Ib and II were 93.7%, 5.8% and 0.5%, respectively [2] Kim et al indicated the rate of stage I, II and III were 82.2%, 11.7% and 5.0% [7] Huscher C et al, the rate of stage Ia was 20.7%; Ib was 20.7%; II was 13.8%, IIIa was 17.2%; IIIb was 10.4% and IV was 17.2% [3] Operative results Mean operative time was 205.7 ± 51.8 minutes, average number of dessected lymph nodes was 21.5 (table 3), which could be acceptable compared with open surgery and other authors’ findings [2] The operative time in Huscher et al’s study was 196 ± 21 minutes, mean number of lymph nodes dissected was 30.0, which were 322.9 ± 116.6 minutes and 28.5 lymh nodes in Park et al’s stduy; 214.0 ± 52.6 minutes and 34.7 lymph nodes in Kim et al’s; 337 minutes and 32 lymph nodes in Fang et al’s; 240 ± 58.2 minutes and 35 lymph nodes in Honda et al’s [3, 6, 7, 8, 9] There were laparoscopy-assisted proximal gastrectomy (LAPG), 140 laparoscopyassisted distal gastrectomy (LADG), 11 laparoscopy-assisted subtotal gastrectomy (LASG) and laparoscopyassisted total gastrectomy (LATG) This result was consistent with Kitano et al’s: LADG was 91.5%, LAPG was 4.2% and LATG was 4.3% [2], Kim et al reported LADG was 90.5%, LAPG was 0.3% and LATG was 9.2% [7] The incidence in surgery was cases (3.03%), of which two patients suffered from bleeding by injury splenic artery during dissected 11p, to clip splenic artery to stop bleeding were not performed splenectomy There was one case of spleen injury This patient had to laparoscopic spelenectomy Two cases of injured transverse colon, we had to make colostomy Kitano et al, complications of intraoperative was 1.7% in LADG group, 7.4% in LAPG group and 1.8% LATG group [2] Postoperative complications: cases (4.8%), in which there were two cases with duodenal stump leak (1.2%), resurgery 225 Journal of military pharmaco-medicine n02-2019 to drainage duodenum, after that the patient was rather well and discharged from hospital There was one patient with anastomotic leak on 5th postoperative day (0.6%), who was performed subtotal gastrectomy with anemia anastomosis This patient had to undergo reoperation for total gastrectomy and was connected jejunum to oesophagus As a result, the patient recovered a little and discharged from hospital In the case of patient undergoing subtotal gastrectomy with lymphadenectomy and resection all of short gastric vessels, total gastrectomy should be performed and jejunum has to be connected to the oesophagus so that it is better nourished Residual abscess was found in two cases on 4th and 5th post-operative day (1.2%), treated conservatively, drained fluid under ultrasound, patients were stable and discharged after days Incision infection was observed in one case (0.6%), the patients were taken care and closed second incision and patient was fine and discharged Compared to open surgery and other authors’s findings, our postoperative complications were acceptable Kitano et al reported complication was 14.8% [2] In Huscher’s study, this rate was 23.3%, including acute pancreatitis, pleural effusion, bleeding and wound infection and conservative treatment, without reoperation [3] Kim et al conducted a study on 753 patients of LG, rate of complication was 10.2%, including six cases of duodenal stump leakage, anastomotic leak were cases, bleeding was encountered in one case and residual abscess was in one case [7] 226 Respiratory failure and death after surgery: case (0.6%) The patient was 74 years old, stage IIIb, pyloric stenosis, respiratory failure on day 6th after surgery Kim et al reported mortality after surgery was 0.1%; in Huscher et al’s study, there was one case of mortality after surgery due to respiratory failure (3.3%) [3, 7] * Recurrence and metastasis: Recurrence and metastasis after gastrectomy for gastric caner were common causes of mortality and decreasing survival In table 4, recurrence and metastasis occurred in 74 patients (44.8%), in which recurrent peritoneal was the highest rate of 30.3%, metastatic liver was 4.2%, liver metastatic lymph node to obstruction of the bide duct were cases (3.36%), metastatic colon: cases (1.8%), lung metastasis: cases (1.2%), metastatic troiser: cases (1.2%), metastatic brain: one case, metastatic Krukenber: one case, metastatic rectum: one case and metastatic spine: one case Of the 74 recurrences, there were cases of reoperation, 71 case were dead and cases were alive with cases of metastatic liver and one case of metastatic colon There were no port-site and no incision metastases were observed Park et al: recurrence was 50.7% in the open surgery group and 29.4% in the laparoscopic group, there was no differences between two groups In the recurrence group, metastatic peritonea was the highest (18.7%), metastatic an intra-abdominal organ was 17.3% and metastases liver was 16.0% [6] Honda et al, years after surgery found that peritoneal metastases was 0.76% and Journal of military pharmaco-medicine n02-2019 metastases liver was 0.87% [9] Chen et al, the mean follow-up was 39.7 months and found that 40 patients developed tumor recurrence, in which peritoneal recurrence was the highest (45.0%), 27.5% of distant recurrence, 17.5% of lymphatic recurrence and 10.0% of locoregional recurrence [10] Follow-up survival results Follow-up survival of after cancer surgery was very interesting, in table and figure 1, the shortest was 60 months, the longest was 111 months, the average survival rate were 53.9 ± 31.3 months cases were lost to follow-up assessment, giving a follow-up rate of 96.96% The 5-year overall survival and disease-free survival was 80 cases (50.3%) and 77 cases (48.4%) Death was found in 77 cases (46.7%) and 71 cases of death (43.0%) was due to recurrence and metastasis, cases of death due to other causes These results were consistent with Huscher et al’s study, followed up with 30 patients of LG, an average survival were 52.2 ± 26.5 months, a survival rate of 58.9% for years, recurrence rates were 37.9% and all died from recurrent disease [3] Kim et al, the average follow-up time were 56.2 months, after years’ surgery, overall survival rate was 97.1% and disease-free survival rate was 96.3%, the recurrence rate was 3.3% [7] Analysis of factors related to postoperation, we used Log Rank test In figure 2, 5-year survival rate in male was 54.9% and 50.0% in female, but the Log Rank χ2 = 0.389, p = 0.533, so the gender was not related to overall survival after surgery Follow-up survival of the macroscopic tip at figure 3, we found that the year overall survival of mass was 68.8% and that of ulcerative was 74.7%, higher than the infiltrative ulcerative and diffused infiltrative was 25.4% and 28.6%, significantly different with the Log Rank test χ2 = 49.22 and p = 0.000 The relative between invasive stages and survival after surgery, figure shows that 5-year survival rate of invasive stage T1, T2, T3 and T4a was 90.5%, 70.1%; 33.3% and 7.1%, significant difference with the Log Rank test χ2 = 56.538 and p = 0.000 Fang et al, year overall survival of LADG group was 59%, Chen et al, the 5years overall survival in T1, T2, T3 and T4a was 92.1%, 84.6%, 65.9%, and 40.7%, respectively [8, 10] Follow-up survival of the lymph node stages at figure The 5-year survival rate of the cases with non-lympho node metastasis (pN0) was 86.4%; the pN1 was 72.4%, the pN2 was 38.9% and pN3 was 4.9%, significant difference with Log Rank test χ2 = 148.978 and p = 0.000 In figure 6, the 5-year overall survival rate of stage Ia, Ib, IIa, IIb, IIIa, IIIb and IIIc was 93.3%; 89.7%, 61.53%, 70.0%, 25%, 7.7% and 0%, significantly different, with test Log Rank χ2 = 56.538 and p = 0.000 Our results were consistent with Kim et al’s: year overall survival of stage I, II and III was 99.5%, 89.5% and 76.1% [7] 227 Journal of military pharmaco-medicine n02-2019 Kitano et al reported the 5-year diseasefree survival rate was 99.8% for stage Ia, 98.7% for stage Ib and 85.7% for stage II [2] Park et al reported in LG group, 5-year overall survival rate of stage I, II and III was 87.5%, 77.3% and 34.8% [6] Honda studied LG for gastric cancer of stage I, the 5-year overall survival rate was 97.1% [9] Chen et al, according to tumor stage, 5-year overall survival was 93.1% for stage I, 67.6% for stage II and 41.5% for stage III [10] Follow-up survival of histopathology at figure 7, the 5-year overall survival of papillary, tubular, mucinous, signet-ring cell and poorly differentiated adenocarcinoma was 87.5%, 63.2%, 53.8%, 47.1% and 38.9%, respectively One patient with squamous cell carcinoma died after 11 months, significant difference with test Log Rank χ2 = 28.073 and p = 0.000 According to Japanese authors, the intestinal type has a better prognosis; diffused type, adenosquamous and squamous cell carcinoma have less prognosis than other cells, the survival rate of years is less than 10% [5] In figure 8, the 5-year survival rate of distant gastrectomy group was 54.3%, the rate of proximal gastrectomy was 80.0%, the rate of total and subtotal group was 44.4% and 36.4% The difference was not significant with Log Rank χ2 = 5.152 and p = 0.161 Although there was no difference, with total and subtotal gastrectomy, their tumor were not detected early, size of tumor were big, wide invasion so surgery and postoperative prognosis will be not good 228 CONCLUSIONS The study on 165 patients with gastric cancer were LAG with D2 lymph nodes dissection, we found that it was technically feasible, safe and a good long-term outcome The median survival was 53.9 ± 31.3 months, the 5-year overall survival was 50.3% The survival time was dependent on TNM stage, T-stage, lymph node metastatis stage, type of macroscopic and histological type with p < 0.01 Survival time was not dependent on gender and type of gastrectomy with p > 0.05 However, the limitation of the study was small and compared with open surgery, therefore, we really need a large-scale multicenter randomized trial to confirm the oncological safety and feasibility of LAG for patients with advanced gastric cancer REFERENCES Bray F, Ferlay J et al Global Cancer Statistics 2018: Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA Cancer J Clin 2018, pp.1-31 Kitano S, Shiraishi N, Uyama I et al A multicenter study on oncologic outcome of laparoscopic gastrectomy for early cancer in Japan Annals of Surgery 2007, 245 (1), pp.68-72 Huscher C, Mingoli A, Sgarzini G et al Laparoscopic versus open subtotal gastrectomy for distal gastric cancer, five-year results of a randomized prospective trial Annals of Surgery 2005, 241 (2), pp.232-237 Ministry of Health Laparoscopic distant gastrectomy with D2 lymphadenectomy for Journal of military pharmaco-medicine n02-2019 gastric cancer List of guiding medical examination and treatment procedures specialized in oncology, promulgated together with Decision No 3338/QĐ-BYT 2013, September, 9, pp.273-276 Japanese Gastric Cancer Association Japanese classification of gastric carcinoma: rd English edition Gastric Cancer 2011, 14, pp.101-112 Park J.H, Jeong S.H, Lee Y.J et al Comparison of long-term oncologic outcomes of laparoscopic gastrectomy and open gastrectomy for advanced gastric cancer: A retrospective cohort study Korean Journal of Clinical Oncology 2018, 12, pp.21-29 Kim K.H, Kim M.C, Jung G.J et al Long-term outcomes And Feasibility with laparoscopy-assisted gastrectomy for gastric cancer J Gastric Cancer 2012, 12 (1), pp.18-25 Fang C, Hua J, Li J et al Comparison of long-term results between laparoscopyassisted gastrectomy and open gastrectomy with D2 lymphadenectomy for advanced gastric cancer American Journal of Surgery 2014, 208, pp.391-396 Honda M, Hiki N, Kinoshita T et al Long-term outcomes of laparoscopic versus open surgery for clinical stage I gastric cancer: The LOC-1 Study Annals of Surgery 2016, 264 (2), pp.214-222 10 Chen K, Mou Y.P et al Short-term surgical and long-term survival outcomes after laparoscopic distal gastrectomy with D2 lymphadenectomy for gastric cancer Gastroenterology 2014, 14 (41), pp.1-7 229 ... of evaluating the long-term survival outcome Therefore, we studied this study: To evaluate long-term survival outcome of LAG with D2 lymph node dissection for gastric cancer - Patient was followed... Vietnam, laparoscopyassisted gastrectomy (LAG) with D2 lymph node dissection for gastric cancer has been performed in big hospitals, but short follow-up time and there have been no studies of evaluating... procedure of LAG was uniform under the treatment guidelines of Ministry of Health issued in 2013 for laparoscopic gastrectomy with D2 lymphadenectomy [4] - Data were processed by the Kaplan- - The patients