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Lymph Node Dissection in Curative Gastrectomy for Advanced Gastric Cancer

Lymph Node Dissection in Curative Gastrectomy for Advanced Gastric Cancer Hindawi Publishing Corporation International Journal of Surgical Oncology Volume 2011, Article ID 748745, 8 pages doi:10.1155/2011/748745 Review Article Lymph Node Dissection in Curative Gastrectomy for Advanced Gastric Cancer Shigeyuki Tamura, Atsushi Takeno, and Hirofumi Miki Department of Surgery, Kansai Rosai Hospital, 1-69 3-Chome, Inabasou, Amagasaki, Hyogo 660-8511, Japan Correspondence should be addressed to Shigeyuki Tamura, stamura@kanrou.net Received 15 January 2011; Accepted 29 March 2011 Academic Editor: Michael Hun ¨ erbein Copyright © 2011 Shigeyuki Tamura et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Gastric cancer is one of the most common causes of cancer-related death worldwide. Surgical resection with lymph node dissection is the only potentially curative therapy for gastric cancer. However, the appropriate extent of lymph node dissection accompanied by gastrectomy for cancer remains controversial. In East Asian countries, especially in Japan and Korea, D2 lymph node dissection has been regularly performed as a standard procedure. In Western countries, surgeons perform gastrectomy with D1 dissection only because D2 is associated with high mortality and morbidity compared to those associated with D1 alone but does not improve the 5-year survival rate. However, more recent studies have demonstrated that western surgeons can be trained to perform D2 lymphadenectomies on western patients with a lower morbidity and mortality. When extensive D2 lymph node dissection is preformed safely, there may be some benefit to D2 dissection even in western countries. In this paper, we present an update on the current literature regarding the extent of lymphadenectomy for advanced gastric cancer. 1. Introduction studies, including a high morbidity and mortality rate in the D2 group associated with inadequate surgical training, Gastric cancer is one of the most common causes of death with inadequate dissection of D2 and with the frequent worldwide [1]. Although the prognosis of patients with performance of distal pancreatectomy and splenectomy in advanced gastric cancer has improved with the introduction the D2 group, which is now considered unnecessary [7]. of effective chemotherapy [2] or adjuvant radiotherapy [3], More recent studies have demonstrated that western surgical resection remains the primary therapeutic modality surgeons at experienced centers can be trained to perform for curable advanced cancer. With regard to surgical pro- D2 gastrectomy for selected western patients with low cedure, dissection of regional LN is regarded an important morbidity and mortality [8–10]. There may be some benefits part of en bloc resection for gastric cancer. However, there to D2 gastrectomy when performed safely, but this assertion are significant differences in the extent of lymphadenectomy requires further validation to establish the global standard in preformed by surgeons in different countries. gastrectomy. In Japan, D2 dissection has been recommended as stan- In this paper, we describe an update on the current dard practice since the 1960s [4]. East Asian surgeons, espe- literature regarding the extent of lymphadenectomy for cially Japanese and Korean surgeons, routinely performed advanced gastric cancer. gastrectomy with D2 dissection. However, most Western surgeons perform gastrectomy with only D1 dissection, because D1 was associated with less mortality and morbidity 2. Grouping of Lymph Nodes than D2 in prospective randomized trials preformed in the Netherland and the UK concluded that there was no The lymph nodes of the stomach have been arranged into survival benefit for D2 over D1 lymph node dissection a very useful classification by the Japanese Gastric Cancer [5, 6]. However, there were significant problems with these Association (JGCA) [11, 12](Table 1, Figure 1). 2 International Journal of Surgical Oncology Table 1: Regional lymph nodes. Table 2: Depth of tumor invasion (T)—Japanese classification and TNN. No. 1 Right paracardial LN Japanese No. 2 Lest paracardial LN TNM JC (14th edi- Depth of tumor classification classification tion)/TNM No. 3a LN along the left gastric vessels invasion (T) (JC: 13th (6th edition) (7th edition) No. 3b LN along the right gastric vessels edition) No. 4sa LN along the short gastric vessels Mucosa and/or muscularis T1 (M) Tis/T1 Tis/T1a No. 4sb LN along the left gastroepiploic vessels mucosa (M) No. 4d LN along the right gastroepiploic vessels Submucosa No. 5 Suprapyloric LN T1 (SM) T1 T1b (SM) No. 6 Infrapyloric LN Muscularis T2 (MP) T2a T2 No. 7 LN along the left gastric artery propria (MP) LN along the common hepatic artery (anterosuperior Subserosa (SS) T2 (SS) T2b T3 No. 8a group) Penetration of T3 T3 T4a No. 8b LN along the common hepatic artery (posterior group) serosa (SE) No. 9 LN along the celiac artery Invasion of adjacent T4 T4 T4b No. 10 LN at the splenic hilum structures (SI) No. 11p LN along the proximal splenic artery No. 11d LN along the distal splenic artery LN in the hepatoduodenal ligament (along the hepatic Table 3: Extent of lymph node metastasis (N)—Japanese classifica- No. 12a artery) tion and TNN classification. LN in the hepatoduodenal ligament (along the bile Japanese No. 12b TNM JC (14th duct) N classification classification edition)/TNM LN in the hepatoduodenal ligament (behind the portal category (JC: 13th No. 12p (6th edition) (7th edition) vain) edition) No. 13 LN on the posterior surface of the pancreatic head No evidence of No evidence of No evidence of No. 14v LN along the superior mesenteric vein LN metastasis LN metastasis LN metastasis Metastasis to Metastasis in 1 Metastasis in 1 No. 14a LN along the superior mesenteric artery N only Group 1 to 6 regional to 2 regional No. 15 LN along the middle colic vessels LN LNs LNs No. 16a1 LN in the aortic hiatus Metastasis to LN around the abdominal aorta (from the upper Group 2 LN, but N 7–15 nodes 3–6 nodes No. 16a2 margin of the celiac trunk to the lower margin of the no metastasis to left renal vein) Group 3 LN LN around the abdominal aorta (from the lower 7 or more nodes No. 16b1 margin of the left renal vein to the upper margin of the Metastasis to 16 or more N3a: 7–15 nodes inferior mesenteric artery) 3 Group 3 LN nodes N3b: 16 or more LN around the abdominal aorta (from the upper nodes No. 16b2 margin of the inferior mesenteric artery to the aortic LN: lymph node. bifurcation) No. 17 LN on the anterior surface of the pancreas head No. 18 LN along the inferior margin on the pancreas system, the most perigastric LNs (stations nos. 1–6) are No. 19 Infradiaphragmatic LN defined as group 1, whereas the nodes along the left gastric No. 20 LN in the esophageal hiatus of the diaphragm artery (station no. 7), common hepatic artery (station no. No. 110 Paraesophageal LN in the lower thorax 8), celiac axis (station no. 9), splenic artery (station no. 11) and proper hepatic artery (station no. 12) are defined as No. 111 Supradiaphragmatic LN group 2. Minor modifications of this grouping system are No. 112 Posterior mediastinal LN necessary according to the location of the primary tumor. D1 gastrectomy is defined as dissection of all the Group 1 nodes, andD2is definedasdissection of all theGroup 1and Group According to this classification, lymph nodes surround- 2nodes. ing stomach are divided into 20 stations and these are Recently, new Japanese Classification of Gastric Carci- classified into three groups depending upon the location noma [12] and guideline for Diagnosis and Treatment of of the primary tumor. This grouping system is based on Carcinoma of the Stomach [14] edited by the Japanese the results of studies of lymphatic flow at various tumor Gastric Cancer Society were published in May and October, sites, together with the observed survival associated with 2010 to match to the standard of TNM classification of UICC metastasis to each nodal station [13]. In this grouping [15, 16](Tables 2 and 3). International Journal of Surgical Oncology 3 APIS AGB AGP 4sa 11d AGB 12a 10 12p 12b 3a 11p 9 8a 8p 4sb AGES 4sb 13 VL 3b 4sb VMS VGED 14a TGC 14v 4d VPDSA AJ VGED VCDA ACM 4d AJ, VJ VCM VCD ACD VCDA VCM VCD (a) (b) Figure 1: Lymph node station numbers according to the Japanese classification of gastric cancer of the 14th edition reproduced form [12] with permission. In this classification, the extent of LN metastasis is dissection is not recommended because D2 is associated with divided into three groups according to the number of high morbidity and mortality rate. metastatic LN, not to the N-number of the extent of LN Two large-scale RCTs wereperformed by the Dutch metastasis. Gastric Cancer Group [5, 17–19] and Medical Research Council Gastric Cancer Surgical Group [6, 20](Table 4). Moreover in this guideline, the main modification about The RCT by the Dutch group was performed between 1989 lymph node dissection is that selection of D1 or D2 and 1993 and involved 711 patients from 80 hospitals but dissection is prescribed by the kind of gastrectomy, for excluded 285 patients who had received palliative treatment example, total gastrectomy or distal gastrectomy, not by [5]. The RCT by the British group was performed between the location of the primary tumor. It is provided that D1 1987 and 1994 and involved 400 patients but excluded gastrectomy includes the dissection of the nodes along the 337 patients based on staging laparoscopy demonstrating left gastric (station no. 7) as well as the perigastric lymph advanced disease [6]. nodes (stations nos. 1–6), regardless of the location of tumor. The stage distribution in the Dutch RCT was slightly less LNs along the superior mesenteric vein (station no. 14v) are advanced than that in the British study; UICC stage I tumors eliminated from D2 dissection for tumor in the lower third comprised 43% and 35% of the total, respectively, and T3 of the stomach. tumors comprised 44 and 27%. In other words, D1 distal gastrectomy consists of LN In the Dutch trial, D2 patients demonstrated higher dissection of station nos. 1, 3, 4sb, 4d, 5, 6, and 7 and D1 postoperative morbidity (43% versus 25% for D1: P< .001) total gastrectomy includes station nos. 1–6 and 7 (Figure 2). and higher morbidity (10% versus 4% for D1: P< .004). In Japan, although the surgical procedure is performed Overall 5-year survival rates were similar in the D1 and D2 according to the new guidelines, standard surgery for cN1 groups (45% for D1 and 47% for D2). or T2 and more cases is defined as gastrectomy with D2 The hazard ratio (HR) comparing the risk of death dissection. within 5 years after D2 surgery to that of 5 years after D1 surgery was 1.00 (95% confidence interval (95% CI), 0.82– 1.22) [5]. However, at 11 years, survival rates were 30% for 3. D1 versus D2 D1 and 35% for D2 (P = .53). When hospital deaths were excluded, survival rates were 32% for D1 (n = 365) and In Japan, D2 dissection was introduced in the 1960’s and 39% for D2 (n = 299) and the relative risks of these patients gastrectomy with D2 dissection has been regarded as a favored the D2 surgery group (P = .07) [17]. safe surgical procedure and performed regularly in ordinary Low-quality surgery due to a very low hospital volume general hospitals [4]. Therefore, in Japan, a clinical trial could explain why D2 surgery was not beneficial, along comparing D1 versus D2 would be considered unethical with high hospital mortality in that series. About 50% of today. the patients in the D2 group did not undergo lymph node dissection at all stations that should have been resected. However, whether D2 LN dissection in radical gastrec- However, 6% of the patients in the D1 group underwent tomy should be routinely performed is still unclear in the world. dissection of more stations that would not been resected in D1 surgery. These factors could have led to the limited Based on the results of several RCTs comparing D1 and D2/D3 dissection performed in western countries, D2 difference in outcomes, between D1 and D2 surgery [18]. 4 International Journal of Surgical Oncology Table 4: Randomized controlled trials comparing D1 with D2/D3. Postoperative Postoperative Study Country Comparison 5-year survival morbidity mortality 45% 25% 4% Dutch trial D1 (n = 380) 47% Netherlands 43% 10% (1989–1993) D2 (n = 331) HR 1.00 (P< .001) (P = .004) (95% CI, 0.82–1.22) 35% 28% 6.5% MRC trial D1 (n = 200) 33% UK 46% 13% (1987–1994) D2 (n = 200) HR 1.10 (P< .001) (P = .04) (95% CI, 0.87–1.39) 53.6% 7.3% Taiwanese trial D1 (n = 110) 0% 59.5% Taiwan 17.1% (1993–1999) D3 (n = 111) 0% HR 0.49 (P = .012) (95% CI, 0.32–0.77) 10.5% 0% IGCSG trial D1 (n = 76) Italy 16.3% 1.3% Under analysis (1999–2002) D2 (n = 86) (P< .029) (N.S) Recently, 15-year follow-up results of a randomized comparable to those reported after the standard Western nationwide Dutch D1D2 trial were reported. The overall gastrectomy and that the more extensive Japanese procedure 15-year survival was 21% (82 patients) for the D1 group with pancreas preservation can be regarded as a safe radical and 29% (92 patients) for the D2 group (P = .34). The treatment for gastric cancer in selected Western patients gastric-cancer related death rate was significantly higher in treated at experienced centers. the D1 group (48%, 182 patients) compared with that in the A small-scale RCT comparing of the morbidity and D2 group (37%, 123 patients), whereas death due to other mortality of D1 to D2 gastrectomy was performed by IGCSG diseases was similar in both groups [19]. [10]. The authors indicated in the interpretation that because a Of 162 patients randomized, 76 were allocated to D1 safer, spleen-preserving D2 resection technique had become and 86 to D2 gastrectomy. The overall postoperative mor- available in high-volume centers, D2 lymphadenectomy bidity rate was 13.6%. Complications developed in 10.5% should be the recommended surgical approach for patients of patients after D1 and in 16.3% of patients after D2 with resectable (curable) gastric cancer. gastrectomy. This difference was not statistically significant In the British study, postoperative complications were (P< .29). The overall postoperative mortality rate was significantly higher in the D2 group (46%) than in the D1 0.6% (one death); it was 1.3% after D1 and 0% after D2 group (28%; P< .001), and the postoperative mortality was gastrectomy. This study confirmed that, at very experienced also significantly higher in the D2 group (13%) than in the centers, morbidity and mortality after extended gastrectomy D1 group (6.5%; P = .04) [6]. could beaslow as thoseafter D1 gastrectomy. In this study, splenectomy was performed for many Another single-institutional small-scale RCT has patients with distal gastrectomy and pancreaticosplenectomy reported from Taiwan that there were no significant was carried out in 56% of patients allocated to the D2 differences in the postoperative and mortality between group and 4% of the D1 group. The high frequency of patients undergoing D3 and D1 gastrectomy [21, 22]. This postoperative complications was influenced by the excessive was the only trial that showed a significantly higher 5-year surgery, which contributed to a misunderstanding of the disease-specific survival in patients with D3 surgery than in definition of D2 gastrectomy defined by the Japanese Gastric those with D1 surgery (Table 4). Cancer Association. The 5-year survival rate was 33% in Therefore, D2 gastrectomy is becoming accepted as a the D1 group and 35% in the D2 group, which did not safe treatment for gastric cancer at experienced centers, in significantly differ between the two groups [20]. western countries. Unlike these two large European trials, the Italian Gastric Cancer Study Group (IGCSG) has shown the safety of D2 dissection with pancreas preservation in a one-arm phase 4. D2 versus D3 I-II trial [9]. Between 1994 and 1996, 191 eligible patients were entered in the study. The overall morbidity rate was In Japan, gastrectomy with more radical extended lym- 20.9%. Surgical complications were observed in 16.7% of phadenectomy had been performed since 1980’s at many patients and reoperation was necessary in six patients and specialized centers in order to improve the prognosis of was successful in all cases. The overall hospital mortality rate patients with advanced gastric cancer [23–26]. The incidence was 3.1%; it was higher after total gastrectomy (7.46%) than of microscopic metastasis in the paraaortic nodes (section after distal gastrectomy (0.8%). This study concluded that no. 16) in patients with gastrectomy undergoing D3 lymph postoperative morbidity and mortality rates were favorably node dissection ranged from 6% to 33%, and the 5-year International Journal of Surgical Oncology 5 Table 5: Randomized controlled trials comparing D2 with D2 plus para-aortic lymph nodes. Postoperative Postoperative Study Country Comparison 5-year survival morbidity mortality 69.2% D2 (n = 263) 20.9% 0.8% JCOG trial 70.3% Japan D2+ PALN 28.1% 0.8% (1995–2001) HR 1.03 (n = 260) (P = .067) (P = .99) (95% CI, 0.77–1.37) D2 (n = 141) 27.7% 4.9% Polish trial Poland D2+ PALN 21.6% 2.2% Under analysis (1999–2003) (n = 134) (P = .248) (P = .37) Japan, Korea, D2 (n = 135) 26% 0.7% 52.6% East Asian trial and Chinese D2+ PALN 39% 3.7% 55.4% (1995–2002) Taiwan area (n = 134) (P = .023) (P = .107) (P = .801) D2: gastrectomy with D2 lymph node dissection. PALN: para-aortic lymph node dissection. survival rate had been reported to range from 12% to 23% in the lower esophagus and the periesophageal lymph nodes patients undergoing gastrectomy with D3 dissection. Extend- and to confirm that the esophageal cut end is negative by ing these previous findings regarding the favorable results performing histological examination using frozen section as of D3 dissection, the Japanese Clinical Oncology Group necessary [33]. Conventionally, this mediastinal procedure (JCOG) conducted a randomized clinical trial between 1995 was done through the left thoracoabdominal approach and 2001 to compare D2 gastrectomy alone with D2 plus (LTA), because the frequency of lymph node metastasis was paraaortic lymph node dissection (PAND) [27]. A total reported to be high with about 20–40% and an adequate of 523 patients with T2b, T3, and T4 gastric cancer were margin from the tumor could be secured. However, a registered and randomly assigned to D2 alone group (263 mediastinal procedure was enabled through the abdominal- patients) or D2 plus PAND group (260 patients). transhiatal approach (TH) with advances in surgical meth- ods using a circular stapler in recent years. The rates of surgery-related complications among patients assigned to D2 lymphadenectomy alone and those In Japan, an RCT comparing LTA versus TH for Siewert assigned to D2 lymphadenectomy plus PAND were 20.9% type II and III tumors with esophageal invasion of 3 cm and 28.1%, respectively (P = .07). There were no significant or less was carried out by JCOG [34]. Between 1995 and differences between the two groups in the frequencies of 2003, 167 patients were enrolled from 27 Japanese hospitals anastomotic leakage, pancreatic fistula, abdominal abscess, and randomly assigned to TH (n = 82) or LTA (n = 85), pneumonia, or death from any cause within 30 days after although the projected sample size was 302. After the first surgery (the mortality was 0.8% in each group). The 5-year interim analysis, the predicted probability of LTA having overall survival rate was 69.2% for the group assigned to D2 a significantly better overall survival than TH at the final lymphadenectomy alone and 70.3% for the group assigned to analysis was only 3.65%; therefore, the trial was closed. The D2 lymphadenectomy plus PAND; the hazard ratio for death 5-year overall survival was 52.3% in the TH group and was 1.03. Moreover, there were no significant differences in 37.9% in the LTA group. The hazard ratio of death for recurrence-free survival between the two groups. LTA compared with TH was 1.36 (0.89–2.08, P = .92). Recently, meta-analyses of D2 lymphadenectomy versus Three patients died in hospital after LTA but none after TH. D2 with PAND were reported [28]. Three RCTs including Morbidity after LTA was worse than that after TH with rates the PGCSG study in Poland [29], EASOG study in Japan, of 49% and 34%, respectively. Korea, and Chinese Taiwan area [30, 31], and JCOG- This study concluded that LTA could not be performed 9501 study in Japan [27]were eligible (Table 5). Another for gastric cancer with esophageal invasion of 3 cm or less, analysis included 4 RCTs and 4 nonrandomized studies were because LTA did not improve survival compared to TH and identified [32]. These meta-analyses showed that D2+ PAND resulted in increased morbidity. can be performed as safely as a standard D2 resection without increasing postoperative mortality but failed to benefit overall survival in patients with advanced gastric cancer. 6. Splenectomy or Pancreaticosplenectomy Gastrectomy with D2 lymphadenectomy plus PAND in the Treatment of Cancer of the Upper cannot be recommended as a routine practice for the surgical Third of the Stomach treatment of gastric cancer. In Japan, pancreaticosplenectomy for LN dissection around 5. Mediastinal Lymph Node Dissection for the splenic artery (station no. 11) and splenic hilus (station no. 10) had been widely performed, because this procedure Gastric Cancer was proposed as a radical dissection of metastatic LN along For patients with esophageal invasion from gastric cancer, the splenic artery [35, 36]. However, Japanese retrospective it is necessary to perform mediastinal resection included analyses proved that there was no survival benefit of these 6 International Journal of Surgical Oncology 4sb 4sb 4d 4d 4sa 6 6 3 3 1 1 5 5 7 7 9 9 10 11d 12a 8a 12a 8a 11p 11p (a) Distal gastrectomy (b) Total gastrectomy Figure 2: Lymph node dissection according to the Japanese gastric cancer treatment guideline 2010 of the 3rd edition reproduced form [14] with permission. D1 distal gastrectomy consists of LN dissection of station nos. 1, 3, 4sb, 4d, 5, 6, and 7 and D1 total gastrectomy consists of station nos. 1–6 and 7 (blue circle). Yellow circles indicate the lymph nodes that belong to D1+, and red circles indicate those to D2. procedures [37, 38]. Recently, pancreas-preserving splenec- Two RCTs compared gastrectomy with splenectomy and tomy has been considered a safe and effective procedure gastrectomy alone in patients with gastric cancer were without decreasing surgical curability [39, 40]. reported with regard to the effectiveness and safety [45, 46]. In the JCOG 9501 study, pancreas-preserving splenec- Csendes et al. reported 187 patients who underwent total tomy was generally performed with low surgical mortality gastrectomy between 1985 and 1992; these patients were [27, 41]. In this study, only 22 of 523 patients underwent randomized into two groups, gastrectomy with splenectomy pancreaticosplenectomy and 59% of patients (13 of 22 cases) and gastrectomy alone. Postoperative complications were developed postoperative complications. more frequent in the splenectomy group than in the surgery In this pancreas-preserving procedure, the splenic artery alone group, including postoperative fever over 38 C (50% is generally divided at the distal site after branching-off versus 39%: P< .04), pulmonary complications (39% versus of the great pancreatic artery in Sasako’s modification and 24%: P< .008), and subphrenic abscess (11% versus 4%: the splenic vein is preserved as distal as possible in order P< .05). There were no significant differences between the to prevent pancreatic fistula and pancreatic atrophy and groups in hospital mortality (4.4% for splenectomy versus consequent glucose intolerance [42]. 3.1% for gastrectomy alone) or in the 5-year survival rate In Western countries as well, pancreaticosplenectomy (42% for splenectomy versus 36% for gastrectomy alone) had a marked adverse effect on both mortality and morbidity [45]. in two RCTs [5, 6]. The other trial reported by Yu et al. was carried out in Currently, pancreaticosplenectomy is considered benefi- Korea between 1995 and 1999. Two hundred seven patients cial only when the primary tumor or metastatic LN directly with gastric cancer were divided randomly into two groups, invades the pancreas, but is not performed for prophylactic total gastrectomy (103 patients) and total gastrectomy plus dissection of lymph nodes around the splenic artery (station splenectomy (104 patients). Postoperative mortality was no. 11). 8.7% in total gastrectomy alone group and 15.4% in total According to the Japanese experience with LN dissection gastrectomy plus splenectomy group, but there was no at the splenic hilus with splenectomy, the incidence of hilar significant difference between the groups. Hospital mortality node metastasis ranged 15–21% for tumors located at or was 1.0% in total gastrectomy alone and 1.9% in total infiltrate to the proximal third of the stomach. About 20– gastrectomy plus splenectomy group; there was no significant 25% of patients with LN metastasis have survived over 5 years difference between the two groups. following LN dissection with splenectomy [35]. However, The 5-year survival rates did not differ statistically hilar nodal metastasis was reported to be not found in between the gastrectomy alone group (48.8%) and gastrec- the early gastric cancer base on retrospective data [43, 44]. tomy plus splenectomy group (54.8%). There was no 5-year Splenectomy is recommended for curative resection of the survivor among patients with lymph node metastasis at the proximal advanced gastric cancer with infiltration to the splenic hilum in either group [46]. greater curvature in the Gastric Cancer Treatment Guidelines Therefore, these results did not support the effectiveness 2010 [14]. of prophylactic dissection at the splenic hilum during International Journal of Surgical Oncology 7 splenectomy in patients undergoing total gastrectomy for [7] R. Biffi, A. Chiappa, F. Luca et al., “Extended lymph node dis- section without routine spleno-pancreatectomy for treatment proximal gastric cancer. of gastric cancer: low morbidity and mortality rates in a single center series of 250 patients,” Journal of Surgical Oncology,vol. 93, no. 5, pp. 394–400, 2006. 7. Future Perspectives [8] F. Roviello, D. Marrelli, P. 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Lymph Node Dissection in Curative Gastrectomy for Advanced Gastric Cancer

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Copyright © 2011 Shigeyuki Tamura et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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10.1155/2011/748745
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Hindawi Publishing Corporation International Journal of Surgical Oncology Volume 2011, Article ID 748745, 8 pages doi:10.1155/2011/748745 Review Article Lymph Node Dissection in Curative Gastrectomy for Advanced Gastric Cancer Shigeyuki Tamura, Atsushi Takeno, and Hirofumi Miki Department of Surgery, Kansai Rosai Hospital, 1-69 3-Chome, Inabasou, Amagasaki, Hyogo 660-8511, Japan Correspondence should be addressed to Shigeyuki Tamura, stamura@kanrou.net Received 15 January 2011; Accepted 29 March 2011 Academic Editor: Michael Hun ¨ erbein Copyright © 2011 Shigeyuki Tamura et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Gastric cancer is one of the most common causes of cancer-related death worldwide. Surgical resection with lymph node dissection is the only potentially curative therapy for gastric cancer. However, the appropriate extent of lymph node dissection accompanied by gastrectomy for cancer remains controversial. In East Asian countries, especially in Japan and Korea, D2 lymph node dissection has been regularly performed as a standard procedure. In Western countries, surgeons perform gastrectomy with D1 dissection only because D2 is associated with high mortality and morbidity compared to those associated with D1 alone but does not improve the 5-year survival rate. However, more recent studies have demonstrated that western surgeons can be trained to perform D2 lymphadenectomies on western patients with a lower morbidity and mortality. When extensive D2 lymph node dissection is preformed safely, there may be some benefit to D2 dissection even in western countries. In this paper, we present an update on the current literature regarding the extent of lymphadenectomy for advanced gastric cancer. 1. Introduction studies, including a high morbidity and mortality rate in the D2 group associated with inadequate surgical training, Gastric cancer is one of the most common causes of death with inadequate dissection of D2 and with the frequent worldwide [1]. Although the prognosis of patients with performance of distal pancreatectomy and splenectomy in advanced gastric cancer has improved with the introduction the D2 group, which is now considered unnecessary [7]. of effective chemotherapy [2] or adjuvant radiotherapy [3], More recent studies have demonstrated that western surgical resection remains the primary therapeutic modality surgeons at experienced centers can be trained to perform for curable advanced cancer. With regard to surgical pro- D2 gastrectomy for selected western patients with low cedure, dissection of regional LN is regarded an important morbidity and mortality [8–10]. There may be some benefits part of en bloc resection for gastric cancer. However, there to D2 gastrectomy when performed safely, but this assertion are significant differences in the extent of lymphadenectomy requires further validation to establish the global standard in preformed by surgeons in different countries. gastrectomy. In Japan, D2 dissection has been recommended as stan- In this paper, we describe an update on the current dard practice since the 1960s [4]. East Asian surgeons, espe- literature regarding the extent of lymphadenectomy for cially Japanese and Korean surgeons, routinely performed advanced gastric cancer. gastrectomy with D2 dissection. However, most Western surgeons perform gastrectomy with only D1 dissection, because D1 was associated with less mortality and morbidity 2. Grouping of Lymph Nodes than D2 in prospective randomized trials preformed in the Netherland and the UK concluded that there was no The lymph nodes of the stomach have been arranged into survival benefit for D2 over D1 lymph node dissection a very useful classification by the Japanese Gastric Cancer [5, 6]. However, there were significant problems with these Association (JGCA) [11, 12](Table 1, Figure 1). 2 International Journal of Surgical Oncology Table 1: Regional lymph nodes. Table 2: Depth of tumor invasion (T)—Japanese classification and TNN. No. 1 Right paracardial LN Japanese No. 2 Lest paracardial LN TNM JC (14th edi- Depth of tumor classification classification tion)/TNM No. 3a LN along the left gastric vessels invasion (T) (JC: 13th (6th edition) (7th edition) No. 3b LN along the right gastric vessels edition) No. 4sa LN along the short gastric vessels Mucosa and/or muscularis T1 (M) Tis/T1 Tis/T1a No. 4sb LN along the left gastroepiploic vessels mucosa (M) No. 4d LN along the right gastroepiploic vessels Submucosa No. 5 Suprapyloric LN T1 (SM) T1 T1b (SM) No. 6 Infrapyloric LN Muscularis T2 (MP) T2a T2 No. 7 LN along the left gastric artery propria (MP) LN along the common hepatic artery (anterosuperior Subserosa (SS) T2 (SS) T2b T3 No. 8a group) Penetration of T3 T3 T4a No. 8b LN along the common hepatic artery (posterior group) serosa (SE) No. 9 LN along the celiac artery Invasion of adjacent T4 T4 T4b No. 10 LN at the splenic hilum structures (SI) No. 11p LN along the proximal splenic artery No. 11d LN along the distal splenic artery LN in the hepatoduodenal ligament (along the hepatic Table 3: Extent of lymph node metastasis (N)—Japanese classifica- No. 12a artery) tion and TNN classification. LN in the hepatoduodenal ligament (along the bile Japanese No. 12b TNM JC (14th duct) N classification classification edition)/TNM LN in the hepatoduodenal ligament (behind the portal category (JC: 13th No. 12p (6th edition) (7th edition) vain) edition) No. 13 LN on the posterior surface of the pancreatic head No evidence of No evidence of No evidence of No. 14v LN along the superior mesenteric vein LN metastasis LN metastasis LN metastasis Metastasis to Metastasis in 1 Metastasis in 1 No. 14a LN along the superior mesenteric artery N only Group 1 to 6 regional to 2 regional No. 15 LN along the middle colic vessels LN LNs LNs No. 16a1 LN in the aortic hiatus Metastasis to LN around the abdominal aorta (from the upper Group 2 LN, but N 7–15 nodes 3–6 nodes No. 16a2 margin of the celiac trunk to the lower margin of the no metastasis to left renal vein) Group 3 LN LN around the abdominal aorta (from the lower 7 or more nodes No. 16b1 margin of the left renal vein to the upper margin of the Metastasis to 16 or more N3a: 7–15 nodes inferior mesenteric artery) 3 Group 3 LN nodes N3b: 16 or more LN around the abdominal aorta (from the upper nodes No. 16b2 margin of the inferior mesenteric artery to the aortic LN: lymph node. bifurcation) No. 17 LN on the anterior surface of the pancreas head No. 18 LN along the inferior margin on the pancreas system, the most perigastric LNs (stations nos. 1–6) are No. 19 Infradiaphragmatic LN defined as group 1, whereas the nodes along the left gastric No. 20 LN in the esophageal hiatus of the diaphragm artery (station no. 7), common hepatic artery (station no. No. 110 Paraesophageal LN in the lower thorax 8), celiac axis (station no. 9), splenic artery (station no. 11) and proper hepatic artery (station no. 12) are defined as No. 111 Supradiaphragmatic LN group 2. Minor modifications of this grouping system are No. 112 Posterior mediastinal LN necessary according to the location of the primary tumor. D1 gastrectomy is defined as dissection of all the Group 1 nodes, andD2is definedasdissection of all theGroup 1and Group According to this classification, lymph nodes surround- 2nodes. ing stomach are divided into 20 stations and these are Recently, new Japanese Classification of Gastric Carci- classified into three groups depending upon the location noma [12] and guideline for Diagnosis and Treatment of of the primary tumor. This grouping system is based on Carcinoma of the Stomach [14] edited by the Japanese the results of studies of lymphatic flow at various tumor Gastric Cancer Society were published in May and October, sites, together with the observed survival associated with 2010 to match to the standard of TNM classification of UICC metastasis to each nodal station [13]. In this grouping [15, 16](Tables 2 and 3). International Journal of Surgical Oncology 3 APIS AGB AGP 4sa 11d AGB 12a 10 12p 12b 3a 11p 9 8a 8p 4sb AGES 4sb 13 VL 3b 4sb VMS VGED 14a TGC 14v 4d VPDSA AJ VGED VCDA ACM 4d AJ, VJ VCM VCD ACD VCDA VCM VCD (a) (b) Figure 1: Lymph node station numbers according to the Japanese classification of gastric cancer of the 14th edition reproduced form [12] with permission. In this classification, the extent of LN metastasis is dissection is not recommended because D2 is associated with divided into three groups according to the number of high morbidity and mortality rate. metastatic LN, not to the N-number of the extent of LN Two large-scale RCTs wereperformed by the Dutch metastasis. Gastric Cancer Group [5, 17–19] and Medical Research Council Gastric Cancer Surgical Group [6, 20](Table 4). Moreover in this guideline, the main modification about The RCT by the Dutch group was performed between 1989 lymph node dissection is that selection of D1 or D2 and 1993 and involved 711 patients from 80 hospitals but dissection is prescribed by the kind of gastrectomy, for excluded 285 patients who had received palliative treatment example, total gastrectomy or distal gastrectomy, not by [5]. The RCT by the British group was performed between the location of the primary tumor. It is provided that D1 1987 and 1994 and involved 400 patients but excluded gastrectomy includes the dissection of the nodes along the 337 patients based on staging laparoscopy demonstrating left gastric (station no. 7) as well as the perigastric lymph advanced disease [6]. nodes (stations nos. 1–6), regardless of the location of tumor. The stage distribution in the Dutch RCT was slightly less LNs along the superior mesenteric vein (station no. 14v) are advanced than that in the British study; UICC stage I tumors eliminated from D2 dissection for tumor in the lower third comprised 43% and 35% of the total, respectively, and T3 of the stomach. tumors comprised 44 and 27%. In other words, D1 distal gastrectomy consists of LN In the Dutch trial, D2 patients demonstrated higher dissection of station nos. 1, 3, 4sb, 4d, 5, 6, and 7 and D1 postoperative morbidity (43% versus 25% for D1: P< .001) total gastrectomy includes station nos. 1–6 and 7 (Figure 2). and higher morbidity (10% versus 4% for D1: P< .004). In Japan, although the surgical procedure is performed Overall 5-year survival rates were similar in the D1 and D2 according to the new guidelines, standard surgery for cN1 groups (45% for D1 and 47% for D2). or T2 and more cases is defined as gastrectomy with D2 The hazard ratio (HR) comparing the risk of death dissection. within 5 years after D2 surgery to that of 5 years after D1 surgery was 1.00 (95% confidence interval (95% CI), 0.82– 1.22) [5]. However, at 11 years, survival rates were 30% for 3. D1 versus D2 D1 and 35% for D2 (P = .53). When hospital deaths were excluded, survival rates were 32% for D1 (n = 365) and In Japan, D2 dissection was introduced in the 1960’s and 39% for D2 (n = 299) and the relative risks of these patients gastrectomy with D2 dissection has been regarded as a favored the D2 surgery group (P = .07) [17]. safe surgical procedure and performed regularly in ordinary Low-quality surgery due to a very low hospital volume general hospitals [4]. Therefore, in Japan, a clinical trial could explain why D2 surgery was not beneficial, along comparing D1 versus D2 would be considered unethical with high hospital mortality in that series. About 50% of today. the patients in the D2 group did not undergo lymph node dissection at all stations that should have been resected. However, whether D2 LN dissection in radical gastrec- However, 6% of the patients in the D1 group underwent tomy should be routinely performed is still unclear in the world. dissection of more stations that would not been resected in D1 surgery. These factors could have led to the limited Based on the results of several RCTs comparing D1 and D2/D3 dissection performed in western countries, D2 difference in outcomes, between D1 and D2 surgery [18]. 4 International Journal of Surgical Oncology Table 4: Randomized controlled trials comparing D1 with D2/D3. Postoperative Postoperative Study Country Comparison 5-year survival morbidity mortality 45% 25% 4% Dutch trial D1 (n = 380) 47% Netherlands 43% 10% (1989–1993) D2 (n = 331) HR 1.00 (P< .001) (P = .004) (95% CI, 0.82–1.22) 35% 28% 6.5% MRC trial D1 (n = 200) 33% UK 46% 13% (1987–1994) D2 (n = 200) HR 1.10 (P< .001) (P = .04) (95% CI, 0.87–1.39) 53.6% 7.3% Taiwanese trial D1 (n = 110) 0% 59.5% Taiwan 17.1% (1993–1999) D3 (n = 111) 0% HR 0.49 (P = .012) (95% CI, 0.32–0.77) 10.5% 0% IGCSG trial D1 (n = 76) Italy 16.3% 1.3% Under analysis (1999–2002) D2 (n = 86) (P< .029) (N.S) Recently, 15-year follow-up results of a randomized comparable to those reported after the standard Western nationwide Dutch D1D2 trial were reported. The overall gastrectomy and that the more extensive Japanese procedure 15-year survival was 21% (82 patients) for the D1 group with pancreas preservation can be regarded as a safe radical and 29% (92 patients) for the D2 group (P = .34). The treatment for gastric cancer in selected Western patients gastric-cancer related death rate was significantly higher in treated at experienced centers. the D1 group (48%, 182 patients) compared with that in the A small-scale RCT comparing of the morbidity and D2 group (37%, 123 patients), whereas death due to other mortality of D1 to D2 gastrectomy was performed by IGCSG diseases was similar in both groups [19]. [10]. The authors indicated in the interpretation that because a Of 162 patients randomized, 76 were allocated to D1 safer, spleen-preserving D2 resection technique had become and 86 to D2 gastrectomy. The overall postoperative mor- available in high-volume centers, D2 lymphadenectomy bidity rate was 13.6%. Complications developed in 10.5% should be the recommended surgical approach for patients of patients after D1 and in 16.3% of patients after D2 with resectable (curable) gastric cancer. gastrectomy. This difference was not statistically significant In the British study, postoperative complications were (P< .29). The overall postoperative mortality rate was significantly higher in the D2 group (46%) than in the D1 0.6% (one death); it was 1.3% after D1 and 0% after D2 group (28%; P< .001), and the postoperative mortality was gastrectomy. This study confirmed that, at very experienced also significantly higher in the D2 group (13%) than in the centers, morbidity and mortality after extended gastrectomy D1 group (6.5%; P = .04) [6]. could beaslow as thoseafter D1 gastrectomy. In this study, splenectomy was performed for many Another single-institutional small-scale RCT has patients with distal gastrectomy and pancreaticosplenectomy reported from Taiwan that there were no significant was carried out in 56% of patients allocated to the D2 differences in the postoperative and mortality between group and 4% of the D1 group. The high frequency of patients undergoing D3 and D1 gastrectomy [21, 22]. This postoperative complications was influenced by the excessive was the only trial that showed a significantly higher 5-year surgery, which contributed to a misunderstanding of the disease-specific survival in patients with D3 surgery than in definition of D2 gastrectomy defined by the Japanese Gastric those with D1 surgery (Table 4). Cancer Association. The 5-year survival rate was 33% in Therefore, D2 gastrectomy is becoming accepted as a the D1 group and 35% in the D2 group, which did not safe treatment for gastric cancer at experienced centers, in significantly differ between the two groups [20]. western countries. Unlike these two large European trials, the Italian Gastric Cancer Study Group (IGCSG) has shown the safety of D2 dissection with pancreas preservation in a one-arm phase 4. D2 versus D3 I-II trial [9]. Between 1994 and 1996, 191 eligible patients were entered in the study. The overall morbidity rate was In Japan, gastrectomy with more radical extended lym- 20.9%. Surgical complications were observed in 16.7% of phadenectomy had been performed since 1980’s at many patients and reoperation was necessary in six patients and specialized centers in order to improve the prognosis of was successful in all cases. The overall hospital mortality rate patients with advanced gastric cancer [23–26]. The incidence was 3.1%; it was higher after total gastrectomy (7.46%) than of microscopic metastasis in the paraaortic nodes (section after distal gastrectomy (0.8%). This study concluded that no. 16) in patients with gastrectomy undergoing D3 lymph postoperative morbidity and mortality rates were favorably node dissection ranged from 6% to 33%, and the 5-year International Journal of Surgical Oncology 5 Table 5: Randomized controlled trials comparing D2 with D2 plus para-aortic lymph nodes. Postoperative Postoperative Study Country Comparison 5-year survival morbidity mortality 69.2% D2 (n = 263) 20.9% 0.8% JCOG trial 70.3% Japan D2+ PALN 28.1% 0.8% (1995–2001) HR 1.03 (n = 260) (P = .067) (P = .99) (95% CI, 0.77–1.37) D2 (n = 141) 27.7% 4.9% Polish trial Poland D2+ PALN 21.6% 2.2% Under analysis (1999–2003) (n = 134) (P = .248) (P = .37) Japan, Korea, D2 (n = 135) 26% 0.7% 52.6% East Asian trial and Chinese D2+ PALN 39% 3.7% 55.4% (1995–2002) Taiwan area (n = 134) (P = .023) (P = .107) (P = .801) D2: gastrectomy with D2 lymph node dissection. PALN: para-aortic lymph node dissection. survival rate had been reported to range from 12% to 23% in the lower esophagus and the periesophageal lymph nodes patients undergoing gastrectomy with D3 dissection. Extend- and to confirm that the esophageal cut end is negative by ing these previous findings regarding the favorable results performing histological examination using frozen section as of D3 dissection, the Japanese Clinical Oncology Group necessary [33]. Conventionally, this mediastinal procedure (JCOG) conducted a randomized clinical trial between 1995 was done through the left thoracoabdominal approach and 2001 to compare D2 gastrectomy alone with D2 plus (LTA), because the frequency of lymph node metastasis was paraaortic lymph node dissection (PAND) [27]. A total reported to be high with about 20–40% and an adequate of 523 patients with T2b, T3, and T4 gastric cancer were margin from the tumor could be secured. However, a registered and randomly assigned to D2 alone group (263 mediastinal procedure was enabled through the abdominal- patients) or D2 plus PAND group (260 patients). transhiatal approach (TH) with advances in surgical meth- ods using a circular stapler in recent years. The rates of surgery-related complications among patients assigned to D2 lymphadenectomy alone and those In Japan, an RCT comparing LTA versus TH for Siewert assigned to D2 lymphadenectomy plus PAND were 20.9% type II and III tumors with esophageal invasion of 3 cm and 28.1%, respectively (P = .07). There were no significant or less was carried out by JCOG [34]. Between 1995 and differences between the two groups in the frequencies of 2003, 167 patients were enrolled from 27 Japanese hospitals anastomotic leakage, pancreatic fistula, abdominal abscess, and randomly assigned to TH (n = 82) or LTA (n = 85), pneumonia, or death from any cause within 30 days after although the projected sample size was 302. After the first surgery (the mortality was 0.8% in each group). The 5-year interim analysis, the predicted probability of LTA having overall survival rate was 69.2% for the group assigned to D2 a significantly better overall survival than TH at the final lymphadenectomy alone and 70.3% for the group assigned to analysis was only 3.65%; therefore, the trial was closed. The D2 lymphadenectomy plus PAND; the hazard ratio for death 5-year overall survival was 52.3% in the TH group and was 1.03. Moreover, there were no significant differences in 37.9% in the LTA group. The hazard ratio of death for recurrence-free survival between the two groups. LTA compared with TH was 1.36 (0.89–2.08, P = .92). Recently, meta-analyses of D2 lymphadenectomy versus Three patients died in hospital after LTA but none after TH. D2 with PAND were reported [28]. Three RCTs including Morbidity after LTA was worse than that after TH with rates the PGCSG study in Poland [29], EASOG study in Japan, of 49% and 34%, respectively. Korea, and Chinese Taiwan area [30, 31], and JCOG- This study concluded that LTA could not be performed 9501 study in Japan [27]were eligible (Table 5). Another for gastric cancer with esophageal invasion of 3 cm or less, analysis included 4 RCTs and 4 nonrandomized studies were because LTA did not improve survival compared to TH and identified [32]. These meta-analyses showed that D2+ PAND resulted in increased morbidity. can be performed as safely as a standard D2 resection without increasing postoperative mortality but failed to benefit overall survival in patients with advanced gastric cancer. 6. Splenectomy or Pancreaticosplenectomy Gastrectomy with D2 lymphadenectomy plus PAND in the Treatment of Cancer of the Upper cannot be recommended as a routine practice for the surgical Third of the Stomach treatment of gastric cancer. In Japan, pancreaticosplenectomy for LN dissection around 5. Mediastinal Lymph Node Dissection for the splenic artery (station no. 11) and splenic hilus (station no. 10) had been widely performed, because this procedure Gastric Cancer was proposed as a radical dissection of metastatic LN along For patients with esophageal invasion from gastric cancer, the splenic artery [35, 36]. However, Japanese retrospective it is necessary to perform mediastinal resection included analyses proved that there was no survival benefit of these 6 International Journal of Surgical Oncology 4sb 4sb 4d 4d 4sa 6 6 3 3 1 1 5 5 7 7 9 9 10 11d 12a 8a 12a 8a 11p 11p (a) Distal gastrectomy (b) Total gastrectomy Figure 2: Lymph node dissection according to the Japanese gastric cancer treatment guideline 2010 of the 3rd edition reproduced form [14] with permission. D1 distal gastrectomy consists of LN dissection of station nos. 1, 3, 4sb, 4d, 5, 6, and 7 and D1 total gastrectomy consists of station nos. 1–6 and 7 (blue circle). Yellow circles indicate the lymph nodes that belong to D1+, and red circles indicate those to D2. procedures [37, 38]. Recently, pancreas-preserving splenec- Two RCTs compared gastrectomy with splenectomy and tomy has been considered a safe and effective procedure gastrectomy alone in patients with gastric cancer were without decreasing surgical curability [39, 40]. reported with regard to the effectiveness and safety [45, 46]. In the JCOG 9501 study, pancreas-preserving splenec- Csendes et al. reported 187 patients who underwent total tomy was generally performed with low surgical mortality gastrectomy between 1985 and 1992; these patients were [27, 41]. In this study, only 22 of 523 patients underwent randomized into two groups, gastrectomy with splenectomy pancreaticosplenectomy and 59% of patients (13 of 22 cases) and gastrectomy alone. Postoperative complications were developed postoperative complications. more frequent in the splenectomy group than in the surgery In this pancreas-preserving procedure, the splenic artery alone group, including postoperative fever over 38 C (50% is generally divided at the distal site after branching-off versus 39%: P< .04), pulmonary complications (39% versus of the great pancreatic artery in Sasako’s modification and 24%: P< .008), and subphrenic abscess (11% versus 4%: the splenic vein is preserved as distal as possible in order P< .05). There were no significant differences between the to prevent pancreatic fistula and pancreatic atrophy and groups in hospital mortality (4.4% for splenectomy versus consequent glucose intolerance [42]. 3.1% for gastrectomy alone) or in the 5-year survival rate In Western countries as well, pancreaticosplenectomy (42% for splenectomy versus 36% for gastrectomy alone) had a marked adverse effect on both mortality and morbidity [45]. in two RCTs [5, 6]. The other trial reported by Yu et al. was carried out in Currently, pancreaticosplenectomy is considered benefi- Korea between 1995 and 1999. Two hundred seven patients cial only when the primary tumor or metastatic LN directly with gastric cancer were divided randomly into two groups, invades the pancreas, but is not performed for prophylactic total gastrectomy (103 patients) and total gastrectomy plus dissection of lymph nodes around the splenic artery (station splenectomy (104 patients). Postoperative mortality was no. 11). 8.7% in total gastrectomy alone group and 15.4% in total According to the Japanese experience with LN dissection gastrectomy plus splenectomy group, but there was no at the splenic hilus with splenectomy, the incidence of hilar significant difference between the groups. Hospital mortality node metastasis ranged 15–21% for tumors located at or was 1.0% in total gastrectomy alone and 1.9% in total infiltrate to the proximal third of the stomach. About 20– gastrectomy plus splenectomy group; there was no significant 25% of patients with LN metastasis have survived over 5 years difference between the two groups. following LN dissection with splenectomy [35]. However, The 5-year survival rates did not differ statistically hilar nodal metastasis was reported to be not found in between the gastrectomy alone group (48.8%) and gastrec- the early gastric cancer base on retrospective data [43, 44]. tomy plus splenectomy group (54.8%). There was no 5-year Splenectomy is recommended for curative resection of the survivor among patients with lymph node metastasis at the proximal advanced gastric cancer with infiltration to the splenic hilum in either group [46]. greater curvature in the Gastric Cancer Treatment Guidelines Therefore, these results did not support the effectiveness 2010 [14]. of prophylactic dissection at the splenic hilum during International Journal of Surgical Oncology 7 splenectomy in patients undergoing total gastrectomy for [7] R. Biffi, A. Chiappa, F. Luca et al., “Extended lymph node dis- section without routine spleno-pancreatectomy for treatment proximal gastric cancer. of gastric cancer: low morbidity and mortality rates in a single center series of 250 patients,” Journal of Surgical Oncology,vol. 93, no. 5, pp. 394–400, 2006. 7. Future Perspectives [8] F. Roviello, D. Marrelli, P. 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