*2.1.1. Extent of lymphadenectomy for early gastric tumours*

Lymphadenectomy is an essential part of radical gastric cancer surgery. According to the latest UICC/AJCC TNM classification (seventh edition), at least 15 lymph nodes must be harvested to perform adequate staging [5]. However, in a USA-based study comprising more than 3000 patients, it was found that only 23.8% of cases had more than 15 lymph nodes harvested [6].

All of the relevant lymph nodes are divided in 16 stations (see **Figure 7**). The first six stations, perigastric nodes, are grouped together as N1. Stations 7–11, coeliac axis, are grouped as N2 [4]. Depending on the extent of lymph node removal, the term D1 (perigastric nodes) or D2 (perigastric nodes plus clearance of coeliac axis) is used [5]. However, traditionally, the extent of lymphadenectomy was classified relative to the location of tumour [6]. In the latest Japanese gastric cancer treatment guidelines (2014), a more rational approach is suggested. What constitutes D1 or D2 lymphadenectomy is actually dependent on the extent of gastrectomy, regardless of tumour location [7]. For example, in total gastrectomy (TG), D1 means removal of the first seven nodal stations, whereas in distal gastrectomy, D1 constitutes removal of stations 1, 3, 4sb, 4d and 5–7 [7].

For all cT1a tumours which are not amenable to endoscopic treatment as well as cT1b tumours, D1 lymphadenectomy is necessary. If the tumour is well differentiated and does not exceed 1.5 cm in diameter, D1 lymphadenectomy is sufficient. For larger and less differentiated tumours, an extended D1+ lymphadenectomy is required based on the tumour localisation and the extent of gastric resection. Several but not all of the D2 nodes are included in this lymphadenectomy [7].

**Figure 7.** Lymph node stations: (1) right paracardial, (2) left paracardial, (3) lesser curvature, (4sa) short gastric, (4sb) left gastroepiploic, (4d) right gastroepiploic, (5) suprapyloric, (6) infrapyloric, (7) left gastric artery, (8a) anterior common hepatic, (8p) posterior common hepatic, (9) celiac trunk, (10) splenic hilum, (11p) proximal splenic, (11d) distal splenic, (12a) left hepatoduodenal and (13) retropancreatic.

#### **2.2. Gastric carcinoma stage IB–III**

**Figure 7.** Lymph node stations: (1) right paracardial, (2) left paracardial, (3) lesser curvature, (4sa) short gastric, (4sb) left gastroepiploic, (4d) right gastroepiploic, (5) suprapyloric, (6) infrapyloric, (7) left gastric artery, (8a) anterior common hepatic, (8p) posterior common hepatic, (9) celiac trunk, (10) splenic hilum, (11p) proximal splenic, (11d) distal splenic,

(12a) left hepatoduodenal and (13) retropancreatic.

*2.1.1. Extent of lymphadenectomy for early gastric tumours*

removal of stations 1, 3, 4sb, 4d and 5–7 [7].

lymphadenectomy [7].

206 Gastric Cancer

Lymphadenectomy is an essential part of radical gastric cancer surgery. According to the latest UICC/AJCC TNM classification (seventh edition), at least 15 lymph nodes must be harvested to perform adequate staging [5]. However, in a USA-based study comprising more than 3000 patients, it was found that only 23.8% of cases had more than 15 lymph nodes harvested [6]. All of the relevant lymph nodes are divided in 16 stations (see **Figure 7**). The first six stations, perigastric nodes, are grouped together as N1. Stations 7–11, coeliac axis, are grouped as N2 [4]. Depending on the extent of lymph node removal, the term D1 (perigastric nodes) or D2 (perigastric nodes plus clearance of coeliac axis) is used [5]. However, traditionally, the extent of lymphadenectomy was classified relative to the location of tumour [6]. In the latest Japanese gastric cancer treatment guidelines (2014), a more rational approach is suggested. What constitutes D1 or D2 lymphadenectomy is actually dependent on the extent of gastrectomy, regardless of tumour location [7]. For example, in total gastrectomy (TG), D1 means removal of the first seven nodal stations, whereas in distal gastrectomy, D1 constitutes

For all cT1a tumours which are not amenable to endoscopic treatment as well as cT1b tumours, D1 lymphadenectomy is necessary. If the tumour is well differentiated and does not exceed 1.5 cm in diameter, D1 lymphadenectomy is sufficient. For larger and less differentiated tumours, an extended D1+ lymphadenectomy is required based on the tumour localisation and the extent of gastric resection. Several but not all of the D2 nodes are included in this There is a consensus amongst specialists and societies that gastric carcinoma invading proper muscular layer or having positive lymph nodes requires a standard gastrectomy [4–7]. A standard gastrectomy means either total gastrectomy (**Figure 8**) or distal subtotal gastrectomy removing at least two-thirds of the stomach (**Figure 9**) [4]. In Japanese guidelines, a D2 lymphadenectomy is an integral part of standard gastrectomy. However, in Western countries this recommendation is not so strict. General recommendation is that a D2 dissection should be performed in high-volume specialised centres with appropriate experience if the patient is medically fit [5].

#### *2.2.1. Extent of lymphadenectomy for stage IB–III gastric carcinoma*

There used to be a fierce debate between Asian and Western surgeons about the extent of lymphadenectomy. Asian specialists advocated D2 lymphadenectomy because of superior oncologic outcomes. However, Western surgeons argued that D2 lymphadenectomy only added to perioperative morbidity and mortality with no significant survival benefit [4]. There were three randomised controlled trials (RCTs) that addressed this issue. The Dutch trial randomised 711 patients in D1 and D2 lymphadenectomy groups. It has to be noted that distal pancreatectomy with splenectomy was performed in all cases with D2 dissection but only selectively in D1 dissection. This trial reported a significantly higher morbidity (42% vs. 4%, *p* < 0.001) and mortality (10% vs. 4%, *p* < 0.004) in D2 group. Furthermore, there was no 5-year survival benefit in D2 group (D1 = 34% vs. D2 = 33%). However, this study was criticised because of many shortcomings. One of them was the fact that surgeons participating in this trial had no previous experience in D2 lymphadenectomies and they were trained using video

**Figure 8.** Total gastrectomy. In total gastrectomy, D1 lymphadenectomy constitutes dissection of nodal stations 1–7. D2 lymphadenectomy constitutes dissection of D1 + stations 8a, 9, 10, 11p, 11d and 12a.

**Figure 9.** Distal subtotal gastrectomy. In distal subtotal gastrectomy, D1 lymphadenectomy constitutes dissection of nodal stations 1, 3, 4sb, 4d, 5, 6 and 7. D2 lymphadenectomy constitutes dissection of D1 + stations 8a, 9, 11p and 12a.

materials and booklets. It was only after the 15-year survival data were analysed that the evidence showed positive results for D2 dissection. Gastric cancer-related deaths were significantly lower in D2 group (37% vs. 48%). Local (12% vs. 22%) and regional (13% vs. 19%) recurrence rates were also lower in D2 group. The overall 15-year survival was 21% in D1 group and 29% in D2, without statistically significant difference (*p* = 0.34) [4, 9].

Another famous study that questioned the usefulness of D2 dissection was Medical Research Council trial. The results of this study drew similar conclusions – there was no evidence to support routine use of D2 lymphadenectomy. Again, distal pancreatectomy with splenectomy was performed in D2 dissections just as it was in the Dutch study. Significantly, lower survival on subgroup analysis was noted in both studies for patients with distal pancreatectomy and splenectomy. The third landmark RCT on this subject, the Italian study, found comparable overall morbidity (12.0% in D1 vs. 17.9% in D2, *p* = 0.178) and no significant difference in 30-day postoperative mortality rate (3.0% in D1 vs. 2.2% in D2, *p* = 0.72). The essential difference was that only experienced surgeons participated in this trial and that distal pancreatectomy with splenectomy was not routinely performed [4, 9]. The main conclusion is that in Western countries D2 lymphadenectomy can be safely performed in high-volume centres by experienced surgeons. Distal pancreatectomy and splenectomy are no longer considered an integral part of modern D2 lymphadenectomy and are considered beneficial only if the primary tumour or metastatic nodes invade these organs [4, 7, 9].

#### *2.2.2. Extent of resection*

Microscopically, negative resection margins are required to qualify any gastric resection as curative. Although not all patients with positive resection margins develop cancer recurrence, this undoubtedly worsens prognosis [10]. There seems to be a lack of agreement about what is an adequate margin from gastric carcinoma with different articles suggesting slightly different numbers. There are studies that have illustrated tumour cell spread as far as 5 cm laterally from the primary tumour. Therefore, a margin of at least 6 cm seems necessary [6]. However, according to other experts, a 4 cm margin is sufficient [1, 4].

Discussion about distal resection margin is simpler. This margin is limited by the papilla of Vater and is generally 2–4 cm from the pylorus. If the tumour invades papilla or further down the duodenum, a metastatic disease is expected, and gastrectomy alone will not suffice [10].

Regarding proximal resection margin, the Japanese guidelines have specific recommendation. For T1 gastric carcinoma, a gross resection margin of 2 cm is recommended. In case the tumour margins are equivocal on preoperative endoscopy, a biopsy-guided marking with clips can be used to aid in intraoperative decision-making [7]. If the cancer is invading proper muscular layer or deeper, a 3 cm margin is needed for expansively growing tumours, and 5 cm are necessary for infiltrating tumours [7]. The idea that optimal proximal margin distance is stage-dependent is highlighted by a multicentre US study reporting on 465 patients who underwent gastric resection due to distal gastric carcinoma. Authors found that in stage I there was no difference in overall survival between 3.1–5.0 cm and >5.0 cm proximal margin [11]. For a diffuse gastric carcinoma, an 8 cm margin is recommended [5]. If the resection margin is negative, the distance from the tumour does not per se influence the prognosis [10]. Therefore, in case the aforementioned criteria regarding proximal margin distance cannot be followed, frozen section examination is highly recommended [7]. In case of positive resection margins on the final histology, the benefits of reoperation must be weighed against the risks of repeated operation. Reoperation is usually warranted in low-stage cases with minimal (N0–N1) nodal involvement [10].

#### *2.2.3. Total vs. subtotal gastrectomy*

materials and booklets. It was only after the 15-year survival data were analysed that the evidence showed positive results for D2 dissection. Gastric cancer-related deaths were significantly lower in D2 group (37% vs. 48%). Local (12% vs. 22%) and regional (13% vs. 19%) recurrence rates were also lower in D2 group. The overall 15-year survival was 21% in D1

**Figure 9.** Distal subtotal gastrectomy. In distal subtotal gastrectomy, D1 lymphadenectomy constitutes dissection of nodal stations 1, 3, 4sb, 4d, 5, 6 and 7. D2 lymphadenectomy constitutes dissection of D1 + stations 8a, 9, 11p and 12a.

Another famous study that questioned the usefulness of D2 dissection was Medical Research Council trial. The results of this study drew similar conclusions – there was no evidence to support routine use of D2 lymphadenectomy. Again, distal pancreatectomy with splenectomy was performed in D2 dissections just as it was in the Dutch study. Significantly, lower survival on subgroup analysis was noted in both studies for patients with distal pancreatectomy and splenectomy. The third landmark RCT on this subject, the Italian study, found comparable overall morbidity (12.0% in D1 vs. 17.9% in D2, *p* = 0.178) and no significant difference in 30-day postoperative mortality rate (3.0% in D1 vs. 2.2% in D2, *p* = 0.72). The essential difference was that only experienced surgeons participated in this trial and that distal pancreatectomy with splenectomy was not routinely performed [4, 9]. The main conclusion is that in Western countries D2 lymphadenectomy can be safely performed in high-volume centres by experienced surgeons. Distal pancreatectomy and splenectomy are no longer considered an integral part of modern D2 lymphadenectomy and are considered beneficial only if the

Microscopically, negative resection margins are required to qualify any gastric resection as curative. Although not all patients with positive resection margins develop cancer recurrence,

group and 29% in D2, without statistically significant difference (*p* = 0.34) [4, 9].

primary tumour or metastatic nodes invade these organs [4, 7, 9].

*2.2.2. Extent of resection*

208 Gastric Cancer

Unlike the debate regarding lymphadenectomy, total gastrectomy (TG) vs. subtotal gastrectomy (SG) is a less polarising topic. Since the 'en principle' total gastrectomy was suggested in the 1970s, several large studies have provided evidence to support the role of distal subtotal gastrectomy [12]. Currently, it is the procedure of choice for early gastric cancer located in the distal and middle third of the stomach if the resection margins are located well within the healthy stomach (distances discussed previously). The advantages of subtotal gastric resection are the following: several studies have reported lower morbidity and mortality, reduced hospital stay and superior nutritional status with better quality of life in long term [12]. Two large randomised trials performed in Europe found no significant difference in long-term survival between TG and SG for distal gastric cancer but lower morbidity, mortality and better quality of life in SG group [12]. A recently performed meta-analysis of six trials also found no significant difference in 5-year survival between TG and SG groups (*p* = 0.18). However, it did not show higher postoperative complication rates (*p* = 0.30) or hospital mortality (*p* = 0.12) in TG group which was in contrast to previously mentioned studies [13].

There are several proposed advantages of TG. It could reduce the risk of inadequate lymph node harvest, thus lowering local recurrence risk. Due to removal of all gastric tissue, it eliminates the risks of multicentric synchronous or metachronous carcinoma [13]. TG is recommended for gastric carcinoma located in the upper third of the stomach, signet ring cell cancers (*linitis plastica*), cancer arising on the background of atrophic gastritis, multicentric cancers, advanced distally located tumours with lymph node metastasis to allow extended lymphadenectomy, invasion of pancreas (which requires pancreaticosplenectomy) and patients with inherited E-cadherin mutation as a prophylactic measure (due to 80% lifetime risk of developing gastric cancer) [1, 6, 7, 12, 13].

#### *2.2.4. Laparoscopic vs. open gastrectomy*

Laparoscopic gastric cancer surgery is technically demanding and is currently performed more routinely by Asian surgeons. Nevertheless, more and more specialists around the globe are becoming more confident in laparoscopic surgery, and, with the help of technological advancements, usage of laparoscopy will certainly increase [14]. As discussed previously, very early gastric carcinomas are preferably treated by endoscopic resection. However, criteria for endoscopic treatment are very strict, and these methods are more widely used in highincidence countries with high proportion of early cases. Therefore, the most solid indication for laparoscopic surgery is gastric carcinoma located in the distal or middle third of the stomach and limited to submucosa without evidence of lymph node involvement or mucosal cancers not amenable to endoscopic treatment [14]. In case of laparoscopic total gastrectomy, the more widely accepted indication is T1N0 tumour of proximal third of the stomach [14]. There is evidence that laparoscopy is a safe and feasible option even for advanced gastric carcinomas if performed in high-volume specialised centres [1]. A systematic review comprising 3411 patients revealed similar lymph node harvest and long-term survival for laparoscopic distal gastrectomy compared to open approach. Hospital stay, analgetic consumption, postoperative complication rate and blood loss in surgery were all reduced in laparoscopic approach group [1]. Surgeons in Eastern Asia have expanded the use of laparoscopy to advanced cancers even with limited involvement of perigastric nodes [14]. There is still a small amount of high-quality evidence to support these expanded indications [4, 14]. However, one large systematic review analysing 23 studies with 7336 patients was recently published. Authors found comparable 5-year overall survival (*p* = 0.45), recurrence (*p* = 0.08) and gastric cancer-related death rates (*p* = 0.28) between laparoscopic and open gastrectomy groups. These results led them to conclude that laparoscopic gastrectomy was comparable to the open approach and did not worsen oncologic results [15]. To evaluate the role of laparoscopy in advanced gastric cancer, a meta-analysis comprising 11 studies and 1904 patients was performed. A D2 dissection was performed in both open and laparoscopic cases. Researchers found reduced blood loss, morbidity, shorter postoperative ileus and length of hospital stay in laparoscopic group, although the operation time was longer by almost 42 min (*p* < 0.05). No significant difference was noted in lymph node harvest, intrahospital mortality, recurrence rate and 3-year overall survival rates. This indicates that laparoscopy has several advantages in short-term results and is equivalent from oncologic standpoint [16].

While many surgeons perform the so-called laparoscopy-assisted gastrectomy which requires mini-laparotomy incision and extracorporeal anastomosis, several options for totally laparoscopic gastrectomy are available. Even single-port laparoscopy is being performed frequently in high-volume centres. A small study comparing 50 single-port laparoscopies with 50 multiport surgeries indicated superior short-term results for single-port surgery. However, this did not lead to reduced hospital stay. Most specialists use at least five ports for laparoscopic gastrectomy [14].

Despite the aforementioned studies, the present state of laparoscopic gastric surgery is not entirely clear. A lot of the evidence comes from Asian countries, high-volume specialised centres with considerable experience. Current studies have been criticised for bias and heterogeneity, for example, not including the most advanced gastric cancers in studies comparing open with laparoscopic approach. Some authors have found reduced lymph node harvest at specific nodal stations during laparoscopic D2 dissection. This has raised the question of robotic surgery as a valid tool to overcome some of the technical difficulties that comes with laparoscopic surgery. Robotic system has superior manoeuvrability and visualisation, which is essential in performing dissection along the celiac axis, spleen and pancreas. Another advantage is the relatively easier restoration of gastrointestinal continuity using robotic system. As with other procedures, robotic gastrectomy seems to take less time to master than conventional laparoscopic surgery although this could in part be related to previous experience in laparoscopic approach. There is currently not enough high-quality evidence to draw any definitive conclusions on robotic gastric cancer surgery in comparison with conventional laparoscopic and open surgery [17].
