Current status of function‐preserving gastrectomy for gastric cancer

Abstract Early gastric cancer (EGC) has excellent postoperative survival outcomes; thus, one of the recent keywords in the treatment of EGC is “function‐preserving gastrectomy (FPG).” FPG reduces the extent of lymphadenectomy and gastric resection without compromising the long‐term prognosis. Proximal gastrectomy (PG) is an alternative to total gastrectomy (TG) for EGC in the upper‐third of the stomach, in which the gastric reservoir, gastric acid secretion, and intrinsic factors are maintained. Distal gastrectomy (DG) with a small remnant stomach, namely subtotal gastrectomy (STG), is another option for upper EGC, where the function of the cardia and fundus is preserved. Pylorus‐preserving gastrectomy (PPG) is a good alternative to DG for EGC in the middle‐third of the stomach, where pyloric function is preserved. Following elucidation of the markedly low incidences of possible metastasis to lymph node stations where dissection is omitted, the oncological safety of these FPG procedures was clarified. Nutritional advantages of PG or STG over TG have been reported; however, the standardized reconstruction methods after PG are yet to be established, and it is important to devise methods to prevent postoperative gastroesophageal reflux and anastomotic complications regardless of the reconstruction method. Nutritional benefits of PPG compared with DG have also been clarified, in which reducing postoperative gastric stasis is important. For the further spread of these FPG procedures, several issues, such as precise evaluation of preserved function, confirmation of oncological safety, and standardization of the technique, should be addressed in future prospective randomized controlled trials.


| INTRODUC TI ON
Early gastric cancer (EGC) has a low incidence of lymph node metastasis and excellent postoperative survival outcomes; thus, recent keywords in the treatment of EGC are "minimally invasive gastrectomy (MIG)" and "function-preserving gastrectomy (FPG)." 1 FPG reduces the extent of lymphadenectomy and gastric resection without compromising the long-term prognosis; thus, FPG can theoretically maintain the gastric function and postoperative quality of life (QOL) of patients. 1 Proximal gastrectomy (PG) and distal gastrectomy (DG) with a small remnant proximal stomach, namely subtotal gastrectomy (STG), are alternatives to total gastrectomy (TG) for EGC in the upper-third of the stomach, whereas pylorus-preserving gastrectomy (PPG) is a good alternative to DG for EGC in the middle-third of the stomach. Recently, these FPG procedures have been performed using an MIG such as laparoscopic or robotic gastrectomy.
Recent studies demonstrated the nutritional advantages of PG or STG over TG. The nutritional benefits of PPG compared with DG were also clarified. In this review article, we summarize the current status of FPG procedures, with a special focus on postoperative functional and nutritional outcomes.

| PROXIMAL G A S TREC TOMY (P G)
Due to the increasing incidence of proximal gastric cancer (GC), the demand for PG is also increasing. 2 In PG, the gastric reservoir, gastric-acid secretion, and intrinsic factors are maintained. On the other hand, patients undergoing PG may develop heartburn due to gastroesophageal reflux, which may lead to a poor postoperative QOL. Although there is no consensus on the optimal procedure, the choice of reconstruction method must be made in consideration of the prevention of gastroesophageal reflux and the guarantee of nutritional benefits.

| Indications and oncological safety of PG
In patients with upper-third EGC, metastasis to lymph node stations #4d/#5/#6 are rare; therefore, dissection of these nodes is considered unnecessary. Many studies reported that the long-term oncological outcomes of PG were similar to those of TG. 3,4 Ichikawa et al 3 reported that the overall survival (OS) rate of the PG group was similar to that of the TG group (5-year survival rate, 95% vs 97%, respectively; P = .86). Accordingly, in the Japanese Gastric Cancer Treatment Guidelines (JGCTG), 5 PG is recommended as an option for cT1N0 tumors in the upper-third of the stomach, in which the size of the remnant stomach can be more than half of the original.
Considering the markedly low metastatic rates and therapeutic index at lymph node stations #4/#5/#6, even proximal advanced GC or esophagogastric junctional (EGJ) cancer <4 cm in diameter may be indicated for PG. 6,7 However, PG for such lesions is technically difficult because of the complete dissection of #11d (and #10) and anastomotic procedure in the mediastinum. Moreover, it is unclear whether wider excision on both the esophageal and gastric sides guarantees the nutritional benefits of PG. At this time, indications of PG for these lesions should be carefully considered.

| Surgical procedures of PG
In PG, D1 lymphadenectomy includes lymph node stations #1/#2/#3a/#4sa/#4sb/#7, and stations #8a/#9/#11p are additionally included for D1+ lymphadenectomy. 5 The right gastric and gastroepiploic vessels will be preserved. The hepatic and pyloric branches of the vagus nerve are routinely preserved, whereas its celiac branch is usually not preserved. The recent prospective phase II study (JCOG1401) confirmed the safety of laparoscopic PG (LPG). 8 Considering the non-inferiority of laparoscopic DG (LDG) to open DG in clinical stage I GC relapse-free survival (RFS) confirmed by a phase III randomized controlled trial (RCT) (JCOG0912), 9 LPG is now considered to be one of the standard treatments for cStage I GC.
There are two major reconstruction methods after PG: one is esophagogastrostomy (EG) and the other uses the small intestine. These procedures have their pros and cons, and the optimal method remains controversial 2 ; therefore, at present, the method of reconstruction after PG is selected depending on the proficiency level of the surgeon at each facility. EG is a simple and physiological reconstruction method as it includes only one anastomotic site; however, a higher frequency of reflux esophagitis may develop postoperatively if additional anti-reflux procedures are not performed together. Reconstruction methods using the small intestine include jejunal interposition (JI), double tract reconstruction (DT) and jejunal pouch interposition (JPI). In a Japanese questionnaire survey in 2010 regarding reconstruction methods after PG, the most common method was EG (48%), followed by JI (28%), DT (13%), and JPI (7%). 10 However, regarding reconstructions using the small intestine, DT has recently gained popularity due to its easier laparoscopic approach. In fact, in JCOG1401, DT was performed in 45 (91.8%) patients and JI in only four patients (8.2%). 8  20 were reported with the reduced incidence of reflux esophagitis. Reconstruction methods using the small intestine have also been performed laparoscopically and have advantages for the prevention of reflux esophagitis. [21][22][23] Although JPI is effective for preserving gastric function, 24 it is complex, and may be associated with dilatation and stasis of the jejunal pouch. 25 Table 1 shows the incidence of postoperative anastomotic stricture and reflux esophagitis in each reconstruction method after LPG. [12][13][14][15][16][17][18][19][20][21][22][23] Following the recent improvements in postoperative shortterm outcomes of laparoscopic procedures, nutritional benefits of LPG have been increasingly reported. Seven studies that assessed the nutritional advantages of LPG over laparoscopic TG (LTG) in terms of body weight (BW), hemoglobin (Hb), albumin (Alb), total protein (TP) and total lymphocyte count are presented in Table 2. 12,14,[26][27][28][29][30] Patients undergoing LPG had a significantly higher BW and Hb level than those undergoing LTG. Several studies reported the higher serum levels of iron and vitamin B12 after LPG. 22

| SUBTOTAL G A S TREC TOMY (STG)
In some patients with EGC in the upper gastric body, there is distance from the tumor to the EGJ. In selected patients, DG with small remnant proximal stomach, namely STG, can be applied, in which the function of the cardia is preserved. STG is usually performed via the laparoscopic approach (LSTG).

| Indications and oncological safety of STG
The basic indications for LSTG are as follows 1 : (i) EGC diagnosed as cT1N0M0; (ii) tumor located in or involving the upper-third of the stomach; (iii) remaining distance from the tumor to EGJ of less than 5 cm,; and (iv) remnant gastric stump 2-3 cm away from EGJ.
When an oncologically safe distance from the tumor to EGJ cannot be secured, LPG or LTG is an alternative procedure. Preserving a proximal stomach may raise two oncological concerns: one is the positive margin and the other is possible lymph node metastasis to stations #2/#4sa. Kano

| Functional and nutritional outcomes of STG
Three studies examining the nutritional advantages of LSTG over LTG or LPG in terms of BW, Hb, Alb, TP, and prognostic nutritional index (PNI) are presented in Table 3. 37

| PYLORUS -PRE S ERVING G A S TREC TOMY (PP G)
PPG was introduced as a surgical procedure for EGC in the middlethird of the stomach designed to preserve pyloric function and maintain a better postoperative QOL. 42 PPG has several functional and nutritional benefits, with a lower incidence of post-gastrectomy syndromes, such as dumping syndrome and bile reflux, compared with conventional DG with Billroth I (BI) reconstruction.

| Indications and oncological safety of PPG
In cT1N0 tumors in the middle-third of the stomach, metastasis to lymph node stations #5/#6i is rare; therefore, dissection of these nodes can be omitted. Previous studies reported low incidences of supra-and infrapyloric lymphatic metastasis (#5 and #6), ranging from 0.00% to 0.45% and from 0.45% to 2.60%, respectively, for EGC in the middle-third of the stomach. 43

| Surgical procedures of PPG
In PPG, D1 lymphadenectomy includes lymph node stations #1/#3/#4sb/#4d/#6/#7, and stations #8a/#9 are additionally included for D1+ lymphadenectomy. 5 As the roots of the right gastric artery and vein are routinely left intact, these vessels are transected after the first branch. The infra-pyloric artery and vein should be preserved. The right gastroepiploic artery and vein are transected after bifurcation of the infra-pyloric vessels. The hepatic and pyloric branches of the vagus nerve are routinely preserved, and its celiac branch is preserved in some cases. Initially, the distal transection line was made 1.5 cm proximal to the pyloric ring; however, meal stasis was common. The kinetics of gastric emptying were investigated and the length of the pyloric cuff was gradually increased. 49,50 Thus, a 3-to 4-cm pyloric cuff is generally preserved in PPG. PPG is now usually performed via the laparoscopic approach (LPPG). 48,51 In laparoscopy-assisted surgery, gastro-gastro anastomosis is ex-

| Functional and nutritional outcomes after PPG
Three studies after 2014 that assessed the functional and nutritional advantages of PPG over DG are presented in Table 4. 45,54,55 Suh et al 45 reported that decreases in serum TP and Alb levels 1 to 6 months postoperatively were significantly smaller in LPPG than in LDG, although delayed gastric emptying was more frequent in LPPG than in LDG (7.8% vs 1.7%). The 3-year cumulative incidence of gallstones was significantly less in LPPG than in LDG (0% vs 6.5%). 45 Fujita et al 54

| CON CLUS I ON S AND FUTURE PER S PEC TIVE S
FPG procedures, such as PG, STG, and PPG, for EGC are attractive surgical procedures to maintain the gastric function and postoperative QOL of patients; however, there is little evidence from prospective trials supporting their usefulness compared with other surgical procedures. The lack of consensus on the optimal reconstruction method after PG is a major problem. Therefore, several issues, such as precise evaluation of preserved function, confirmation of oncological safety, and standardization of the technique, need to be strictly addressed in prospective well-designed RCTs. In recent years, evidence supporting the clinical safety and efficacy of sentinel node navigation surgery for EGC has accumulated. 62 In the near future, segmental gastrectomy, local resection, and endoscopic submucosal dissection with sentinel basin dissection may become the standard FPG procedures for EGC.

D I SCLOS U R E
The authors declare no conflict of interests for this article.