Surgical management of invasive gastric cancer

INTRODUCTION — 

For invasive gastric cancer, surgery may be required as a component of the staging evaluation, for potentially curative treatment of localized disease, or for palliation in cases of advanced disease.

This topic review will focus on the indications, techniques, and outcomes of surgery for cancers arising in the stomach. Adjuvant and neoadjuvant therapy for gastric cancers, multimodality approaches for esophagogastric junction cancers, and the management of advanced and metastatic disease are discussed in detail separately.

●(See "Adjuvant and neoadjuvant treatment of gastric cancer".)

●(See "Neoadjuvant and adjuvant therapy for locally advanced resectable esophagogastric junction and gastric cardia adenocarcinoma".)

●(See "Initial systemic therapy for metastatic esophageal and gastric cancer".)

●(See "Local palliation for advanced gastric cancer".)

Diffuse gastric and lobular breast cancer syndrome (previously known as hereditary diffuse gastric cancer), which is also treated surgically, follows different treatment algorithms that are discussed separately. (See "Diffuse gastric and lobular breast cancer syndrome" and "Surgical management of gastric cancer in patients with DGLBCS".)

PREOPERATIVE AND STAGING EVALUATION — 

Accurate staging of the extent of disease is crucial for determining optimal therapy. Clinical staging is performed before resection using radiographic, endoscopic, and often, laparoscopic data. The primary goal of clinical staging is to assess whether a patient's tumor is potentially resectable. Complete pathologic staging, however, can only be achieved after surgical resection and is used to direct adjuvant therapy and inform prognosis.

Preoperative evaluation — The preoperative evaluation permits the assessment of clinical stage, which is important in guiding decisions about preoperative or perioperative therapy. Complete clinical or preoperative staging of patients with gastric cancer includes the following:

●Physical examination, including evaluation of appropriate nodal areas (especially left supraclavicular nodes) as well as the abdomen.

●Contrast-enhanced computed tomography (CT) scans of the abdomen and pelvis, and for proximal lesions, a CT scan of the chest. Although CT is not very accurate for assessing the depth of tumor invasion of the stomach wall or regional nodal involvement, it may detect distant nodal or visceral metastases, ascites, or carcinomatosis. Preoperative CT scans often underestimate the extent of disease, principally because of radiographically undetectable metastases involving the liver and peritoneum [1]. (See "Clinical presentation, diagnosis, and staging of gastric cancer", section on 'CT imaging'.)

●If it has not been performed previously, patients being evaluated for surgical resection should undergo full esophagogastroduodenoscopy prior to the procedure; we find this to be optimally performed at the time of another endoscopic procedure, such as endoscopic ultrasound (EUS). EUS may provide a more accurate staging evaluation of the tumor and nodal stage than CT and allows for preoperative biopsies. Its principal roles are to evaluate a patient for neoadjuvant therapy and to identify tumors that may be amenable to endoscopic resection. (See "Early gastric cancer: Clinical features, diagnosis, and staging" and "Overview of endoscopic resection of gastrointestinal lesions" and "Clinical presentation, diagnosis, and staging of gastric cancer".)

●For esophagogastric junction cancer of any stage or gastric cancer that is beyond T1 stage by EUS, we routinely perform diagnostic staging laparoscopy (DSL) with peritoneal washing before resection or neoadjuvant chemotherapy. The rationale and technique of DSL are explained in detail separately. (See "Diagnostic staging laparoscopy for digestive system cancers", section on 'Esophagogastric junction and gastric cancer'.)

DSL, while more invasive than CT or EUS, has the advantage of directly visualizing the liver surface, peritoneum, and local lymph nodes, and permitting biopsy of any suspicious lesions. Laparoscopy may identify radiographically occult metastatic disease, thus avoiding unnecessary exploratory laparotomy. In addition, peritoneal cytology by peritoneal washings should be obtained during staging laparoscopy. (See "Clinical presentation, diagnosis, and staging of gastric cancer", section on 'Staging laparoscopy'.)

●Multimodal treatment for gastric cancer can negatively impact a patient's physical function [2]. Time permitting, prehabilitation programs can potentially prepare such patients for the surgery. Specific prehabilitation protocols that are applicable to patients with gastric cancer are discussed separately. (See "Overview of prehabilitation for surgical patients".)

Pathologic staging — Pathologic staging depends on the findings at subsequent surgical exploration and examination of the pathologic specimen. Pathologic staging is used to assess tumor response to preoperative therapy and facilitates evaluation for adjuvant therapy.

The eighth edition of the tumor, node, metastasis (TNM) staging system of the combined American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) is most frequently used to stage gastric cancer (table 1) [3]. The TNM system can be used for both clinical and pathologic staging. (See "Clinical presentation, diagnosis, and staging of gastric cancer", section on 'Staging systems'.)

SEQUENCES OF TREATMENT BY STAGE

Resectable diseases — For patients with resectable gastric cancer, complete surgical eradication of the gastric tumor and adjacent lymph nodes represents the best chance for long-term survival.

Early gastric cancer — Early gastric cancer is a cancer that invades the mucosa or submucosa (T1), irrespective of lymph node metastasis. Early gastric cancer is primarily encountered in Eastern countries where a gastric surveillance program is in place. Patients with early gastric cancer that meet a set of criteria may be treated with endoscopic resection, others require surgical resection primarily due to the risk of lymph node metastasis. This is discussed separately. (See "Early gastric cancer: Management and prognosis".)

Resectable non-early gastric cancer — In medically fit patients with resectable gastric cancer, abdominal exploration with curative intent should be undertaken unless it is an early gastric cancer that meets the criteria for endoscopic resection [4].

In North America and Europe, the standard of care for most patients with clinical T2N0 or higher resectable gastric cancer is to receive perioperative chemotherapy (ie, both before and after surgery) [4-6]. In Japan, neoadjuvant chemotherapy is only used in the presence of bulky lymph nodes [7]. For patients with resectable gastric cancer, we do not add neoadjuvant chemoradiation (CRT) to perioperative chemotherapy, as this approach did not achieve an overall survival benefit in randomized trials [8]. (See "Adjuvant and neoadjuvant treatment of gastric cancer", section on 'No role for adding neoadjuvant CRT to perioperative chemotherapy'.)

The goals of preoperative therapy are to increase the resectability rate, reduce the rate of local and distant recurrence, avoid resection in patients with highly aggressive disease who will not benefit from resection, and ultimately, improve overall survival. Commonly used treatment protocols are discussed separately. (See "Adjuvant and neoadjuvant treatment of gastric cancer", section on 'Potentially resectable clinical T2N0 disease or higher that is not yet resected'.)

The techniques of gastric resection for cancer are discussed in detail. (See 'Radical resection of gastric cancer' below.)

Unresectable diseases — Curative gastric resection is deferred when there is unequivocal evidence of either locoregionally advanced disease or disseminated disease (distant metastasis or peritoneal seeding). Such patients are typically treated with systemic chemotherapy. If performed, surgery will be for a palliative, rather than curative, purpose.

Locoregionally advanced disease — Locoregionally advanced disease is evidenced by either infiltration of the root of the mesentery or para-aortic lymph node highly suspicious on imaging or confirmed by biopsy, or by invasion or encasement of major vascular structures (eg, aorta, hepatic artery, celiac axis, proximal, but not distal splenic vessels). Direct involvement of the spleen, pancreas, left lateral segment of the liver, or even diaphragm are not necessarily contraindications to resection.

Data from several uncontrolled series suggest that some patients with initially locally advanced unresectable disease may respond to chemotherapy or chemoradiation sufficiently enough that they are able to undergo potentially curative surgery. Resultant perioperative morbidity and mortality rates are acceptable. The risk-to-benefit ratio may be less favorable in patients who are overweight and those over the age of 60 [9], although this has not been seen in all studies [10]. However, this approach has not been widely adopted, largely due to the lack of randomized trials defining benefits, particularly relative to postoperative CRT. This topic is discussed in detail separately. (See "Adjuvant and neoadjuvant treatment of gastric cancer", section on 'Initially locally unresectable nonmetastatic disease'.)

In approximately 5 percent of primary gastric cancers, a broad region of the gastric wall or even the entire stomach is extensively infiltrated by malignancy, resulting in a rigid, thickened stomach, termed linitis plastica. The prevalence may be higher in younger individuals [11,12]. Although most commonly due to poorly differentiated (diffuse-type) infiltrating gastric cancers, this pattern can, in rare circumstances, represent metastatic spread from lobular cancer of the breast. In such cases, it is imperative that the patient be checked for a pathogenic CDH1 gene mutation. Patients with CDH1 mutations who present with invasive gastric cancer often have linitis plastica. The management of patients who carry a CDH1 mutation and have diffuse gastric and lobular breast cancer syndrome, previously known as hereditary diffuse gastric cancer, is discussed separately. (See "Diffuse gastric and lobular breast cancer syndrome" and "Surgical management of gastric cancer in patients with DGLBCS" and "Gastric cancer: Pathology and molecular pathogenesis" and "Pathology of breast cancer".)

Linitis plastica has an extremely poor prognosis [13-17], and this is attributed to the potential for early spread and advanced stage at diagnosis, as well as the frequent presence of microscopic disease at the surgical margins because of its diffuse nature. Fifty to 60 percent of all patients have metastatic disease (mainly within the peritoneal cavity) at diagnosis [17,18]. Nodal involvement is frequent, and extensive surgery may be required for complete excision, though this is controversial [15,19]. For many surgeons, linitis plastica is thought to be a contraindication to potentially curative resection [15]. However, others report that long-term survival in selected patients who undergo optimal resection (negative margins guided by intraoperative frozen section analysis and a D2/D3 lymphadenectomy) is comparable to that of optimally resected patients without linitis plastica [20,21].

In our view, patients with nonmetastatic linitis plastica would especially benefit from initial diagnostic laparoscopy and systemic therapy, and we often repeat diagnostic laparoscopy just prior to resection to identify the subset of patients who might benefit from resection [22]. Even with this approach, long-term survival in these patients is uncommon [23]. (See "Adjuvant and neoadjuvant treatment of gastric cancer" and "Clinical presentation, diagnosis, and staging of gastric cancer", section on 'Staging laparoscopy' and "Diagnostic staging laparoscopy for digestive system cancers".)

Disseminated disease — Disseminated disease includes distant metastasis or peritoneal seeding (including positive peritoneal cytology). Such patients are generally palliated with systemic chemotherapy unless they are candidates for a peritoneal-directed therapy, optimally on a clinical trial. Palliative resection of the primary should only be performed when symptoms cannot be adequately controlled with nonsurgical treatments. (See 'Surgery in the setting of metastatic disease' below.)

RADICAL RESECTION OF GASTRIC CANCER — 

In patients with resectable gastric cancer, complete surgical removal of the gastric tumor and adjacent lymph nodes represents the best chance for long-term survival.

Extent of resection — Gastrectomy is the most widely used approach for therapy of invasive gastric cancer, although superficial early gastric cancers (cT1a) can sometimes be treated endoscopically. (See "Early gastric cancer: Management and prognosis".)

The choice of operation for gastric cancer depends on the location of the tumor within the stomach:

●Distal tumors – For patients with lesions in the distal (lower two-thirds) stomach, we suggest a distal rather than a total gastrectomy. A distal gastrectomy is oncologically equivalent to a total gastrectomy while reducing perioperative complications. (See 'Distal tumors' below.)

●Proximal, large midgastric, or infiltrative disease – For patients with proximal (upper third) tumors or large midgastric lesions or infiltrative disease (eg, linitis plastica), we suggest a total gastrectomy rather than a partial gastrectomy. (See 'Proximal tumors' below.)

Distal tumors — Partial gastrectomy (distal gastrectomy, subtotal gastrectomy) (figure 1) with resection of adjacent lymph nodes appears to be sufficient for lesions in the distal (lower two-thirds) of the stomach. Patients with large midgastric lesions or infiltrative disease (eg, linitis plastica) may require total gastrectomy. (See "Partial gastrectomy and gastrointestinal reconstruction".)

A meta-analysis of four randomized trials and seven nonrandomized comparative series associated total gastrectomy with a higher rate of overall postoperative complication, anastomotic leakage, wound complication, peritoneal abscess, and mortality [24]. There were no significant differences between total and distal gastrectomy in the rate of recurrence and cancer-related death. In the era of neoadjuvant therapy, a randomized trial (LOGICA) confirmed the same findings favoring distal gastrectomy over total gastrectomy, including lower overall complication rates and shorter median hospital stay [25]. In addition, quality of life at the one-year postoperative time point was also better after distal gastrectomy versus total gastrectomy.

Proximal tumors — The issues guiding the extent of surgical resection are more complex for tumors of the proximal stomach. Tumors of the proximal stomach that do not invade the esophagogastric junction can technically be approached with either total gastrectomy or proximal gastrectomy.

●Total gastrectomy (figure 2), which removes the entire stomach, remains the preferred treatment for most proximal gastric cancers [26]. (See "Total gastrectomy and gastrointestinal reconstruction".)

●Proximal gastrectomy resects the cardia and upper portion of the corpus, but more than half of the stomach remains (figure 3). Proximal gastrectomy is intended for early gastric cancer (cT1) that is not amenable to endoscopic resection and is usually performed in Eastern countries where such early-stage diseases are prevalent, but not commonly in Western countries. Although esophagogastrostomy after proximal gastrectomy may be a simple and safe reconstruction technically, it can lead to a high incidence of reflux esophagitis and impair postoperative quality of life. This is discussed separately. (See "Partial gastrectomy and gastrointestinal reconstruction", section on 'Proximal gastrectomy'.)

Surgical management of tumors of the esophagogastric junction is discussed in detail separately. (See "Surgical management of resectable esophageal and esophagogastric junction cancers", section on 'Esophagogastric junction cancer resection'.)

Extent of lymph node dissection — For most patients undergoing curative gastrectomy for an invasive gastric cancer, we suggest a D2 rather than a D1 or D3 resection. A D2 resection confers better disease-specific survival than a D1 resection and lower perioperative mortality and morbidity than a D3 resection. The goal is to recover at least 16 regional nodes to be assessed pathologically, but the removal and evaluation of more nodes (30 or more) is desirable. This approach is consistent with guidelines from the National Comprehensive Cancer Network (NCCN) [4] and the European Society for Medical Oncology (ESMO) [5].

Definition of D1, D2, and D3 resections — The draining lymph node basins for the stomach have been meticulously divided into 16 stations by Japanese surgeons (table 2); stations 1 to 6 are perigastric, and the remaining 10 are located adjacent to major vessels, behind the pancreas, and along the aorta (figure 4) [27].

●D1 lymphadenectomy refers to a limited dissection of only the perigastric lymph nodes (stations 1 to 7). In the Japanese literature, a D1+ lymphadenectomy refers to a D1 lymphadenectomy plus stages 8a, 9, and 11p [28].

●D2 lymphadenectomy is an extended lymph node dissection, entailing the removal of nodes along the hepatic, left gastric, celiac, and splenic arteries, as well as those in the splenic hilum (stations 1 to 12a) [28].

●D3 dissection is a superextended lymphadenectomy. The term has been used by some to describe a D2 lymphadenectomy plus the removal of nodes within the porta hepatis and periaortic regions (stations 1 to 16), while others use the term to denote a D2 lymphadenectomy plus periaortic nodal dissection (PAND) alone [29]. Most Western surgeons (and the American Joint Committee on Cancer [AJCC]/Union for International Cancer Control [UICC] tumor, node, metastasis [TNM] staging classification [30]) classify disease in these regions as distant metastasis and do not recommend removing nodes in these areas during a potentially curative gastrectomy.

D1 versus D2 — In a Cochrane meta-analysis that included five randomized trials of D1 versus D2 dissection [31-35], there was no significant advantage for D2 lymphadenectomy for overall survival (n = 5 trials, hazard ratio [HR] 0.91, 95% CI 0.71-1.17) or disease-free survival (n = 3 trials, HR 0.95, 95% CI 0.84-1.07). However, there was a significant difference in disease-specific survival, favoring D2 lymphadenectomy (643/1000 versus 580/1000). The quality of the evidence was judged as moderate [36].

Although D2 lymphadenectomy was also associated with a higher postoperative mortality rate (7.8 versus 3.9 percent) than D1 lymphadenectomy in this meta-analysis [36], it was attributed by most to the liberal use of splenectomy and distal pancreatectomies in the earlier trials in the D2 cohort. If it is carried out in specialized, high-volume centers with appropriate surgical expertise and postoperative care, a pancreas- and spleen-preserving D2 lymphadenectomy provides superior staging information and may provide a survival benefit while avoiding excess morbidity.

D2 versus D3 — There is no evidence that a D3 (para-aortic) lymphadenectomy confers a survival benefit over a D2 dissection, and it may be associated with greater perioperative mortality and morbidity.

The 2015 Cochrane meta-analysis of the JCOG 9501 trial [29,37] and two other randomized trials of D2 versus D3 with para-aortic node dissection [38,39] concluded that resection of the para-aortic nodes did not provide any significant survival benefit [36]. Furthermore, while there was no significant difference in perioperative mortality with extended lymphadenectomy, the 95 percent confidence intervals were very wide (relative risk 1.67, 95% CI 0.41-6.73) and included the possibility of a nearly sevenfold increase in the risk of perioperative mortality. In another trial that compared D2 versus D2 plus para-aortic node dissection, the surgical complication rate was higher after the more extended lymphadenectomy (38 versus 22 percent) [40].

Minimum number of harvested lymph nodes — The presence and number of involved lymph nodes are one of the most important prognostic indicators. The number of examined nodes influences the accuracy of staging, and influences survival [41-43]. The AJCC staging guidelines recommend that at least 16 regional nodes be assessed pathologically, but that the removal/evaluation of more nodes (30 or more) is desirable [3]. The same guidance applies to patients treated with neoadjuvant therapy [44].

The influence of total lymph node count on stage-specific survival was studied in a series of 3814 patients undergoing gastrectomy for T1-3N0-1 (classified according to the 1997 AJCC gastric cancer staging system and reported to the Surveillance, Epidemiology, and End Results [SEER] database between 1973 and 2000) [45]. For every stage subgroup (T1/2N0, T1/2N1, T3N0, T3N1), survival was significantly better as more nodes were examined. Although cut-point analysis revealed the greatest survival difference when 10 lymph nodes were examined, there were significant survival differences for cut-points up to 40 nodes examined, always in favor of a greater number of nodes in the specimen.

The arguments in favor of extended lymphadenectomy (ie, D2 or D3 versus D1) are that removing a larger number of nodes more accurately stages disease extent and that failure to remove these nodes leaves behind disease (which would be a potentially fatal event) in as many as one-third of patients [46-48]. A consequence of more accurate staging is to minimize stage migration (the "Okie phenomenon," as described by Will Rogers) [48,49]. The resulting improvement in stage-specific survival may explain, in part, the better results in Asian patients. By contrast, the inadequacy of lymphadenectomy in contemporary North American series of gastric cancer resection is notable, even among patients treated predominantly at academic institutions [50-56]. The number of reported nodes is a critical measure that reflects both the quality of the surgical resection and the thoroughness of the pathologist's assessment of the specimen.

What is the role of sentinel lymph node biopsy for early gastric cancer? — For patients with early-stage gastric cancer, the risk of lymph node metastasis is low (2 to 18 percent for T1, 20 percent for T2). Sentinel lymph node (SLN) mapping has been proposed in this setting to identify those patients undergoing surgical rather than endoscopic management who need more extensive surgery [57,58]. At least in theory, patients with positive SLNs should undergo partial or total gastrectomy with requisite D2 lymphadenectomy while those with a negative SLN biopsy are recommended for a more limited gastric (eg, wedge or segmental) resection with a D1 or no formal lymphadenectomy [59]. However, the available data on the accuracy of SLN mapping for early gastric cancer are conflicting, and in our view, the use of SLN mapping for early gastric cancer remains investigational and should be limited to clinical trials outside of Eastern countries such as Japan where early gastric cancer is prevalent. (See "Partial gastrectomy and gastrointestinal reconstruction", section on 'Sentinel lymph node dissection'.)

Open versus minimally invasive gastrectomy — Open gastrectomy remains the preferred surgical treatment for gastric cancer worldwide. In high-volume, experienced centers, however, laparoscopic or robotic gastric resection provides an alternative that offers patients a faster recovery and fewer complications [60]. The surgeon performing minimally invasive gastrectomy must be experienced with both complex gastrointestinal and advanced minimally invasive procedures and be supported by staff and hospital resources of equal competence.

Compared with open gastrectomy, minimally invasive gastrectomy has superior or equal short-term patient outcomes and comparable long-term oncologic outcomes. Patients undergoing minimally invasive gastrectomy also report better quality of life in the early postoperative period, but the difference disappears after two years. (See "Laparoscopic gastrectomy for cancer", section on 'Outcomes'.)

Adjuvant therapy — Complete resection is the strongest predictor of long-term survival. However, the poor outcomes of surgery alone justify the use of adjuvant chemotherapy, radiation therapy, or both, particularly in patients with nodal metastases. Further details on the approach to adjuvant therapy for gastric cancer are discussed separately. (See "Adjuvant and neoadjuvant treatment of gastric cancer", section on 'Adjuvant chemoradiation'.)

Post-treatment surveillance — There are no randomized trials to guide the postoperative surveillance strategy. For cancer surveillance, we follow the consensus-based guidelines such as those from the National Comprehensive Cancer Network (NCCN) [4]. (See "Adjuvant and neoadjuvant treatment of gastric cancer", section on 'Post-treatment cancer surveillance'.)

Nutritional support — For long-term survivors, the more important aspect of post-treatment monitoring may be for nutritional sequela. In particular, one needs to keep a high index of suspicion for the development of micronutrient deficiencies in these patients. (See "Bariatric surgery: Postoperative nutritional management", section on 'Micronutrient deficiency, supplementation, and repletion'.)

●Following partial or total gastrectomy, patients should take daily vitamin and mineral supplements for their lifetime. Bariatric vitamins are often a good place to start because they contain all the micronutrients except calcium. Patients should take one or two pills of bariatric vitamins daily depending on the formulation. If preferred, generic over-the-counter multivitamins can also be used, but should be augmented with additional Vitamin D and B12 supplements.

●Besides multivitamins, patients should also take daily calcium supplements. Calcium citrate is better absorbed than calcium carbonate or other calcium supplements. It should be taken in divided doses of 500 to 600 mg two to three times a day timed at least two hours apart from multivitamins to maximize absorption.

●Patients should undergo the following laboratory evaluations every three months in the first year after surgery and yearly afterward:

•Complete blood count

•Comprehensive metabolic panel

•Ferritin, iron, total iron-binding concentration, soluble transferrin receptor

•Folate

•Vitamin B12, methylmalonic acid

•Calcium, 25-hydroxyvitamin D, intact Parathyroid Hormone

•Vitamin A

Additionally, vitamin B1, zinc, copper, and selenium levels can be measured when prompted by clinical symptoms. Hemoglobin A1C and thyroid-stimulating hormone levels are measured in patients who have diabetes or are on thyroid medications, respectively.

Slight variations exist in the panels endorsed by different programs and societies [61-63]. A comprehensive panel that includes all the labs above can be ordered commercially for the convenience of patients and providers.

●Bone density dual-energy X-ray absorptiometry at two years and beyond [64].

Prognostic factors — Prognosis after resection varies according to the pathologic extent of disease (stage), the tumor location, the population studied, and other factors.

●Pathologic stage – The most important prognostic factor after complete resection of gastric cancer is the pathologic stage (reflecting disease extent). Limited data are available on observed survival stratified by stage using the 2017 eighth edition tumor, node, metastasis (TNM) staging classification (table 1) [3]. Overall survival can be stratified according to pathologic stage in the absence of neoadjuvant therapy (figure 5) [65] and following neoadjuvant therapy (figure 6) [3].

Among patients undergoing neoadjuvant therapy, outcomes are dictated by the post-treatment stage rather than the pretreatment clinical stage. Patients who have substantial residual disease at resection after neoadjuvant therapy (particularly nodal metastases [66-68]) have a relatively poor prognosis. The best way to manage these patients is not established. (See "Adjuvant and neoadjuvant treatment of gastric cancer", section on 'Postoperative management of poor responders'.)

●Tumor location – In general, proximal tumors (cardia, esophagogastric junction) have a worse prognosis than distal cancers [69].

●Population studied – In general, proximal tumors (cardia, esophagogastric junction) have a poorer prognosis than distal cancers [70,71]. Although stage distribution accounts for some of this difference [72], outcomes differ even when stratified by stage [11,73-76]. It is possible that part of the difference may be genetically based, as a survival advantage for individuals with genetic ancestry from Asian countries was shown in another analysis that included only patients treated in the United States [77].

●Other clinical factors – Other factors that have been associated with prognosis include histology, margin status, age, sex, and date of resection (outcomes may be improving over time) [78,79]. Nomograms have been developed and validated to predict disease-specific survival following complete (R0) resection in both Asian and Western populations, which take into account the patient's age and sex, the primary tumor site and Lauren histologic subtype (ie, diffuse, intestinal, mixed), the depth of invasion, and the number of both positive and negative resected nodes [80-87]; one such nomogram is available (figure 7) [83]. An important point is that nomograms such as these do not take into account adjuvant or perioperative treatments, and thus, may underpredict prognosis in certain groups of patients [88].

Nomograms have also been developed to predict conditional survival probability (ie, prognosis for patients surviving a specified period of time) after an R0 resection [89]. Risk stratification models are also under development using both clinicopathologic and molecular factors [78].

●Surgeon and hospital volume – Higher hospital volume was associated with lower, unadjusted procedure-related mortality [90-94]. Surgeon volume, level of training, hospital volume, and specialization were also associated with procedure-related morbidity, procedure-related mortality, and five-year survival, but the effect was not consistent across all studies.

SURGERY IN THE SETTING OF METASTATIC DISEASE — 

The role of surgical therapy is very limited in patients with metastatic gastric cancer. The mainstay treatment for such patients is palliative systemic therapy. (See "Initial systemic therapy for metastatic esophageal and gastric cancer" and "Second- and later-line systemic therapy for metastatic gastric and esophageal cancer".)

Positive peritoneal cytology — Positive peritoneal cytology in the absence of metastatic disease elsewhere identifies a group of patients who are at particularly high risk for peritoneal failure [95,96]. Survival is dismal when gastrectomy is the first line of therapy [97-100]. This is a controversial area; approaches vary and include:

●At some (predominantly but not exclusively) institutions in Asia, patients with positive peritoneal cytology are thought to be suitable candidates for peritoneum-directed therapy [101-106]. At our own institution, such therapies are offered in the context of clinical trials. (See 'Isolated peritoneal metastases' below.)

●Those who decline entry into the trials for peritoneum-directed therapy may be referred for four to six months of upfront chemotherapy, then reassessed. If there is no evidence of extra-gastric progression, they then historically received five weeks of chemoradiation (CRT), followed by a five-week rest period and a formal restaging evaluation (including a repeat laparoscopy with peritoneal washings). Patients with no evidence of metastatic disease who convert to negative cytology are eligible for potentially curative surgery since a small number can achieve long-term disease-specific survival [107,108]. However, there are no randomized trials proving the benefit of neoadjuvant therapy in this setting, and the role of CRT is being re-evaluated in light of the result of the TOPGEAR study [8]. (See "Adjuvant and neoadjuvant treatment of gastric cancer", section on 'No role for adding neoadjuvant CRT to perioperative chemotherapy'.)

●At other institutions, these patients are offered only palliative systemic chemotherapy.

Additional clinical trials are needed to define the best treatment option for this highly select group of patients.

Isolated peritoneal metastases — For patients with apparently isolated peritoneal metastases, the role of cytoreductive surgery (CRS) with or without heated intraperitoneal chemotherapy (HIPEC) is not widely offered as a standard approach [101,104,109-111]. Such patients should only be evaluated for CRS and/or HIPEC within the context of a clinical trial [110].

●In a randomized phase III trial (GASTRIPEC-1) of 105 patients with gastric cancer and peritoneal metastases, relative to perioperative chemotherapy plus CRS, CRS plus HIPEC improved progression-free survival (median seven versus four months) but demonstrated similar overall survival (median 15 months for both groups) [111]. Adverse event rates were similar between the two treatment arms.

●The phase III CYTO-CHIP study analyzed the impact of CRS alone versus CRS plus HIPEC in highly selected patients with apparently isolated peritoneal metastases from gastric cancer, with data derived from prospective databases of 19 French cancer treatment centers [104]. All patients had to have complete CRS with curative intent (no residual nodules >2.5 mm). The addition of HIPEC to CRS improved overall survival (median 19 versus 12 months) and five-year recurrence-free survival (17 versus 4 percent). However, this study had several limitations. For example, it did not compare these interventions with systemic chemotherapy. A significant proportion of patients in both groups had positive cytology only. These patients were accumulated over a 25-year period and these 277 total patients (or less than one patient per center per year) represent a very highly selected population. All clinicians who care for significant numbers of patients with gastric cancer have occasional patients who have been long-term survivors despite the presence of stage IV disease by cytology or histology and without HIPEC.

●A retrospective analysis of the National Cancer Database from 2004 to 2020 identified 148 patients with gastric adenocarcinoma who underwent CRS/HIPEC (one-third of patients with pT4 disease) [112]. The medium overall survival among the stage IV patients managed with CRS/HIPEC was significantly longer than for the patients receiving only systemic chemotherapy (18.1 versus 9.3 months).

●One phase II trial examining the role of laparoscopic HIPEC in conjunction with neoadjuvant systemic chemotherapy prior to evaluation for gastrectomy in 20 patients with either isolated positive peritoneal cytology or peritoneal carcinomatosis without other distant metastases reported a three-year overall survival rate of 28 percent [106]. There were four patients still alive without disease recurrence from 32 to 49 months after the diagnosis of metastatic disease.

Palliative gastrectomy — For patients with metastatic disease, radical gastrectomy provides no survival benefit. A palliative gastrectomy may occasionally be required for symptoms such as pain, nausea, persistent bleeding, or obstruction when they cannot be palliated by any of the nonoperative methods. The criteria for selection of patients who may benefit from palliative gastrectomy as compared with other palliative procedures (including radiation therapy, endoscopic intervention, and surgical bypass) are not firmly established. These issues are discussed in detail separately. (See "Local palliation for advanced gastric cancer".)

Metastasectomy — Reports of metastasectomy for gastric cancer are limited to highly selected patients with oligo-metastatic disease. Hepatic or pulmonary metastasectomy has occasionally been performed in rare cases of isolated, small-volume metastases following a prolonged disease-free interval. However, there is no consensus on its indications, as long-term survival remains exceedingly rare even with stringent selection [113-118].

TREATMENT OF RECURRENT DISEASE — 

Treatment failure in patients with resected gastric carcinoma can be broken into local recurrence and distant metastases. In most series, distant failures predominate, even in patients with a positive surgical margin [11,119-121]. In data from the American College of Surgeons (ACS), recurrence following attempted curative resection was local or regional in 40 percent and systemic in 60 percent [11]. However, locoregional recurrences may be more frequent in patients treated with surgery alone or surgery plus postoperative chemotherapy without radiation therapy, and among those who have a smaller number of negative resected lymph nodes in the operative specimen [122].

Locally recurrent disease — Sites of locoregional failure include the luminal margins, the resection bed, and the regional nodal basins [42]. A small proportion of patients undergoing subtotal gastrectomy for gastric cancer or peptic ulcer disease may develop a gastric remnant carcinoma [123-128]. The incidence varies from 1.3 to 4 percent depending on the series and the length of follow-up [123,125]. The diagnosis of a metachronous gastric cancer versus recurrence may be difficult, but a different histologic type compared with the original tumor and location that is non-anastomotic favors metachronous cancer in the gastric remnant.

The early diagnosis of a local recurrent or gastric remnant carcinoma relies on endoscopic examination. For patients who have had a partial gastrectomy, National Comprehensive Cancer Network (NCCN) guidelines recommend surveillance endoscopy at six months, one year, two years, and three years after a partial gastrectomy [4]. By contrast, routine endoscopic surveillance is not required for asymptomatic patients who have undergone total gastrectomy.

Other experts have suggested longer (more than five years) endoscopic surveillance for early detection of asymptomatic remnant gastric cancers [123]. As an example, in a Korean population study of over 40,000 postgastrectomy patients, 4 and 9.4 percent developed recurrent cancer between 5 and 10 years and after 10 years, respectively [129]. Longer routine follow-up with a combination of endoscopy and CT scan was associated with both improved overall mortality (49 versus 37 years at 15 years) and postrecurrence survival (71 versus 33 percent). This area of practice is controversial and heavily depends on geography (East versus West).

The usual treatment for gastric remnant carcinoma is completion gastrectomy. Endoscopic management might be an option for early gastric remnant carcinomas (ie, those limited to the mucosa or submucosa), although the available data on the long-term success of this approach are limited [130].

There are only a few case series that describe long-term survivors following curative resection of a locally recurrent or gastric remnant gastric cancer [124,131-136]. In a series of 60 patients (seen over a 30-year period) who underwent an attempted resection for recurrent gastric or gastroesophageal cancer, 29 were resectable at laparotomy, 14 of whom required adjacent organ resection, and six, interposition grafting [131]. The median overall survival for patients undergoing resection was 26 months, compared with six months for unresectable patients.

Results of surgical resection may be more favorable when a gastric remnant adenocarcinoma develops at a non-anastomotic site. These cancers can represent new primary cancers, which should be differentiated from recurrence if possible. In one series of 52 such patients who underwent a second operation with curative intent because of a remnant gastric cancer, the overall five-year survival rates were significantly higher for those with a non-anastomotic recurrence (96 versus 37 percent) [124].

While these results suggest that salvage surgery may contribute to prolonged survival, the opportunity to resect locally recurrent gastric tumors is infrequent at best [137]. Curative surgery should be restricted to highly selected, fit patients with an isolated local recurrence and no evidence of distant spread.

Rather than surgery, most patients with recurrent disease are offered systemic chemotherapy for palliation of symptoms. Occasionally, local palliative procedures, such as radiation therapy (in patients not previously having received radiation therapy at the site of recurrence), are needed for symptom control. The treatment of advanced gastric cancer is discussed in detail separately. (See "Initial systemic therapy for metastatic esophageal and gastric cancer" and "Local palliation for advanced gastric cancer", section on 'Radiation therapy'.)

Distant metastasis — The predominant sites of systemic recurrence in the era of preoperative therapy are the liver and peritoneum [138]. With the more widespread use of preoperative systemic therapy, there seems to be a shift of recurrences to later time periods. Metastatic disease beyond the abdomen is uncommonly the first site of recurrence aside from the supraclavicular nodes. Patients who develop distant metastasis are generally treated with palliative systemic therapy, although radiation therapy may be used for isolated bone metastases. (See "Initial systemic therapy for metastatic esophageal and gastric cancer" and "Second- and later-line systemic therapy for metastatic gastric and esophageal cancer" and "Radiation therapy techniques in cancer treatment".)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Gastric cancer" and "Society guideline links: Gastric surgery for cancer".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Stomach cancer (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Resectable gastric cancer – For patients with resectable gastric cancer, complete surgical eradication of the gastric tumor and adjacent lymph nodes represents the best chance for long-term survival. In North America and Europe, the standard of care for most patients with clinical T2N0 or higher resectable gastric cancer is to also receive perioperative chemotherapy (ie, both before and after surgery). (See 'Sequences of treatment by stage' above and "Adjuvant and neoadjuvant treatment of gastric cancer" and "Neoadjuvant and adjuvant therapy for locally advanced resectable esophagogastric junction and gastric cardia adenocarcinoma".)

•Extent of surgical resection – The choice of operation for gastric cancer depends on the location of the tumor within the stomach. (See 'Extent of resection' above.)

-Distal tumors – For patients with lesions in the distal (lower two-thirds) stomach, we recommend a distal rather than a total gastrectomy (Grade 1B). A distal gastrectomy is oncologically equivalent to a total gastrectomy while reducing perioperative complications. (See 'Distal tumors' above.)

-Proximal, large midgastric, or infiltrative disease – For patients with proximal (upper third) tumors or large midgastric lesions or infiltrative disease (eg, linitis plastica), we suggest a total gastrectomy rather than a partial gastrectomy (Grade 2C). (See 'Proximal tumors' above.)

-Esophagogastric tumors – Surgical management of tumors involving the esophagogastric junction is discussed separately. (See "Surgical management of resectable esophageal and esophagogastric junction cancers", section on 'Esophagogastric junction cancer resection'.)

•Extent of lymphadenectomy – For most patients undergoing curative gastrectomy for invasive gastric cancer, we suggest a D2 rather than a D1 or D3 resection (Grade 2B). A D2 resection confers better disease-specific survival than a D1 resection and lower perioperative mortality and morbidity than a D3 resection. The goal is to recover at least 16 regional nodes to be assessed pathologically, but the removal and evaluation of more nodes (30 or more) is desirable. (See 'Extent of lymph node dissection' above.)

●Metastatic disease – The role of surgical therapy is very limited in patients with metastatic gastric cancer. The mainstay treatment for such patients is palliative systemic therapy. (See 'Surgery in the setting of metastatic disease' above.)

For patients with limited or no (positive cytology only) peritoneal metastasis, cytoreductive surgery (CRS) with or without heated intraperitoneal chemotherapy (HIPEC) is offered at some centers, but only within the context of a clinical trial. (See 'Surgery in the setting of metastatic disease' above.)

●Recurrent disease – After gastrectomy, gastric cancer recurs more frequently at distant sites than locoregionally. Patients who undergo partial gastrectomy can develop cancer in the gastric remnant. At a minimum, surveillance endoscopy should be performed at six months, one year, two years, and three years after resection. Highly selected, fit patients with an isolated local recurrence and no evidence of distant spread may undergo completion gastrectomy; the others receive palliative systemic therapy. (See 'Treatment of recurrent disease' above.)