|PRACTICE CHANGING CONTINUING EDUCATION: GASTROINTESTINAL SURGERY
|Year : 2014 | Volume
| Issue : 1 | Page : 41-49
Current strategies in the diagnosis and management of resectable gastric adenocarcinoma
Savio G Barreto
Department of Gastrointestinal Surgery, Gastrointestinal Oncology, and Bariatric Surgery, Medanta Institute of Digestive and Hepatobiliary Sciences, India
|Date of Web Publication||3-May-2014|
Dr. Savio G Barreto
Department of Gastrointestinal Surgery, Gastrointestinal Oncology, and Bariatric Surgery, Medanta Institute of Digestive and Hepatobiliary Sciences, Medanta, The Medicity, Sector 38, Gurgaon, Haryana
Source of Support: None, Conflict of Interest: None
Gastric cancer is generally associated with a dismal outcome. One of the major reasons for this is the fact that patients often ignore the early symptoms of the disease, which masquerade benign diseases such as reflux disease and gastritis, and hence present when the cancer is advanced or metastatic. Multidisciplinary management has emerged as an important determinant of outcomes in patients with gastric cancer. Complete surgical resection remains the cornerstone if cure is to be achieved, especially in those patients with non-metastatic disease. This article provides an updated review of the multidisciplinary management of patients with resectable gastric adenocarcinoma.
Keywords: D2 lymphadenectomy; morbidity; mortality; radical
|How to cite this article:|
Barreto SG. Current strategies in the diagnosis and management of resectable gastric adenocarcinoma. Astrocyte 2014;1:41-9
Savio G. Barreto∗
(∗Member, ICMR Gastric Cancer Task Force)
| Introduction|| |
The incidence of gastric cancer in the whole of India is not as high as some of the other regions of the world, such as Eastern Asia, Eastern Europe, and South America,  except for the North Eastern states, such as Mizoram and Sikkim. ,,,, However, gastric cancer has been reported to be among the five most common cancers affecting young Indian men and women (age, 15-44 years).  Additionally, it has been found to be the second most common cause of cancer-related deaths among Indian men and women.  A multidisciplinary approach that encompasses medical and surgical gastroenterologists, as well as medical and radiation oncologists has emerged as the cornerstone in achieving the best outcome for patients with resectable gastric cancer. Thus, the dissemination of knowledge of the appropriate treatment approach is essential. This article provides an evidence-based review of the existing literature with respect to the evaluation and management of patients with resectable gastric adenocarcinoma or cancer, with or without lymph nodes, and no distant metastases.
| Etiology|| |
Factors associated with the development of gastric cancer are largely lifestyle-related, including diet, smoking, and alcohol. Infections (such as Helicobacter pylori), too, have been reported, although inconsistently.
- Diet: Salt intake has been consistently linked with the increased risk for developing gastric cancer  possibly related to the chronic inflammation causing chronic atrophic gastritis.  On the other hand, fruits and vegetables are associated with a reduced risk of gastric cancer. In Kashmir, the consumption of "salted tea" has been postulated to predispose to the development of gastric cancer.  Preserved and pickled foods are also notorious for predisposing an individual to the development of gastric cancer. However, the continued consumption of fermented foods as well as salted and smoked fried meat and dried, smoked, and preserved meat in Sikkim  may be the cause for the high incidence of gastric cancer noted there. In fact, the use of refrigeration has been touted to be one of the important causes for the worldwide reduction in the incidence of gastric cancer  in the last 50 years.
- Smoking and alcohol: Tobacco is a known risk factor for gastric cancer.  The alcohol drink (chang) and tobacco smoking  have been suggested to predispose an individual to gastric cancer in the North East of India.
- Infections: A link between H. pylori and Epstein-Barr virus (EBV) and the development of gastric cancer have been suggested. ,,,
- Hereditary factors: Patients with hereditary cancer syndromes such as hereditary nonpolyposis colon cancer (HNPCC),  familial adenomatous polyposis (FAP), and Peutz-Jeghers syndrome are at risk for the development of gastric cancer. An autosomal dominant mutation in the gene encoding the cell adhesion molecule, E-cadherin may lead to the development of hereditary diffuse gastric cancer. ,
- Other factors: Obesity,  prior radiation exposure for other malignancies,  and the blood group A  have been reported to influence the development of gastric cancer in individuals.
| Classification of Gastric Cancer|| |
Lauren divided gastric cancers into two main types, namely, intestinal and diffuse.  The World Health Organization (WHO) subsequently provided a classification for gastric cancers.  However, from a clinical management stand point, the important classifications of gastric cancer include the differentiation between early and advanced gastric cancer and the appreciation of the extent of spread [locoregional and distant or tumor, node, and metastasis (TNM)]. Although the actual TNM is detected in retrospect following pathological assessment of the resected tumor, preoperative prediction of the TNM staging assumes importance in deciding the best approach for the patient.
Early gastric cancer is defined as a cancer in which the depth of invasion is limited to the submucosal layer of the stomach on histological examination,  irrespective of lymph node metastasis. , These tumors, classified as Type 0,  have been further subdivided into protruding (type 0-I), superficial elevated (type 0-IIA), superficial flat (type 0-IIB), superficial depressed (type 0-IIC), and excavated (type 0-III).
However, advanced gastric cancers have been macroscopically classified as follows,  namely,
Type 1: Mass-Polypoidtumors, sharply demarcated from the surrounding mucosa.
Type 2: Ulcerative-Ulcerated tumors with raised margins, surrounded by a thickened gastric wall with clear margins.
Type 3: Infiltrative ulcerative-Ulcerated tumors with raised margins, surrounded by a thickened gastric wall without clear margins.
Type 4: Diffuse infiltrative-Tumors without marked ulceration or raised margins, the gastric wall is thickened and indurated and the margin is unclear.
Type 5: Unclassifiable-Tumors that cannot be classified into any of the above types.
American Joint Committee on Cancer staging - 7th Edition 
The most widely used classification of tumors based on locoregional and distant spread is provided by the American Joint Committee on Cancer. This classification describes the tumor (T) and lymph node (N) involvement as well as distant tumor spread (M). The classification system that was recently updated in 2010 has been highlighted in [Table 1].
|Table 1: Seventh edition of American Joint Committee on Cancer Staging of Gastric Cancer|
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Signs and Symptoms of Gastric Cancer
Patients with new-onset dyspepsia after the age of 40 years should always be advised an upper gastrointestinal (GI) endoscopy to rule out an underlying malignancy. The features commonly associated with gastric cancer, namely, anemia and associated fatigue, anorexia, and marked weight loss are generally late signs of the disease. Dysphagia or difficulty in swallowing may be encountered in tumors in the proximal stomach, whereas vomiting of ingested food a couple of hours to even days after a meal (gastric outlet obstruction) is generally encountered in tumors involving the antrum and pylorus of the stomach. Malaena due to chronic bleeding from the ulcer is another important symptom that should alert the clinician to advise an upper GI endoscopy.
Clinical signs in a patient with gastric cancer include pallor from bleeding and a succession splash in a distal tumor. Features such ascites, jaundice (unless associated with a coincidental stone in the bile duct or hepatitis), a Blummer shelf/palpable large adnexal masses on digital rectal examination (Krukenberg tumor), an umbilical nodule (Sister Mary Joseph nodule), or a left supraclavicular lymph node generally suggest advanced disease. Very rarely cutaneous deposits have been reported on the entire abdominal wall. 
Diagnosis and Staging of Gastric Carcinoma
Following the clinical evaluation, an approach to a patient with suspected gastric cancer should include the following:
- An upper GI endoscopy-this will not only provide a confirmation of the lesion location, but also pathological proof of the cancer (which is essential for planning treatment). Narrow band imaging, an image-enhancement system employing optic digital methods to enhance images of blood vessels on mucosal surfaces, allowing improved visualization of mucosal surface structures has not been found to be vastly useful in the stomach (as compared with the esophagus) owing to the presence of mucus and regurgitated bile, the light volume insufficiency created by the wide cavity, and finally chronic food-associated stimuli and H. pylori-related gastritis. 
- Contrast-enhanced computed tomography (CT) scan of the abdomen and pelvis-this will enable localization of the primary tumor, its extent, and its relationships with the surrounding structures such as the pancreas, liver, diaphragm, transverse colon, and portal structures. It will also provide an objective visual demonstration of the presence or absence of gastric outlet obstruction. Besides, it can also be useful for evaluation of regional lymph nodes and distant metastases. Another important indication for CT scan is in the assessment of response to neoadjuvant chemotherapy by the RECIST guidelines.  Although CT may not be as accurate as magnetic resonance imaging (MRI) for evaluation of the T-stage (72% vs 83%), it surpasses MRI in terms of nodal staging (66% vs 53%) and in the evaluation of distant metastases , and is hence preferred as the initial investigation. Moreover, the availability of the technology as well as the expertise of interpretation of CT scan makes CT the first, and often the only, imaging employed in the preoperative evaluation of gastric cancer.
- Tumor markers-tumor markers, serum carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9), although not routinely recommended owing to lack of sufficient evidence, may have a role if they are elevated at diagnosis. In these patients, these tumor markers can be used in the follow-up to detect recurrent disease.
- Chest X-ray- helps to rule out lung metastases and co-existent pulmonary pathologies that may deserve attention when planning patient treatment.
- Routine blood investigations (complete blood count, renal and liver function tests)-although these do not aid in the confirmation of the diagnosis of a patient with gastric cancer, they are included here as they need to be performed in patients who are going to be treated by the clinician using a mutlimodality approach.
Based on the above investigations, the clinician will be able to confidently determine if the cancer is early or advanced. If the cancer is early and an endoscopic therapeutic approach is being planned, an endosonography (EUS) forms an important investigative adjunct to rule out lymph node metastases with a reasonable degree of confidence. A recent meta-analysis exploring the role of EUS in the preoperative staging of gastric cancer,  comprising 22 articles, found that with regard to nodal staging, the pooled sensitivity was 74%, and specificity was 80%. On the other hand, if the above investigations indicate that the disease is locally advanced (T3 or T4), the clinician may either choose between 18 fluoro-deoxy glucose positron emission tomography (FDG-PET) in proximal gastroesophageal well-differentiated tumors to assess metastases, or a staging laparoscopy (SL).  In such patients, detection of metastatic disease by SL could help direct the patient toward palliative chemotherapy rather than neoadjuvant therapy. PET should be avoided in patients with non-solid-type poorly differentiated carcinoma or signet ring cell tumors owing to the high false negative rates.  PET, however, has the ability to also guide treatment response in FDG-avid tumors. 
Her-2 testing has been recommended for patients with metastatic or recurrent advanced gastric cancer.  However, it has no role in resectable, non- metastatic disease.
Treatment of Resectable Gastric Cancer
Complete removal of the tumor with microscopically negative margins (R0 resection) offers the best chance of survival in patients with gastric cancer. Removal of the tumor may be achieved by endoscopy or surgery-the choice depending on the extent of the tumor and nodal involvement. Chemotherapy, radiotherapy, and novel targeted therapies serve as adjunctive tools to surgery in improving survival and/or delaying recurrence of disease, whenever they are indicated.
Early Gastric Cancer
Generally, early gastric cancers are rare in places that do not have an active screening program (as is the case in Japan). However, detecting these lesions in patients who undergo an endoscopy and biopsy for early symptoms is certainly possible.
Caution is advised, at the outset, in interpreting data that may suggest that endoscopy is an option in all early gastric cancers. By definition, early gastric cancer is defined by the extent of gastric wall invasion (into submucosa  ) irrespective of lymph node involvement. , Although endoscopic excision is certainly feasible in early lesions, they cannot be performed if there is a suspicion of lymph node disease-in which case surgery is the sole option at the present time.
Therapeutic Endoscopy for Early Gastric Cancer
Endoscopic submucosal dissection (ESMD) and endoscopic mucosal resection (EMR) are the two therapeutic endoscopic techniques. Despite the evidence that ESMD has a higher risk of complications, such as perforation and bleeding, the success rate of complete (en bloc) resection is higher  with a lower local recurrence rate.  Before performing either procedure, it is imperative that an EUS be done to determine the extent of local disease and lymph node involvement (which has been reported to be up to 42% even in early gastric cancer. , ).
Factors Predictive of the Lymph Node Metastases
Size of Lesion
Rong et al.  recently reviewed the data and noted that in lesions >2 cm, the incidence of lymph node involvement increases to 25.64% as compared with 5.13% in lesions between 1 and 2 cm.
Lymphovascular Invasion (LVI)
The presence of LVI is an independent risk factor for the presence of lymph node metastases. ,,
Depth of Invasion
Tumors invading into the submucosa are at risk of spreading to lymph nodes.  The Japanese Gastric Cancer Association  has subdivided submucosal (SM) invasion into SM1 (tumor invasion within 0.5 mm of the muscularis mucosae) and SM2 (tumor invasion is 0.5 mm or more into the muscularis mucosae). Park et al.  found that the incidence of lymph node metastasis rate in patients with poorly differentiated SM2, or more, lesions rose sharply to 30% from 3.4% (in lesions confined to the mucosa).
Undifferentiated lesions are at a significantly higher risk for lymph node metastases as compared with differentiated lesions. ,
The available evidence of features such as ulceration and macroscopic type of tumor is conflicting and thus no firm conclusions can be drawn from the data.
Thus, in lesions more than 2 cm, or those that have features, such as LVI, submucosal invasion, and undifferentiation, surgery should be the preferred option in view of the higher risk of lymph node metastasis.
Surgery for Gastric Carcinoma
Treatment of the Primary Tumor
In tumors other than early gastric cancer (<2 cm with no concerning features mentioned above), surgery remains the mainstay of tumor removal.
Extent of Resection
The extent of resection of the tumor depends on tumor location in the stomach. Three surgeries have been defined oncologically for the removal of the primary tumor, namely, subtotal (distal), proximal, and total gastrectomy.
Based on the anatomical division of the stomach as proposed in the "Japanese Classification of Gastric Carcinoma,"  the prescribed surgeries are as follows:
• Lesions in the Upper Third
The choice of surgery is between a total (with a Roux-en-Y esophagojejunostomy with or without pouch) and a proximal gastrectomy (where at least half of the stomach can be preserved). In terms of oncological outcomes, Wen et al.  recently concluded that there exists no difference between the two procedures.
• Lesions in the Middle Third
Tumors arising from and involving the upper middle third of the stomach are best managed by a total gastrectomy.  In some tumors of the middle third, the lesion may be preferentially located in the lower part of the middle third for which a (distal) subtotal gastrectomy can be offered to the patient so long as negative resection margins can be obtained.
• Lesions in the Lower Third
Although total gastrectomy was considered the standard operation in the past, current evidence clearly supports no difference in oncological outcomes for subtotal gastrectomy performed for lesions in this location of the stomach. ,
Although staplers have been shown to be associated with an increased risk for anastomotic strictures in reconstruction following esophagectomy,  the only study comparing the two techniques following resection for gastric cancer by Takeyoshi et al.  found no difference in anastomotic stricture formation with a lower incidence of anastomotic leak in the stapled group.
Intraoperative Frozen Section for Margins
Given that a positive resection margin is associated with poor overall outcomes,  especially in patients with less than five lymph nodes involved by disease,  performing intraoperative frozen section (IOFS) in routine practice for T3/T4 lesions or those in whom the gross resection margin is less than 5 cm is encouraged.  However, this also raises an important issue on the ability to revise the margin. Sun et al.  found that the impact of a positive final pathological margin (following a negative frozen section result) was negated by the presence of higher disease stage (including T stage) and nodal involvement. Thus, should a safe revision of the resection margin be achievable, this should be performed and confirmed on IOFS. However, the choice of performing a more extensive resection (eg, a pancreatoduodenectomy to achieve a distal negative margin) needs to be tempered by taking into account the extent of disease and the patient's ability to tolerate an extensive resection  (see "Multivisceral resections" section).
Reconstruction after a Total Gastrectomy
Removal of the stomach, with the resultant loss of its reservoir and nutritional functions does alter the patient's life following surgery. Although there exists no strategy to compensate the lack of gastric acid in digestion post-total gastrectomy, Vitamin B12 supplementation may help in overcoming the absence of intrinsic factor production. With regard to the reservoir function, various techniques for reconstruction following total gastrectomy have been attempted, which aim at targeting three important aspects, namely, prevention of reflux, preservation of duodenal transit, and creation of a gastric reservoir.  In the past, esophagoduodenostomy was suggested as a form of reconstruction.  Currently, the main technique of reconstruction performed the world over is the esophagojejunostomy, which can be performed as a Roux-loop of jejunum anastomosed to the esophagus or a pouch (J-, S- or Ω-shaped) constructed from the jejunum and anastomosed to the esophagus. The evidence in the literature on the types of reconstruction after total gastrectomy has indicated that creation of a small bowel reservoir in the form of a pouch improved early postoperative eating capacity, body weight, and quality of life, as well as helped reduce symptoms of dumping and heartburn. ,
[Table 2] provides the anatomical lymph node stations as described by the Japanese Gastric Cancer Association.  The extent of lymphadenectomy has been described as D0-D2 based on clearance of the lymph node echelons for a particular subsite of the stomach. The use of the terminology D3 and D4 lymphadenectomy has now been ceased owing to the appreciation of the lack of benefit of paraaotic lymphadenectomy as compared with a D2 lymphadenectomy. ,,, The 3rd edition of the Japanese Gastric Cancer Association has provided the prescribed extent of lymphadenectomy as per the extent of resection, which is summarized in [Table 3].
|Table 2: Regional Lymph Nodes Draining the Stomach from the Japanese Gastric Cancer Associationa|
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|Table 3: Definition of Lymphadenectomy as per the Type of Gastrectomy|
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A D2 lymphadenectomy (removal of lymph nodes up to, and including, the second echelon) is currently regarded as the standard of care, the world over, for tumors ≥ T1b.  For tumors that are either carcinoma in situ or T1a, a D0/D1 lymphadenectomy would suffice.  For an adequate staging of gastric cancer, a minimum of 16 lymph nodes need to be assessed. 
Even in patients who receive neoadjuvant chemotherapy as part of planned perioperative therapy for locally advanced (but nonmetastatic) cancers, the performance of a D2 lymphadenectomy is considered essential. 
The rationale for performing a bursectomy, the dissection of the peritoneal lining of the lesser sac (the lining over the anterior transverse mesocolon and pancreas) along with omentectomy, , is to remove potential micrometastases disseminated into the bursa omentalis, which may occur in cancers located in the posterior wall of the stomach.  There is no high-level evidence in literature to currently recommend bursectomy more so if the patient is undergoing a D2 lymphadenectomy.  A randomized controlled trial is currently underway in Japan (JCOG1001, Bursectomy Phase III trial (Clinical Trials no: UMIN000003688))-the results of which are awaited.
Multivisceral Resections (Including Splenectomy)
The available data on the impact of multivisceral resections on outcomes in gastric cancer is very much heterogeneous. The factors in a multivisceral resection that influence survival include the ability to achieve an R0 margin and extent of lymph node disease. A systematic review of 17 studies published in 2012  indicated that multivisceral resection, although feasible, remains a procedure with a high perioperative morbidity (12%-91%) and even mortality (up to 15%). Thus, based on the available data that a margin-positive resection does not provide a 5-year survival benefit, routine performance of these procedures is not recommended.
Some studies have included the performance of splenectomy under the broad umbrella of "multivisceral resections." The main indications for performing a splenectomy in gastric cancer are (1) as part of total gastrectomy performed for tumors located along the greater curvature of the stomach with metastases to No. 4sb; and (2) in patients with T2-T4 tumors along the greater curvature of the stomach in whom a clearance of No. 10 lymph nodes needs to be performed. 
The decision to embark on multivisceral should be tempered taking into account the experience of the surgeon, the performance status of the patient, the disease burden (especially lymph node), the extent of resection and the true and honest likelihood of achieving a complete resection.
Laparoscopic Surgery in Gastric Cancer
Open surgery remains the standard surgical approach at the present time. Laparoscopic gastric surgery is feasible and has been shown to be comparable to open surgery for resection of early gastric lesions. However, the data on the ability to perform a D2 lymphadenectomy is not yet convincing. Two published meta-analyses compared laparoscopy with open surgery for gastric cancer and found that laparoscopy results in a smaller size of the surgical scar and is accompanied by a reduction in minor complications, and faster recovery of gastrointestinal function, there has been no difference in major complications and mortality. However, laparoscopic surgery was found to be significantly longer than the open procedure , and is associated with a lower lymph node harvest. 
Chemotherapy and Chemoradiotherapy for Resectable Gastric Adenocarcinoma
Following a number of trials comparing the benefit of surgery versus surgery and adjuvant or neoadjuvant therapy,  guidelines for management have been developed. ,,,
[Table 4] provides pertinent information from the landmark randomized controlled trials for chemotherapy and chemoradiotherapy in resectable gastric cancer. ,,,,,,
|Table 4: Some of the landmark trials in chemotherapy and chemoradiotherapy in resectable gastric cancer (including the most updated follow-up of the trials)|
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The GOIRC trial (Italian trial) comparing surgery alone versus surgery and adjuvant chemotherapy failed to demonstrate a benefit of adjuvant chemotherapy over surgery alone.  One of the major criticisms of the trial was the lack of surgical standardization. A randomized controlled trial form Japan comparing surgery alone versus surgery followed by adjuvant uracil-tegafur chemotherapy had to be prematurely terminated owing to poor accrual.  However, despite this, the study demonstrated a clear survival benefit for adjuvant chemotherapy.
Suggested Treatment Approach
In summary, patients with early gastric cancer (suspected to be T1a with N0 disease), therapeutic endoscopic procedures such as EMR or ESMD remain a valid option so long as the expertise is available and the presence of lymph node involvement can be confidently ruled out. If after therapeutic endoscopy, negative prognostic factors as mentioned above are found, the patient must be offered a surgical resection. If the facilities for therapeutic endoscopy are not available, a D1/D0 gastrectomy must be performed.
In patients with T1b N0 disease, a D1 gastrectomy would suffice as optimal treatment.
However, in patients with T2N0 disease, a D2 gastrectomy would serve as an optimal treatment.
In patients with radiologically predicted disease, that is, ≥T3N0/N+ (node positive) or T2N+, neoadjuvant treatment as part of perioperative chemotherapy would be advisable followed by surgery (D2 gastrectomy). However, if these patients undergo upfront surgery owing to bleeding tumors, gastric outlet obstruction, or refusal for neoadjuvant chemotherapy, then the preferred adjuvant therapy, as per the available evidence, would be chemoradiotherapy for N+ disease or chemotherapy alone for T3/4N0 disease.
| Summary|| |
Gastric cancer remains a disease with a poor prognosis in most parts of the world, including India, owing to a delay in diagnosis. A proper workup using contrast-enhanced CT scans to stage the disease is imperative so as to plan perioperative chemotherapy in patients with locally advanced tumor (including nodal disease). Surgery, in the form of a complete surgical resection, remains the cornerstone of management of resectable gastric adenocarcinoma. There is a high level of evidence to support the role for perioperative chemotherapy as well as adjuvant chemoradiotherapy to improve the overall and recurrence-free survival in these patients.
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[Table 1], [Table 2], [Table 3], [Table 4]