Cancer Stomach

Current Problems in Surgery: Gastric Cancer
Gastric cancer is the fourth most common cancer worldwide. Approximately 600,000 new cases are diagnosed each year; almost two thirds of these individuals will die of their disease.1 Most cases (65% to 75%) of gastric cancer occur in developing countries.1 In many regions of Eastern Europe and East Asia, gastric cancer is the leading cause of cancer death. The countries with the highest incidence rates (more than 40 new diagnoses per 100,000 individuals per year) are Korea, Japan, Chile, Belarus, Kazakhstan, China, and Costa Rica. Within many countries, there is also regional variation emphasizing the differences in physical, biological, social, and environmental factors involved in the pathogenesis of gastric cancer.2,3 The United States has 1 of the lowest incidence rates. The incidence of gastric cancer globally and in the United States has steadily declined for the last 60 years. Surveillance Epidemiology and End Results (SEER) data have reported a decrease in incidence from 11.7 per 100,000 in 1975 to 8.8 per 100,000 in 2002.4 Within the United States, there is a regional difference in incidence (the highest incidence is in Hawaii). Similarly, there are racial and gender differences in incidence, with higher rates in men and blacks: 15.4 cases of gastric cancer per 100,000 black males versus 6 per 100,000 white women.4 In Los Angeles, ethnic variation in incidence is pronounced, with the highest incidence in the Korean population and lowest in the Hispanic-white population.2 However, with each successive generation, the incidence in Asian immigrants approaches their host country, suggesting that environmental factors play a greater role than genetic factors.5 Even rst generation Japanese residents of Hawaii and So Paulo, Brazil, have been found to have decreased rates of gastric cancer compared with their native countries.5,6 The precise cause of the overall decline in stomach cancer worldwide is unknown. Many experts attribute the decline to the advent of refrigeration
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and the increased access to fresh fruits and vegetables.3 However, the relationship between refrigeration and the etiology of stomach cancer is unproven. Studies from England, Germany, and Venezuela have suggested that there is a decreased risk of gastric cancer if refrigeration is used for greater than 30 years.7-9 In contrast, a Polish cohort study showed no association between long-term refrigerator use and stomach cancer.10 More recently, the large Netherlands Cohort Study representing 120,852 men and women showed no association between the duration of refrigerator use and stomach cancer.11 In addition to decreased incidence of gastric cancer, recent epidemiologic studies suggest a changing anatomic pattern in the incidence of gastric cancer. Although the incidence of distal cancers has greatly decreased, the incidence of cardia or proximal stomach cancers has increased.12 The Rochester Epidemiology Project, a longitudinal study of Olmsted County, Minnesota, in residents from 1941 and 1990, showed an overall decline in gastric cancer, but found that the decline represented only distal and intestinal-type gastric cancers. The incidence of proximal and diffuse-type gastric cancers remains stable.13 The shift from distal to proximal location of gastric cancers has been noted in many studies and likely represents a change in environmental factors that play a role in the pathogenesis of cancer of the stomach.14-16 In summary, the lifetime risk of gastric cancer for current U.S. residents is approximately 1% and the lifetime risk of dying from gastric cancer is 0.6%. The mean age at time of diagnosis is 72 years. Approximately 24% of stomach cancers currently diagnosed in the United States are localized at the time of presentation, 32% have spread to regional lymph nodes or directly beyond the primary site, and 32% are associated with metastatic disease.
Pathophysiology of Gastric Cancer

Development of stomach cancer is a complex process involving environment factors, host susceptibility, and a viral or bacterial infection. Risk factors include male gender; family history; polyposis syndromes; pickled foods; diets high in nitrates and salts; gastric adenomas; previous partial gastrectomy, and Menetriers disease. Aspirin, a fresh fruit and vegetable diet, selenium, and vitamin C may decrease the risk for gastric cancer3,14,17,18 (Table 1). Familial Gastric Cancer. Hereditary gastric cancer represents only 10% of gastric cancers. Hereditary nonpolyposis colorectal cancer (HNPCC), familial adenomatous polyposis (FAP), and BRCA2 mutations are all associated with gastric cancer in addition to colon cancer.19-22 In 1964, familial gastric cancer was identied in a large kindred of Maori
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TABLE 1. Risk factors for gastric cancer High salt and pickled food diet Exogenous chemicals Intragastric synthesis of carcinogens (converting nitrates to nitrites) Genetic factors Infectious agents (Helicobacter pylori, Epstein-Barr virus) Pathologic conditions of the stomach (atrophic gastritis, intestinal metaplasia) Adapted with permission from Shang and Pena. Multidisciplinary Approach to Understand the Pathogenesis of Gastric Cancer. World J Gastroenterol 2005;11:41319.
TABLE 2. Genetic alternations identied in gastric cancer Polymorphism Microsatellite instability Oncogenes Cell proliferation and apoptosis Cell-cell interaction Neoangiogenesis Epigenetic changes Interleukin-1 K-sam, c-met, c-erbB-2 bcl-2, Cyclin D1, E2F-1, SC-1 ICAM-1, VCAM-1, E-cadherin (CDH1), beta-catenin, MMPs VEGF, HIF-alpha, ECM1 Hyper- or hypomethylation by DNA methyltransferases (DNMTs) Repress chromatin states by histone deacetylase (HDAC) p16INK4a, p15INK4b, p73, p14ARF, p73, adenomatous polyposis coli (APC), BRCA1 hMLH1 E-cadherin (CDH1), TIMP3, DAPK
Tumor suppressor genes
DNA repair Metastasis and invasion genes
Adapted with permission from Chen et al. Recent advances in molecular diagnosis and therapy of gastric cancer. Dig Dis 2004;22:381.
from New Zealand and recently identied as a germline mutation in E-cadherin.23 Loss of function or low levels of E-cadherin is seen in 50% of diffuse-type stomach cancers.24 Loss of E-cadherin function may disrupt cell-cell adhesion thus altering growth-control signals.23 Genetic Alteration. Numerous other genetic alterations have been identied in gastric cancers. They include gene deletion, suppression, amplication, overexpression, microsatellite instability, and DNA aneuploidy25 (Table 2). Environment. The dramatic reduction in the incidence and mortality of gastric cancer worldwide has been attributed to environmental factors including improvement in socioeconomic status, refrigeration, and improved access to fresh fruits and vegetables. The relationship between refrigeration and the decreased incidence of gastric cancer is likely due to decreased use of salt and other nitrate-based preservatives in food preservation and the increased availability of fresh vegetables and fruit.
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Salt, pickled foods, and smoked foods are probable risk factors for stomach cancer according to a WHO/FAO expert panel.26 Establishing a link between cancer and diet is complex given the difculties in measuring diet and the lag time between exposure and diagnosis. Most research is based on case-control and cohort studies.27 The carcinogenic effect of dried and cured meat, pickled foods, and smoked sh is likely due to the high content of salt and nitrates. Early animal models from the 1960s support the carcinogenic effect of N-nitroso compounds (N=-nitro-N-nitrosoguanidine).28 Nitrates are converted to carcinogenic nitrite compounds in the stomach. Low gastric pH and antioxidants vitamin C and -carotene inhibit this endogenous process.29 Conversely, high gastric pH facilitates the process. Based on these ndings, randomized controlled trials have studied vitamin supplementation and its role in cancer prevention. The results of these studies have been mixed. A Chinese study of 29,584 men found a 21% reduction (relative risk [RR], 0.79; 95% condence interval [CI], 0.64-0.99) in stomach cancer mortality in a group using a diet supplemented with vitamin E, -carotene, and selenium.30 On the other hand, the Finnish Alpha-Tocopherol, Beta-Carotene, Cancer Prevention Study (ATBC) of 29,133 middle-aged smokers showed no risk reduction with vitamin supplementation.31 A follow-up study to the ATBC study suggested that there are no benets and that -carotene may actually increase the risk of lung cancer in smoking patients.32 Diets high in raw and fresh vegetables are inversely related to the incidence of gastric cancer.3 Cohort and case-control studies show raw, fresh vegetables to be the most protective. However, the anticarcinogenetic properties of fruits and raw vegetables have yet to be proven, and it may be that populations with higher fruit and vegetable consumption have lower consumption of animal products. Research has focused on nding the active anticarcinogens in fruits and vegetables. Potential candidates include antioxidants, coumarins, avonoids, isoavones, isothiocyanates, phytosterols, and gucosinolates.3 Like the vitamin studies described above, there are no good human studies to support the positive ndings of in vitro studies. Future reports by the European Prospective Investigation into Cancer and Nutrition (EPIC) study representing over 500,000 individuals will help outline the impact of diet on stomach cancer (see http://www.iarc.fr/epic). It is likely that a combination of foods or overall dietary habits impact the incidence of gastric cancer rather than specic foods or nutrients. Tobacco and Alcohol. The carcinogenetic effect of tobacco is well established in oropharyngeal and lung cancer. The link between smoking and gastric cancer has not been as clear. In 1997, Tredaniel and colleagues33 reviewed multiple cohort studies and 40 case-control studies and found an
increased risk ( 1.5) of gastric cancer among smokers. These investigators concluded that 11% of all gastric cancers are due in part to smoking.33 In a multicenter, case-control study of esophageal and gastric cancer, Gammon and colleagues showed an increased risk of gastric adenocarcinoma in smokers.34 These studies make a convincing case for a link between smoking and stomach cancer. On the other hand, an association between alcohol consumption and gastric cancer is unlikely. The case-control study by Gammon and colleagues showed no association between the two.34 Other studies have found no association.35,36 Helicobacter Pylori. H. pylori was described by J. Robin Warren in 1983.37 H. pylori is a microaerophilic, sheathed bacteria with 7 agella that infects the gastric mucosa. H. pylori is now known to play a central role in the pathogenesis of gastric cancer and considered to be carcinogenic by the International Agency for Research on Cancer at the World Health Organization (WHO).38 There is a strong association between H. pylori infection and stomach cancer.39 However, not all regions with high rates of H. pylori colonization have high rates of gastric cancer, emphasizing the fact that H. pylori is only 1 of many contributors to the development of stomach cancer. For example, there is a very high incidence of H. pylori infection (70% to 80% of population) in West Africa but a low incidence of gastric cancer (less than 2% of malignant tumors)the African enigma.40 Most studies suggest that the carcinogenic effect of H. pylori infection is subtle, requiring chronic exposure over more than 40 years.41 H. pylori infects a majority of people worldwide at an early age, particularly in developing countries and regions with low socioeconomic status.41,42 In developing countries, 80% to 90% of children are infected with H. pylori.29 Although H. pylori infection varies with ethnicity, this variability may actually be a reection of socioeconomic status.41,43 H. pylori is a chronic infection that rarely resolves spontaneously.29 Prolonged exposure to H. pylori and the associated inammatory reaction leads to cancer. Tahara has outlined the combined effect of H. pylori infection and the genetic alterations that lead to gastric cancer25 (Fig 1). Numerous inammatory factors are upregulated by a H. pylori infection including: interleukin 1-beta (IL-1 ), IL-6, IL-8, IL-18, and tumor necrosis factor-alpha (TNF- ).14 Polymorphisms in the IL-1 gene cluster are associated with H. pylori-induced hypochlorhydria and gastric cancer.44 The genetic variability caused by these polymorphisms might explain the increased incidence in specic families. Specic variable virulence factors of H. Pylori, such as cytotoxinassociated gene A (cagA) and vaculating toxin A (vacA), appear to
FIG 1. Different pathways in the carcinogenesis of intestinal (A) and diffuse-type (B) gastric cancer.
increase the likelihood of cancer.45 Family history and cagA-positive infection results in a 16-fold increase in risk for gastric cancer.14 However, the risk still increases 4-fold if there is a cagA-positive infection and no family history.29 These factors may partially explain the variable incidence of gastric cancer in specic populations. H. pylori
infection also acts synergistically with nitrate infections to induce gastric cancer in animal models. The combination of H. pylori and N-methylN-nitrosurea has been shown to induce gastric cancer, suggesting that combinations of environmental factors act in concert with H. pylori to affect ones risk of gastric cancer.46 What is the signicance of H. pylori infection? In a case-control study of 7498 Japanese Hawaiians, the odds ratio of developing gastric cancer with H. pylori infection was 6.0 (95% CI, 2.1-17.0).47 In another case-control study involving 186 gastric cancer patients, H. pylori infection was found to be associated with an increased risk for cancer with an odds ratio of 3.6 (95% CI, 1.8-7.3).48 The EUROGAST study, investigating 17 populations in 13 countries, reported a signicant relationship between H. pylori infection and gastric cancer incidence and mortality, with coefcients of 2.68 (P 0.001) and 1.79 (P 0.002), respectively. This study indicated that populations with 100% H. pylori seropositivity have a 6-fold increased risk of gastric cancer.49 In a meta-analysis of 19 studies with 2491 patients and 3959 controls, Huang and colleagues demonstrated an odds ratio for gastric cancer in H. pylori-infected patients to be 1.92 (95% CI, 1.32-2.78).39 Is there justication for eradication of H. pylori? Several studies suggest that eradication of H. pylori will affect the incidence of gastric cancer.38,50 In a 5-year study of 67 patients with early gastric cancer, eradication of H. pylori infection made a signicant impact on the development of gastric cancer.51 As of 2001, 8 interventional studies were investigating the effects of treating a H. pylori infection on the development of stomach cancer and regression of precancerous lesions (intestinal metaplasia, atrophic gastritis).52 In a randomized controlled trial of 1630 healthy adult carriers of H. pylori, Wong and colleagues showed mixed results with the eradication of H. pylori.53 Eradication of H. pylori was not associated with an overall decrease of gastric cancer in the entire population. However, in subgroup analysis of patients without precancerous lesions, no patient developed gastric cancer. Until results from the other prospective randomized trials are available, expert opinion recommends testing for and treatment of H. pylori infection in rst degree relatives of patients with gastric cancer.54
Clinical Presentation
Signs and Symptoms
Stomach cancer usually does not become symptomatic until there is extensive disease. Early symptoms are nonspecic. Weight loss, nausea, vomiting, anorexia, and fatigue frequently present at the time of diagnosis
and manifest late in the disease process. The location or type of tumor may affect the symptoms at presentation. Dysphagia is associated with proximal masses whereas distal tumors manifest with gastric outlet obstruction. Patients with scirrhous-type (linitis plastica) lesions will complain of early satiety due to loss of stomach distensibility. Typical symptoms in patients with linitus plastica tumors include nausea and vomiting (61%), weight loss (58%), dysphagia (46%), and abdominal pain (38%).55 Gastric Perforation. Perforation of gastric cancer at clinical presentation is rare, occurring in only 1% to 4% of cases.56 Although more common in T3 and T4 gastric cancer patients, perforation can occur in early gastric cancers, emphasizing the importance of biopsy and frozensection analysis during emergency operations for perforated gastric ulcers. Palliative gastric resection should be considered at the time of emergency exploratory laparotomy.56 Upper Gastrointestinal Bleeding. Upper gastrointestinal bleeding is a well-described presentation of gastric cancer. However, a minority (approximately 2%) of patients presenting with acute upper gastrointestinal bleeding will have cancer. For example, in a large United Kingdom study, only 27 of 1105 patients with acute upper gastrointestinal bleeding had gastric cancer. More than 70% of these patients had stage IV gastric cancer with a dismal median survival of 9 months. No patient in this series required emergency resection to control bleeding and those treated nonoperatively (8 patients) did not have further acute bleeding.57 Paraneoplastic Syndromes. Paraneoplastic syndromes associated with gastric cancer are not common. Cutaneous systemic manifestations include diffuse seborrheic keratoses (sign of Leser-Trelat) and acanthosis nigricans (velvety, dark pigmented lesions) involving the axilla and skin folds. Hematologic abnormalities including Trouseaus syndrome and microangiopathic hemolytic anemia have been described.
Physical Examination
The physical examination is unremarkable until the late stages of gastric cancer. Classic physical ndings represent metastatic lesions of incurable stage IV patients. Virchows supraclavicular node, Sister Mary Josephs periumbilical node, Blumers shelf, and Krukenbergs tumor represent incurable lymphatic and/or peritoneal metastases. End-stage physical signs include hepatosplenomegaly, jaundice, ascites, hematemesis, melena, and cachexia. Late complications include perforation, bleeding, gastrocolic stulae, and obstruction.
Diagnosis
Population Screening
With gastric cancer being a leading cause of cancer-related deaths in Japan, double-contrast barium studies have been used as the main screening tool since the 1960s. However, only 10% to 20% of the target population was represented in these screening programs. In 1983, a mass screening program was implemented in Japan. Age-adjusted death rates during this period show a decrease in gastric mortality and have been attributed to this screening program. The Japanese 5-year survival rate is 40% to 60%, compared with only 20% in other developed countries.58 Studies suggest mass screening does decrease mortality; however, no randomized controlled trials exist to support this conclusion.59 In a case-control study of postgastrectomy patients, no signicant difference was noted between those screened and not screened for gastric cancer.60 The possible ineffectiveness of screening programs may be due to differences in the pathophysiology of early gastric cancer and advanced gastric cancer.61 Mass screening should be limited to countries with high incidence.
Screening Laboratory Tests

Carcinoembryonic antigen (CEA) and CA 19-9 serum levels are frequently elevated in patients with advanced gastric cancers. However, only approximately one-third of all patients have abnormal CEA and/or CA19-9 levels.62 With low sensitivity and specicity, these markers have no role as a screening test in high risk patients. The tumor-associated glycoprotein antigen, TAG-72 (commercially CA 72-4 assay), may be a useful postresection tumor marker. In 1 study, CA 72-4 demonstrated a specicity of 40% to 50% and a sensitivity of 100%.62 The E-cadherin gene, recognized in familial forms of gastric cancer, may be a useful genetic marker for recurrent disease. It has a sensitivity of 59% and specicity of 75%.63 Vascular endothelial growth factor (VEGF) has also been proposed as a postoperative marker.64 A serum VEGF level greater than 533 pg/mL was found to be an independent factor for cancer-specic survival (hazard ratio, 2.9; 95% CI, 1.3-6.4; P 0.007). Analysis of aberrant methylation of key genes involved in gastric cancer may be a novel molecular marker system for detecting early cancer.65 No single laboratory test yet exists to facilitate diagnosis and detection of recurrent gastric cancer. New techniques are emerging for the detection of individuals at increased risk for gastric cancer based on their genetic composition. These technologies include cDNA microarray, serial anal574 Curr Probl Surg, Aug/Sept 2006
ysis of gene expression (SAGE), differential display, and subtractive hydridization.65-68
Upper Gastrointestinal Barium Examination (UGI)

Endoscopy and the upper gastrointestinal barium examination (UGI) are the primary modalities for the detection of gastric cancer. Although endoscopy offers the advantage of immediate biopsy and expedited diagnosis, a UGI remains a viable alternative initial diagnostic examination due to its less invasive nature, lack of need for sedation, and lower cost.69 In addition, a gastric neoplasm may be a fortuitous nding on a barium examination performed for unrelated symptoms or on a study directed at the evaluation of the esophagus or small bowel. Technical Considerations. A combination of techniques is optimal for barium evaluation of the stomach. The examination should include a double-contrast technique, in which thick barium is used in combination with effervescent CO2 granules for gas distention, thereby producing a mucosal relief image. The double-contrast examination is the single best radiologic technique for the detection of early gastric cancer (Fig 2). In 1 study of 80 patients with gastric cancers, 99% were detected successfully on a double-contrast examination.70 During a double-contrast examination the patient must perform rolling maneuvers for optimal mucosal coating. The patient must also be able to retain the ingested CO2 gas. Patients with limited mobility or those with patulous lower esophageal sphincters may not be able to perform this portion of the examination successfully. The radiographic examination should also include a single-contrast or lled evaluation with compression views. This technique requires less patient assistance and may be the only method of evaluation possible in a debilitated patient. A single-contrast examination alone has an overall sensitivity of only 75% in diagnosing gastric cancer.70 Corresponding to morphologic types described by the Japan Research Society of Gastric Cancer, early gastric cancers may be detected on UGI as small polyps (type I), supercial lesions that are minimally elevated (type IIa), or at (type IIb), slight depressions (type IIc), or shallow ulcers (type III)71 (Fig 3). Advanced gastric cancer may present as a polypoid mass, an ulcer, or an inltrative process (linitis plastica pattern) (Fig 4). With the double-contrast technique, a mass will be etched in white by the barium, or be recognized by abnormal nodularity or curvilinear lines interrupting the normal background of areae gastricae. On a singlecontrast image, the mass will be seen as a lling defect in the barium pool. An ulcer is a common nding on an UGI examination. However, only
FIG 2. Double contrast UGI study showing polypoid adenocarcinoma of the cardia and fundus. Courtesy of Dr. Felicia Cummings, Department of Radiology at Virginia Mason Medical Center.
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FIG 3. Five types of early gastric cancer. Reproduced with permission from Sleisenger and Fordtran.
Neoplasms of the Stomach. Gastrointestinal Disease. 4th Edition. Philadelphia: Saunders, 1989: 747.
3% to 5% of gastric ulcers are malignant.72,73 Although earlier studies performed between 1955 and 1975 suggested that up to 16% of gastric ulcers thought to be benign on single-contrast turned out to be malignant, later studies using double-contrast technique have shown that virtually all ulcers demonstrating unequivocally benign appearances are in fact benign.74,75 Benign ulcers have a round or oval shape, a smooth rim representing a mound of edema with folds radiating to the edge of the ulcer crater, and tend to project beyond the expected lumen of the stomach. A malignant ulcer, on the other hand, will be associated with a mass, have an irregularly shaped crater, nodular or clubbed folds that do not extend to the edge of the ulcer crater, and project inside the lumen of the stomach. A benign ulcer should demonstrate signicant healing after 6 to 8 weeks of therapy. Any ulcer that has a mixed pattern is not unequivocally benign and warrants biopsy.
FIG 4. Double contrast UGI study showing lack of distensibility and abnormal contour of most of the stomach due to inltrative adenocarcinoma (linitis plastica pattern). Courtesy of Dr. Felicia Cummings, Department of Radiology at Virginia Mason Medical Center.
Limitations of Examination. There are operator-dependent factors that affect the performance and interpretation of a UGI. For demonstration of subtle lesions, the UGI requires meticulous technique. In addition, perceptual errors may occur, most commonly due to overlooking or misinterpreting shallow depressions in early cancers.76 The number of UGIs ordered has decreased in the past 2 decades due to greater utilization of endoscopy, diluting the experience for trainees. The diagnostic accuracy for detection of early lesions is likely greater in countries with large screening programs, such as Japan, than in the United States. The sensitivity is likely decreased in postgastrectomy patients due to anatomic distortion of the surgical reconstruction.
Staging and Histologic Classication

Histology
An understanding of the anatomy of the stomach and its lymphatic drainage is essential to understanding the modern staging systems for gastric cancer. The stomach is divided into 5 major areas: cardia, fundus,
FIG 5. Anatomic divisions of the stomach. Reproduced with permission from Townsend and
colleagues. Sabiston Textbook of Surgery. 17th Edition. Philadelphia: Elsevier, 2004: 1266.
body, antrum, and pylorus (Fig 5). The 5 layers of the stomach are serosa, subserosa, muscularis, submucosa, and mucosa (Fig 6). The lymphatic drainage system of the stomach has been well described by the Japanese and is comprised of 33 regional lymph node stations. Regional lymph node stations are classied into 3 groups based on the location of the primary tumor.77 Numerous histologic classication systems have been proposed for gastric cancer. In 1926, Borrmann identied 5 types using simple gross examination: supercial spreading, polypoid, fungating, ulcerative, and scirrhous-inltrating (linitis plastica). The WHO has outlined a histologic classication system with 9 subtypes: papillary adenocarcinoma, tubular adenocarcinoma, mucinous adenocarcinoma, signet-ring cell carcinoma, squamous cell carcinoma, adenocanthoma, undifferentiated carcinoma, unclassied carcionoma, and carcinoid tumor. Ming proposed a classication system based on expanding or inltrating growth pattern.78 In 1965, Lauren described a simple and widely accepted classication system: diffuse gastric cancer, intestinal gastric cancer, and other.79 In a recent Western series, approximately 70% of patients have diffuse tumors; 30% have intestinal type tumors.80 The simplicity and clinical relevance of the Lauren histology classication is emphasized in a recent
FIG 6. Layers of the stomach. Reproduced with permission from Townsend and colleagues. Sabiston Textbook of Surgery. 17th Edition. Philadelphia: Elsevier, 2004: 1268.
review of the long-term survivors of gastric cancer at Memorial SloanKettering Cancer Center (Fig 7). After multivariate analysis, Lauren histologic type had the highest statistical association with long-term survival of all the variables analyzed. Furthermore, as described below, the Lauren histologic type frequently affects surgical management and/or decision making. The distinction between diffuse (glandular) and intestinal-type stomach cancer assumes greater importance given the current changes in the epidemiology of and debates regarding the pathogenesis of gastric cancer. The worldwide decline in gastric cancer is restricted to intestinal-type
FIG 7. Importance of Lauren classication. T stage and N stage determine the prognosis within the rst 5 years after resection. Shown above is the survival of the subset of patients who survived 5 years. On multivariate analysis, Lauren classication becomes the strongest predictor of long-term survival. (From Hochwald SN, Kim S, Klimstra DS, Brennan MF, Karpeh MS. Analysis of 154 actual ve-year survivors of gastric cancer. J Gastrointest Surg 4:520, 2000. Reproduced with permission.)
stomach cancers, whereas the incidence of diffuse-type tumors remains stable. Tahara outlined the carcinogenetic pathways of these 2 distinct histological types of gastric cancer.25 Intestinal-type tumors demonstrate a classic progression of carcinogenesis similar to colon cancer. Initial environmental exposures (eg, high salt and low vitamin C/E diet, H. Pylori infection) result in a chronic supercial gastritis. There is then a progression from atrophic gastritis to intestinal metaplasia, dysplasia, and nally cancer. Intestinal-type tumors are more common in elderly males. Genetic alternations unique to intestinal-type include the following gene mutations: microsatellite instability, DCC (deleted in colorectal cancer),
FIG 8. Diffuse-type gastric cancer with scattered signet ring cells. Cytokeratin (bh11) immunohistochemistry staining (100X). Reproduced with permission from Balch CM, et al: Cancer Staging for Stomach. In: Greene FL, Page DL, Fleming ID, et al, editors. AJCC Cancer Staging Manual, 6th Edition. New York: Springer-Verlag, 2002: 101.
and APC (adenomatous polyposis coli).81 Precancerous lesions, like atrophic gastritis and intestinal metaplasia, are major targets for the prevention of intestinal-type gastric cancer. Detection, treatment, and prevention of these lesions may play an important role in reducing the incidence of gastric cancer. Diffuse-type gastric cancer is a disease of young and more frequently female patients.82 Familial forms have been identied. An association with blood type A is recognized. Diffuse-type tumors are poorly differentiated with signet-ring cells (Fig 8). Transmural and lymphatic spread is more common. Metastases occur early and there is a worse overall prognosis.25 Overexpression of c-met, a protooncogene, is greater in diffuse-type tumors, especially advanced forms.81 Decreased function and expression of E-cadherin (CDH1), a transmembrane protein involved in cell-cell adhesion, is unique to diffuse-type stomach cancers. In contrast to intestinal-type tumors, gastritis is uncommon.
Staging
There are currently 2 major staging systems for patients with gastric cancer. The Japanese use an elaborate system that focuses on a complex anatomic nodal classication scheme. Western countries have adopted a system developed jointly by the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC). The Japanese Gastric Cancer Associations most recent staging system, Japanese Classication of Gastric Carcinoma, 2nd English Edition, uses T and M staging similar to the AJCC system. However, the nodal staging is signicantly different (see http://www.jgca.jp). The Japanese system focuses on detailed description of the lymphatic spread of gastric cancer and outlines different nodal stations (echelons). Staging is thus based on lymphatic spread in relation to the primary tumor (versus the total number of positive nodes). That is, anatomic distribution of metastatic spread assumes importance over quantitative extent of nodal metastatic disease. In 2002, the AJCC and UICC agreed on a common staging system with the release of the AJCC 6th Edition (Table 3). The UICC and AJCC changed from a nodal staging system based on distance from the primary tumor to a staging system based on the number of positive nodes. This new approach to handling lymph nodes requires a minimum of 15 nodes in the resection specimen. Although understanding the Japanese staging system is useful for research purposes, the AJCC/UICC classication system is more practical and more widely used in the United States and Europe. The AJCC stage of patients in the National Cancer Database (NCDB) presenting with gastric cancer in this country is shown in Fig 9. For comparison, a recently published large U.S. single-institution study reported the following distribution of presenting stages: stage 1, 20%; stage 2, 19%; stage 3, 34%; and stage 4, 27%.80
Survival and Patterns of Recurrence

Cancer of the stomach continues to have 1 of the worst 5-year survival rate statistics of any cancer (Fig 10). Due to geographic variation in incidence within the United States, there is wide geographic variation in mortality rates in this country. The highest mortality rate is in Hawaii (13.4 per 100,000) and the lowest is in Kansas (4.8 per 100,000).4 For unexplained reasons, survival rates are improving in the United States. SEER data have shown consistent improvement in overall 5-year survival: 16% in the mid-1970s to 23% by 2001.4 Similarly, the 5-year survival rate in Sweden has improved from 13% in the 1970s to 19% in the mid-1980s.83 No cause for improved survival was identied in the
TABLE 3. TNM classication and staging of stomach cancer Category Primary tumor (T) TX T0 Tis T1 T2a T2b T3 T4 Regional lymph nodes (N) NX N0 N1 N2 N3 Distant metastasis (M) MX M0 M1 Stage grouping Stage 0 Stage 1A Stage 1B Stage II Criteria Primary tumor cannot be assessed. No evidence of primary tumor. Carcinoma in situ: intraepithelial tumor without invasion of the lamina propria Tumor invades lamina propria or submucosa Tumor invades muscularis propria Tumor invades subserosa Tumor penetrates serosa (visceral peritoneum) without invasion of adjacent structures Tumor invades adjacent structures Regional lymph node(s) cannot be assessed No regional lymph node metastasis Metastasis in 1 to 6 regional lymph nodes Metastasis in 7 to 15 regional lymph nodes Metastasis in more than 15 regional lymph nodes Distant metastasis cannot be assessed No distant metastasis Distant metastasis Tis T1 T1 T2a/b T1 T2a/b T3 T2a/b T3 T4 T3 T4 T1-3 Any T N0 N0 N1 N0 N2 N1 N0 N2 N1 N0 N2 N1-3 N3 Any N M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M0 M1
Stage IIIA
Stage IIIB Stage IV
Reproduced with permission from Greene et al. American Joint Committee on Cancer Staging Handbook. 6th Edition. New York: Springer; 2001.
Swedish cohort. The Italian Trials in Medical Oncology has recently reported results of a randomized trial of patients with T3-4 gastric cancers. In this series, the 7-year overall survival rate was approximately 50%.84 The survival by stage in U.S. patients entered into the National Cancer Database is illustrated in Fig 10. Five-year survival data from more recent Western series suggest that these data are representative of current outcomes. For example, 5-year survival rates for patients treated at Johns
FIG 9. AJCC stage of U.S. patients presenting with gastric cancer. Based on American Joint Committee on Cancer data. Reproduced with permission from Balch CM, et al: Cancer Staging for Stomach. In: Greene FL, Page DL, Fleming ID, et al, editors. AJCC Cancer Staging Manual, 6th Edition. New York: Springer-Verlag, 2002: 100.
FIG 10. Gastric cancer survival by AJCC stage. Reproduced with permission from Balch CM, et al: Cancer Staging for Stomach. In: Greene FL, Page DL, Fleming ID, et al, editors. AJCC Cancer Staging Manual, 6th Edition. New York: Springer-Verlag, 2002: 101. Curr Probl Surg, Aug/Sept 2006 585
Hopkins University between 1984 and 2002 were: stage 1, 63%; stage 2, 28%; stage 3, 18%; stage 4, 10%; and all patients, 26%. Many factors affect prognosis in gastric cancer patients. The number of positive lymph nodes is the most consistent prognostic indicator. Fiveyear survival rates in patients with 1-6, 7-15, and greater than 15 positive nodes are 43%, 21%, and 13%, respectively.85 Further supporting the current AJCC staging system, a multicenter observational study of 477 gastric cancer patients in the German Gastric Cancer Study Group (GGCS) demonstrated that the number of positive lymph nodes was of better prognostic value than the location of the involved nodal basin.86 Positive peritoneal cytology is also associated with decreased survival but is currently not part of the AJCC staging system.87 Recent studies suggest that the sensitivity of peritoneal cytologic evaluation is enhanced with real-time reverse transcriptase-polymerase chain reaction (RT-PCR) amplifying CEA.88 Cytologic evaluation for malignant cells using this technique was positive in 10%, 29%, 66%, and 81% of patients with T1, T2, T3, and T4 tumors, respectively. Positive tests were strongly correlated with eventual peritoneal carcinomatosis and survival. Similarly, metastasis to the bone marrow is correlated with poor survival in T1 and T2 patients.89 Decreased survival has been reported in patients with histologically negative but immunohistochemically positive lymph node micrometastasis. In a Japanese prospective study of node-negative T2 or T3 patients, the 5-year survival rate in those with lymph nodes that stained positive with anticytokeratin antibody (CAM 5.2) was only 66%. On the other hand, there was a 95% survival rate in patients with no evidence of immunohistochemical micrometastasis. Detection of micrometastases of gastric cancer may nd a role in staging before neoadjuvant therapy.90 Other systems have been proposed to guide treatment and/or predict survival of patients with gastric cancer. Maruyama has developed computer software (Maruyama Program) based on 7 demographic and clinical features of 3834 gastric cancer patients at the National Cancer Center Hospital in Tokyo. The software can be used to guide surgeons in the extent of lymphadenectomy in a specic patient.91 A Maruyama Index of Unresected Disease (MI) can be derived from this software model and has been shown to be an independent predictor of survival.92 The clinical signicance of the Maruyama Program and MI has yet to be established. Similarly, nomograms or scoring systems have been developed that predict survival based on weighted importance of sex, age, tumor location, Lauren histologic type, T stage, N stage, and extent of lymphadenectomy.93-95 The results of a nomogram developed at Memo586 Curr Probl Surg, Aug/Sept 2006
rial Sloan-Kettering Cancer Center, combining sex, age, tumor location, Lauren histotype, number of positive and negative nodes, as well as depth of invasion is illustrated in Fig 11. A recent study has shown that lymphovascular invasion is also a strong independent predictor of recurrence.96 What are the patterns of recurrence? Recent case series suggest that the ratio of distant to locoregional recurrence rates is approximately 2:1. For example, in the Italian Trials in Medical Oncology study, distant and local recurrences occurred in 34% and 16% of patients, respectively. Chemotherapy had no effect on this recurrence pattern or on survival rates.84 Tumor factors affect patterns of recurrence. Gastric remnant cancers tend not to develop peritoneal metastasis. There are also established risk factors for the development of liver metastasis. In 1 series, intestinal-type tumors were much more likely to recur as liver metastases.97 Only 9% of patients with diffuse-type tumors developed liver metastasis versus 36% of patients with intestinal tumors. In addition, preoperative positivity for serum tumor markers and lymph node involvement are risk factors for liver metastasis. Eighty-ve percent of patients with liver metastasis had elevated tumor markers preoperatively. In contrast, only 1 patient with negative tumor markers developed liver metastasis. Virtually all liver metastases developed within 2 years of surgical resection.
Staging Modalities
Once the diagnosis of gastric cancer is established, further studies are directed at staging to assist with therapeutic decisions. Neither routine endoscopy nor the UGI examination can assess the depth of invasion of the primary tumor, which is the sole criterion for T staging. Endoscopic ultrasound (EUS) and computed tomography (CT) are the current primary staging modalities for gastric cancer.
Endoscopic Ultrasound
The era of EUS, or endosonography, began in the early 1980s when researchers at the Mayo Clinic welded an ultrasound transducer to the tip of an endoscope.18 Despite the rise in sophistication and availability of extracorporal imaging techniques over the last 3 decades, concurrent improvements in EUS technology have positioned EUS as an integral part of the diagnosis and staging of gastric cancers. Transabdominal ultrasound utilizes low frequency signals. Lower frequency signals travel further, but provide lower resolution. Since the target organ in EUS is usually close to the transducer, higher frequencies can be used, producing a high resolution image.
588
Tumors tend to be denser than other tissues and can be detected as dark structures that obliterate the normal interfaces between tissue layers. Larger tumors that extend into adjacent organs and vessels obliterate the endosonographic interfaces between these structures. Endosonographic T staging is based on the number of visceral wall layers that are disrupted as well as the preservation or destruction of sonographic interfaces between adjacent organs and vessels. N staging is based on the presence and location of perivisceral lymph nodes that t certain criteria (diameter 10 mm, round shape, uniform hypoechoic structure, well-circumscribed margins) or that are found to harbor malignant cells by EUSguided transvisceral ne needle aspiration (FNA). Due to its limited depth of penetration, endosonography is less useful for M staging. However, with low frequency options on newer echoendoscopes, much of the liver can often be surveyed and even sampled from the stomach and duodenum.98 Three types of EUS devices are currently available. The workhorse of most diagnostic EUS imaging in the stomach is the radial scanning echoendoscope. This device employs either a multifrequency transducing crystal attached to a mechanically rotating shaft, or a series of smaller crystals mounted in a xed, circular array, mounted at the tip of an endoscope. This generally creates a cross-sectional image of the hollow organ into which it is passed, although angulation changes the imaging plane. These images usually show the visceral wall and adjacent organs, up to as far as 12 cm with a 5-MHz transducer. Frequencies of 20 MHz may penetrate only 2 or 3 cm. The endoscope itself houses standard optics, a light source, an accessory channel, and 4-point cables for directional manipulation. The second type of device, a curved linear array (CLA) echoendoscope takes the same basic endoscope design, but places a series of transducing crystals on a curved head of the scope. This produces a wedge-shaped ultrasound image oriented along the axis of the endoscope. This design allows for the incorporation of Doppler imaging to show ow in blood vessels and, more importantly, to track the passage of a needle from the
FIG 11. Nomogram, developed based on 1039 gastric cancer patients at Memorial Sloan-Kettering
Cancer Center, factors sex, age, tumor location, Lauren histotype, number of positive and negative nodes, and tumor depth. Survival in patients in 4 quartiles of nomogram (A, top) are compared with that determined by AJCC stage (B, bottom). (From Novotny AR, Schuhmacher C, Busch R, and colleagues, Predicting individual survival after gastric cancer resection. Ann Surg. 243:74, 2006. Reproduced with permission.)
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accessory channel into the image eld. These 2 characteristics make CLA endosonography ideal for sampling submucosal and extraluminal tissue with either FNA or, in some cases, core biopsy technique. The third device is a simple, rotating ultrasound probe that can be passed through the accessory channel of most standard endoscopes. These probes are small, easy to use, and relatively inexpensive. Their lower power and small size, however, enables them to produce only higher frequency, low depth images, making them useful only for visualizing the visceral wall and directly adjacent structures. In this capacity, probes can be quite useful for dening submucosal nodules. Although the initial diagnosis of gastric cancer is usually made with standard endoscopy, it is of limited value in assessing the T stage and unable to assess the N or M stage. Computed tomography scanning is useful for identifying distant metastases, especially in the liver, but demonstrates only fair accuracy in T and N staging. Accuracy for T staging of gastric cancers by spiral CT is approximately 64%, with much lower accuracy for early stage cancers.99 Nodal staging by spiral CT scan is also unreliable, with sensitivity rates ranging from 24% to 43%.100 Endoscopic ultrasound adds to the preoperative staging of gastric cancers in several ways. Accuracy of EUS for T staging in gastric cancer is approximately 82%, with a sensitivity and specicity of 70% to 100% and 87% to 100%, respectively.101-103 Unfortunately, even in experienced hands, differentiating T2 and T3 gastric cancer can be difcult. Desmoplastic reaction associated with a tumor that does not breach the serosa can, on EUS, sometimes look like T3 invasion because the edema distorts the interface between the stomach and adjacent tissue. N-stage accuracy has been shown to be approximately 70%, with sensitivity and specicity that ranges from 69.9% to 100% and 87.5% to 100%, respectively. Addition of FNA of suspicious nodes increases the accuracy even further, bringing specicity to 100%.18 In addition, EUS-guided FNA or Tru-Cut (Baxter, Deereld, IL) biopsy of submucosa can provide a tissue diagnosis in the setting of linitis plastica where carcinoma spreads along the submucosal interfaces and leaves the overlying mucosa intact (Figs 12 and 13). In these cases, simple pinch biopsies often show only normal mucosa.104 Endoscopic ultrasound can also identify some liver metastases and early ascites associated with stage 4 gastric cancers, both of which can be sampled safely by EUS-guided FNA across the gastric or duodenal wall.105,106 Endoscopic ultrasound can be particularly useful in early stage gastric cancer where identication of disease limited to the mucosa (intramucosal carcinoma) can sometimes allow for endoscopic resection rather than gastrectomy107,108 (Fig 14). Although rare outside of Japan, endoscopic
FIG 12. Endoscopic view of linitis plastica in the body of the stomach. Despite the thickened
appearance of gastric folds, the mucosa is normal. Courtesy of Dr. Drew Schembre, Department of Gastroenterology at Virginia Mason Medical Center. Note Figs 12 and 13 are imaging from the same patient.
resection has become the standard of care in many major medical centers in Japan. The ability of EUS to provide images and tissue in a quick and minimally invasive manner will likely keep EUS as a major tool for gastric cancer for the foreseeable future. Better resolution echoendoscopes and improved techniques for endoscopic mucosal resection and submucosal dissection will broaden the treatment options for early gastric cancer as well.
Computed Tomography
Computed tomography scanning provides critical information in treatment planning for gastric cancer patients. Data obtained from CT complement as
FIG 13. EUS image of linitis plastica. Double-headed arrow represents the thickened submucosal area
due to tumor inltration. Thin single-headed arrow indicates hypertrophied muscularis propria with likely tumor inltration extending beyond the gastric wall into peri-gastric fat (thick white arrow). Courtesy of Dr. Drew Schembre, Department of Gastroenterology at Virginia Mason Medical Center. Note: Figs 12 and 13 are imaging from the same patient.
FIG 14. (A) Endoscopic image of early gastric cancer at the incisura. Courtesy of Dr. Drew Schembre, Department of Gastroenterology at Virginia Mason Medical Center. (B) Endoscopic ultrasound (EUS) image of T1 cancer. Thick dark arrow demonstrates mucosal tumor invading the broad white layer (hypoechoic) of hyperechoic submucosa (white arrow) but not disrupting the dark layer (hypoechoic) of the muscularis propria (thin dark arrow) in the same patient. Courtesy of Dr. Drew Schembre, Department of Gastroenterology at Virginia Mason Medical Center. 592 Curr Probl Surg, Aug/Sept 2006
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well as reinforce ndings on EUS. Computed tomography can provide information about the primary tumor, detect lymphadenopathy, and predict invasion of adjacent organs, with some limitations. Computed tomography is the single best noninvasive means of detecting metastatic disease. T Staging. Evaluation of intramural tumor involvement and extension beyond the wall is critical in therapeutic planning. The depth of involvement is directly related to prognosis. The role of CT in T staging of gastric cancer has been controversial and is in rapid evolution. Standard CT techniques are notoriously poor at evaluating the stomach. Wall thickness is difcult to judge without distention and parts of the gastric wall that are coplanar with the axial scan angle (the gastric cardiac region in particular) may appear artifactually thickened. A pseudomass appearance of the gastroesophageal (GE) junction on standard CT was described in 23% of 100 patients with normal GE junctions.109 Endoscopic ultrasound has been the most accurate method available for T staging of gastric cancer. A study from 1991 demonstrated 92% accuracy of EUS for depth of tumor penetration compared with 42% for CT.110 Many technical advances in CT scanning have occurred over the past 15 years and this gap has narrowed. A more recent study demonstrated CT T-staging accuracy of 76% compared with 86% for EUS.111 Enhancing mucosal lesions may be subtle or obscured when adjacent to standard high density positive oral contrast, and the use of water as a negative oral contrast agent has increased the conspicuity of enhancing lesions.112-117 Distention achieved with the use of water lling (300 to 800 mL) is important for an accurate assessment of wall thickness (Fig 15). Hypotonic agents such as glucagon or scopolamine may be administered to assist in maintaining distention throughout the examination. Helical CT scanning made possible by slip-ring technology was introduced in the early 1990s and permitted faster scanning with reduced artifact from motion compared with incremental CT scanners. In 1999, Dux and colleagues evaluated 115 gastric carcinomas using water as the oral contrast and single-slice helical CT with conventional 5-mm-thick slices at 8-mm intervals and reported a disappointing 51% overall accuracy in T staging.112 More recently, multidetector CT (MDCT) has enabled even faster scanning with simultaneous acquisition of multiple thin slices. Use of thin slice collimation decreases partial volume artifact that enables more accurate assessment of the wall in a curved organ. The acquisition of volumetric high resolution data made possible by MDCT also allows multiplanar reconstructions (MPR) to be performed on a workstation, depicting most segments of the gastric wall in the optimal orthogonal plane with enhanced anatomic detail. In 2005, Shimizu and
FIG 15. CT performed with water distention of the stomach demonstrates a mass in the gastric cardiac region. Courtesy of Dr. Patrick Freeny and Dr. Gita Rabbani at the University of Washington.
colleagues published data demonstrating an 85% accuracy of CT for T staging, using MDCT with 1.25-mm multiplanar reconstructed images.126 Using the MPR technique, Shimizu and colleagues were able to detect 96% of advanced gastric cancers and 41% of early gastric cancers (compared with 20.5% detection rate for early gastric cancers by using standard 5-mm-thick collimation). Some authors have advocated the use of 2 or 3 phases of scanning including arterial, equilibrium, and delayed phases to optimize detection of the wall layers.115-117 Optimized CT techniques allow visualization of 2 or 3 layers of the gastric wall, and several studies have been performed correlating the CT appearances of wall involvement with histologic ndings.113-119
FIG 16. CT demonstrates T4 gastric carcinoma of proximal body with extension into perigastric fat
and involvement of splenic artery. Courtesy of Dr. Felicia Cummings, Department of Radiology at Virginia Mason Medical Center.
Kumano reported 93% accuracy in assessment of serosal invasion by using MDCT compared with previous reports of 80% to 87% by using conventional techniques.114 In this study, CT tended to understage scirrhous-type tumors, which do not enhance as well in general as differentiated tumors.114 T3 scirrhous tumors also may be understaged as T2 due to the relative smooth outer surface of the wall and tendency of the tumor to inltrate perigastric adipose tissue without an observable mass.114 Invasion of adjacent organs such as liver, pancreas, and transverse mesocolon is suspected when intervening fat planes are lost on CT (Fig 16). However, fat planes may be lost without tumor invasion due to
benign inammation and in cachectic patients with little intra-abdominal fat. Conversely, tumor inltration may be sufciently subtle to preserve fat planes on CT. Halvorsen and colleagues reported only 27% sensitivity (3 of 11 patients) in the detection of pancreatic invasion by adjacent gastric cancer.69 Nodal Staging. Accuracy of CT for nodal involvement by gastric cancer is limited. The limitation is due to the fact that size remains the primary diagnostic criteria for determining tumor involvement. The cutoff for normal nodal size is 8 to 10 mm, but metastases may be found in lymph nodes smaller than 8 mm. In a study of 58 patients with gastric cancer and 1082 histologically sampled lymph nodes, cancer was found in 82.6% of nodes larger than 14 mm, 23.0% of nodes 10 to 14 mm, 21.7% of nodes 5 to 9 mm, and 5.1% of nodes smaller than 5 mm.120 The same study also noted that lymph nodes smaller than 5 mm were rarely detected by CT. Nodes may be difcult to detect in cachectic patients with little fat, and perigastric lymph nodes may be incorporated into the primary tumor mass and be difcult to isolate. In a series of 85 patients with gastric cancer who had histologic correlation, Dux and colleagues reported a majority of lymph nodes containing metastases were between 2 and 10 mm.112 Halvorsen and colleagues reported 67% sensitivity and 61% specicity for nodal metastasis in a series of 75 patients with gastric cancer.69 In summary, CT has a tendency to understage nodal disease despite the potential for low specicity due to enlarged lymph nodes due to inammation rather than metastatic disease.111 Metastases. Hematogenous metastases most commonly arise in the liver, lung, and adrenals, and uncommonly bone, kidneys, and brain. CT remains the single best modality for detection of metastatic disease. Technical advances in the past 10 years have included contrast bolus tracking, which enables imaging of the liver in optimal phases of organ perfusion. Liver metastases are well visualized on the equilibrium or portal venous phase of CT (Fig 17). Signs of peritoneal carcinomatosis include ascites, omental stranding, and peritoneal studding. Metastases to the ovaries (Krukenbergs tumor) may be seen as enhancing ovarian enlargement (Fig 18). However, when no ascites is present and peritoneal implants are small, carcinomatosis may be below the resolution of CT.
Magnetic Resonance (MR)

Currently, MR is used primarily when CT iodinated contrast is contraindicated due to a signicant contrast allergy or renal failure. MR may also be used to conrm the presence of equivocal liver masses seen
FIG 17. CT demonstrates extensive liver metastases from gastric carcinoma. Courtesy of Dr. Felicia
Cummings, Department of Radiology at Virginia Mason Medical Center.
on CT. With respect to T staging of gastric cancer, MR is comparable or minimally superior to CT.121,122 CT and MR are comparable when assessing nodal staging.121,122 Due to the cost, longer scanning times, and susceptibility to motion, CT remains the imaging technique of choice. Further developments in MR may include the use of endoluminal coils for better denition of the gastric wall layers and improved T staging and regional nodal staging accuracy.
Positron Emission Tomography

Potential uses of PET in gastric cancer patients are in staging, detecting recurrence, determining prognosis, and measuring therapy response. The
FIG 18. CT demonstrates large pelvic masses representing drop metastases to bilateral ovaries (Krukenbergs tumor). Courtesy of Dr. Felicia Cummings, Department of Radiology at Virginia Mason Medical Center.
major advantage of PET over anatomic modalities, such as CT, is substantially greater contrast resolution. For example, PET can detect lymph node metastases before lymph nodes are enlarged on CT (Fig 19). Many pathologic lesions are much more conspicuous on PET than on CT. The limitations of PET are lower sensitivity for small lesions and false-positive results from infectious or inammatory processes. In addition, PET studies are relatively expensive compared with other imaging modalities. Combined PET and CT (PET/CT) scanners have been introduced recently. These scanners perform both a PET and CT scan in the same session and fuse the images. A PET/CT scanner combines the excellent
FIG 19. Axonal positron emission tomography (PET) image of gastric cancer. Short arrow is gastric lesion. Long arrows represent nodal metastases. Courtesy of Dr. Felicia Cummings, Department of Radiology at Virginia Mason Medical Center.
contrast resolution of PET with the excellent spatial resolution of CT. Numerous studies have shown improved accuracy of PET/CT compared with PET alone.123 However, the accuracy of PET/CT in gastric cancer has not been well dened. PET has been reported to have poor sensitivity with signet-ring cell and mucinous tumors.124,126 Although PET does not have a role in the primary detection of gastric carcinoma, the degree of uptake in a known gastric carcinoma has prognostic value. Moderately intense uorodeoxyglucose (FDG) uptake in the gastric wall is a normal variant. Despite this, the majority (60% to 96%) of primary gastric neoplasms are detected by PET.125,126 A greater degree of FDG uptake is associated with greater depth of invasion, size of tumor, and lymph node metastases.127 The survival rate in patients with high FDG uptake is signicantly lower than in patients with low FDG uptake.127 However, the degree of the primary tumor uptake is related to tumor histology and tumors with poor prognoses can have low FDG uptake. In particular, signet-ring cell and mucinous carcinomas have low FDG uptake.124,126 PET has potential value in staging gastric cancer. Yoshioka and
colleagues reported an overall sensitivity of 71% and specicity of 74% in a group of 42 patients with advanced, metastatic, or recurrent gastric cancer.128 The reported sensitivities for nodal metastases vary substantially (23% to 73%).127,128 Positron emission tomography is limited in the detection of perigastric nodes that can be obscured by activity in the primary tumor. Positron emission tomography is particularly insensitive for detection of nodal metastases from signet-ring cell carcinoma.125 The primary value of PET in the detection of nodal metastases from gastric carcinoma is its specicity (78% to 96%).125,128,129 The overall accuracy of PET and CT for the detection of local and distant nodes is similar.124 Although CT is more sensitive than PET for detection of lymph node metastases in N1 and N2 disease, PET is more specic.124,125,129 Positron emission tomography may be more sensitive for the detection of nonnodal sites such as liver and lung metastases but not bone, peritoneal, and pleural metastases.124,128 Limited data are available regarding the value of PET in evaluating recurrent gastric carcinoma. De Potter and colleagues130 evaluated 33 patients for recurrence after surgical treatment with curative intent. Positron emission tomography had a sensitivity of 70% and specicity of 69% in this group of patients.130 A negative PET scan was associated with a signicantly longer survival than a positive PET scan. PET may also have value in the prediction of response to preoperative chemotherapy in gastric cancer. Ott and colleagues prospectively studied 44 patients with locally advanced gastric carcinomas at baseline and 14 days after the initiation of cisplatin-based polychemotherapy.131 Response on the PET scan 14 days after therapy predicted histopathologic response 3 months after therapy and was positively correlated with survival.
Laparoscopy
Laparoscopy now plays a fundamental role in guiding management of patients with gastric cancer felt to be eligible for resection. In 1985, Shandall and Johnson reported that routine use of laparoscopy resulted in detection of metastatic disease to the liver or peritoneum and avoidance of laparotomies in 29% of patients.138 Subsequent studies conrmed that 12% to 52% of patients felt to be appropriate for gastric resection were found to have metastatic lesions at the time of laparoscopy and thus unnecessary laparotomies were avoided.132-137 Burke and colleagues at Memorial Sloan-Kettering Cancer Center (MSKCC) demonstrated that laparoscopy has 100% sensitivity and 84% specicity. Twenty-four of the 110 patients who underwent laparoscopy in the MSKCC study had occult metastatic disease. None of these patients required palliative surgery.138
FIG 20. Clinical management of gastric cancer. Adapted with permission from National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology, 2005. 1Radiation Therapy, 45-50 Gy 5-FU-based radiosensitization. 2Salvage therapy guided by Karnofsky performance score and ECOG performance score and includes chemotherapy, clinical trial participation, or supportive care. 3Peritoneal seeding, distant metastases, inability to perform complete resection, or invasion/encasement of major vascular structure(s). Available at http://www.nccn.org/professionals/physician_gls/PDF/gastric.pdf
With the emergence of laparoscopic ultrasound, nodal staging is now possible with laparoscopy. Unfortunately, like endoscopic ultrasound, it is a specialized technique with operator variability. Finch and colleagues indicate that laparoscopic ultrasound is 84% accurate in TNM staging of esophageal cancers.139 This study compared laparoscopy ultrasound to CT and laparoscopy and showed a clear benet for ultrasound in assessing gastrointestinal cancers.135 Controlled studies specic to gastric cancer comparing laparoscopy with and without ultrasound have yet to be published. Conrming the importance of staging laparoscopy, the practice guidelines provided by the National Comprehensive Cancer Network recommend that patients with gastric cancer and locoregional disease (M0) undergo laparoscopy to guide further management140 (Fig 20). Laparoscopy should not be restricted to the patients felt to be resectable. Accurate staging even in unresectable patients will help determine if combined chemoradiation will be benecial, since radiation may not be appropriate in patients with metastatic disease.140 Laparoscopy can also be used in staging before entry into neoadjuvant trials.141 Laparoscopy is not
necessary in T1 or T2 lesions given the low incidence of metastases.141 Furthermore, as discussed below, laparoscopy may not be indicated in the preoperative evaluation of patients with gastric remnant cancers, since they do not tend to develop peritoneal metastasis.
Surgical Treatment
Extent of Lymph Node Dissection
The optimal extent of lymphadenectomy in a patient with potentially curable gastric cancer has been debated for decades. The Japanese rst reported large cohort studies suggesting that disease-free and overall survival is increased in patients treated with extended resections, including radical lymphadenectomies.142 Unfortunately, a variety of nomenclatures (Japanese vs. AJCC) make understanding this literature difcult. Japanese nodal staging categorizes nodal basins into 4 groups: N1 perigastric nodes in proximity to the stomach; N2 nodes associated with the major gastric vessels (eg, left gastric, splenic, and common hepatic); N3 nodes in the hepatoduodenal ligament, the celiac plexus, and at the base of the superior mesenteric artery; and N4 nodes in the para-aortic region. Similarly, Japanese nomenclature describes R0-R4 resections based on the extent of lymph node and gastric resection versus marginfree or positive resections in the AJCC nomenclature. Over the last decade, however, most series have settled on designations of D1 or D2 lymphadenectomies when describing surgical procedures for gastric cancer. In our opinion, the best description of D1 and D2 lymph node dissections is the simplest: D1 resections remove lymph nodes within 3 cm of the tumor en bloc with the greater omentum and stomach; D2 resections also include the omental bursa and lymph nodes of the celiac axis, hepatoduodenal, splenic and retroduodenal nodes. To resect completely the nodes in the splenic hilum, the classic D2 resections also included splenectomy and distal pancreatectomy. The differences in D1 and D2 resections are nicely illustrated in Figs 21 to 23 (using the R nomenclature). The controversy surrounding the relationship between radical operations and oncologic outcomes has been reviewed in several recent publications. As mentioned above, initial studies from Japan suggested that cure rates were improved in patients with gastric cancer treated with extended lymph node dissections or radical operations. Cure rates for patients in the radical surgical cohorts approximated 50% to 60%, far exceeding the 15% to 30% cure rates reported in series from the United States. Subsequent large series from Western centers conrmed these
FIG 21. Extent of lymph node dissection for D1 (
R1) or D2 ( R2) resections for distal gastric cancers. (From Smith JW, Shiu MH, Kelsey L, Brennan MF. Morbidity of radical lymphadenectomy in the curative resection of gastric carcinoma. Arch Surg 1991;126:1469. Reproduced with permission.)
R1) or D2 ( R2) resections for mid-gastric cancers. (From Smith JW, Shiu MH, Kelsey L, Brennan MF. Morbidity of radical lymphadenectomy in the curative resection of gastric carcinoma. Arch Surg 1991;126:1469. Reproduced with permission.)
reports.143,144 However, these studies have been appropriately criticized because of the inevitable stage migration effect, which compromises any study comparing survival in patients treated with extensive versus standard lymph node dissections. That is, the more lymph nodes examined, the greater the probability of positive nodes. Some patients in the limited lymph node dissection group are inaccurately labeled node
R1) or D2 ( R2) resections for proximal gastric cancers. (From Smith JW, Shiu MH, Kelsey L, Brennan MF. Morbidity of radical lymphadenectomy in the curative resection of gastric carcinoma. Arch Surg 1991;126:1469. Reproduced with permission.)
negative and will have lower survival rates than node-negative patients in the extended lymph node group. When the 2 groups are compared stage for stage, survival rates will be better in the extended lymph node group. Will Rogers once said, When the Okies left Oklahoma and moved to California, they raised the intellectual level in both states. Stage migration, also called the Will Rogers phenomenon, shifts stage 2 patients treated with extensive lymph node dissection to stage 3, thereby resulting in a false nding of treatment advantage in stage-matched patients. Since conventional staging cannot be used to compare 2 treatment arms because of the stage migration effect, the best method to assess effect of surgery on survival is to compare intermediate stage patients (T3 tumors) regardless of the nodal status. This group would be most likely to benet from extended lymph node resections. For example, the Memorial Sloan-Kettering Cancer Center reviewed their results in 774 patients who had undergone curative gastric resections.144 They reported survival rates in patients with T3 tumors treated with D2 and D1 dissections of 54% and 39%, respectively. They concluded, D2 dissection offered a survival advantage for T3 tumors.144 Two large randomized studies have compared D1 and D2 resections in patients with gastric cancer. In the rst study, the Medical Research Council (MRC) trial, 400 patients were randomized.145 The Dutch
Gastric Cancer Group randomized 711 patients.146 In the Dutch trial, the authors calculated that stage migration occurred in approximately 30% of the D2 group. Both groups reached nearly identical conclusions that D2 resections: (1) offered no survival advantage and (2) were accomplished at the expense of greater operative morbidity and mortality. In the Dutch trial, 5-year survival rates in D1 and D2 patients were 45% and 47%, respectively.146 However, major complications were more likely in D2 patients than in D1 patients (43% vs. 25%, P 0.001). Perioperative death rates were also higher (10% vs. 4%, P 0.004). These ndings were duplicated in the MRC trial.145 Both groups reported a strong association between splenectomy/distal pancreatectomy and poor outcome. Although many have challenged the conclusions of these studies, all experts agree that splenectomy should be avoided in nearly all operations for gastric cancers.147-151 What were the systematic aws of these studies and what is the current role of extended lymphadenectomy? A recent Cochrane Review nicely summarizes the status quo and makes the following observations and conclusions.152 First, a frequently cited problem with both studies is that most participating surgeons had little or no pretrial experience with D2 dissections. Furthermore, the mean within-study case volume per surgeon was low (mean 4.7 D2 procedures per surgeon per year.) In addition, both randomized studies validated the extent of lymph node dissections by counting retrieved lymph nodes. There was likely considerable overlap between treatment groups. In the Dutch study, 36% of D1 patients had additional lymph nodes resected, whereas 51% of D2 cases had lymph nodes missing in specic designated nodal specimens.146 In our opinion, these criticisms ignore the importance and variability of diligence of the pathologist in retrieving lymph nodes and of patient body habitus on the success of nodal retrieval. The second important systematic aw in the randomized trials was the clear and signicant excess mortality in the D2 resections, with a risk ratio of 2.23 (95% CI, 1.45-3.45). This suggests that death is more than twice as often after D2 surgery. Subgroup analysis showed a strong independent association between postoperative death and resection of the spleen and tail of pancreas (combined risk ratio for splenectomy, 5.5, and for pancreatic resection, 5.8). The Cochrane Review concludes that modied D2 resections can be and currently are being performed with much lower operative morbidity and mortality.152 Whereas operative mortality rates were approximately 10% after D2 resections in the Dutch and MRC trials, weighted mean postoperative mortality rates for 9 recent cohort studies of D2 resections
performed at high volume centers is only approximately 4%. Considering the potential sources of systematic bias in these 2 randomized trials, the Cochrane authors concluded that they were not condent that the trials gave a reliable estimate of treatment outcome.152 In other words, these studies neither proved nor disproved an advantage for extended or D2 resections. Interestingly, follow-up publications and subgroup analyses of the data from these 2 studies have claimed advantages for D2 resections.151-154 First, the modern version of the D2 operation, in which resection of the spleen and pancreas are avoided, is safer.150 The Dutch, MRC, and several prospective studies have demonstrated the safety of extended lymph node dissection with splenic preservation.147,150,151 Preservation of the spleen is associated with better survival and local failure rates. There are few indications for splenectomy during operations for gastric cancer.147,149 A D2 lymphadenectomy can be performed with postoperative morbidity and mortality equivalent to limited lymph node dissection. Improved outcomes with D2 resections rst described in Japan are emerging. The Cochrane Review and others have estimated, based on subgroup analyses, that there is approximately a 30% survival advantage for patients with T3 cancers undergoing D2 surgery.152 Examination of mature results of the Dutch trial noted recurrence rates in D1 and D2 groups of 41% and 29%, respectively (P 0.02). Prospective cohort studies from the United States have also concluded that an absolute number of lymph nodes retrieved and/or examined are a reasonable means to assess the adequacy of surgical dissection and resection. Karpeh and colleagues at Memorial SloanKettering Cancer Center have concluded that survival estimates based on the number of involved or positive lymph nodes are better represented when at least 15 lymph nodes are examined.155 That is, correct staging requires that at least 15 lymph nodes be examined. This requires dedicated cooperation with the surgical pathology department. The 10-year results of the German Gastric Cancer Study also support the notion that increased numbers of lymph nodes removed and examined has an effect on survival86 (Fig 24). In this study, 1654 patients with gastric cancer undergoing operation between 1986 and 1989 were followed prospectively. D1 or D2 operations were arbitrarily determined by numbers of lymph nodes examined, with a break point of less than or greater than 25 lymph nodes. As expected, multivariate analysis conrmed that nodal status was the major independent prognostic factor for survival. However, the extent of
FIG 24. Cumulative survival in patients with resected T3N0 gastric cancers. Number of lymph nodes removed (and by inference D2 versus D1 resection) strongly correlates with survival. (From Siewert JR and the German Gastric Carcinoma Study Group. Relevant prognostic factor in gastric cancer. Ann Surg 1998;228:457. Reproduced with permission.)
lymph node dissection had a signicant and independent effect on the 10-year survival rates in patients with stage 2 tumors. Since this subgroup effect was seen even in patients with pT3N0 tumors, this nding appears not to be due to the phenomenon of stage migration.86 In addition, a recently published prospective comparison of 118 gastric cancer patients undergoing D1 or modied D2 resections in the United Kingdom reported 5-year survival rates of 32% and 59% in D1 and D2 resection patients, respectively.151 Operative morbidity and mortality were the same. In conclusion, whereas the benets of D2 resections are unproven, the modern (splenic preservation) D2 resection is an acceptable procedure when performed at high volume centers. It is likely the preferred treatment for patients with T3 tumors and/or intermediate stage (2 to 3) gastric cancers.143 Finally, modern quality assessment process measures for surgeons and pathologists should require 15 or more nodes in the resected specimens.
Extent of Gastric Resection

At least 6 factors determine the extent of gastric resection in patients with potentially curable gastric cancers: tumor stage, tumor histology or type, tumor location, nodal drainage, perioperative morbidity, and longterm gastrointestinal function. Tumor Stage. The extent of surgical resection is dictated largely by the extent of microscopic spread of the tumor beyond palpable or visible tumor. Recent studies suggest that the extent of operation can be modied based on tumor stage. Early gastric cancer (T1a lesions) may be treated with endoscopic techniques and/or limited wedge gastric resections. Larger tumors require greater surgical margins. Most studies have concluded that for T2-3 tumors, a 6-cm length of proximal margin, measured in the operating room, results in clear margins in virtually all cases. These measurements are obtained during intraoperative assessment and need not be adjusted for retraction of the esophagus once the specimen has been delivered to the pathologist. Margins between 3 and 6 cm are associated with positive microscopic margins in at least 5% to 10% of cases. In T2 tumors, a 3-cm clearance may be adequate. This latter recommendation is not valid for poorly differentiated, diffuse tumors. The effect of T stage on ideal surgical margins emphasizes the importance of accurate preoperative staging, preferably with endoscopic ultrasound. If preoperative staging suggests a T3-4 tumor, preoperative laparoscopy is usually warranted and a modied D2 resection with 6-cm margins is appropriate. Tumor Histology. The extent of tumor and tumor histology affects the surgical margin and therefore the extent of resection. Diffuse, poorly differentiated tumors require 6-cm proximal margins.156 Supercial, well-differentiated intestinal-type tumors may be treated with lesser margins. Tumor Location. The extent of gastric resection is affected by the location of the tumor. As shown in Figs 25 to 27, tumors of the antrum, body, or proximal stomach have different nodal drainage and hence different requirements for lymphadenectomy. The frequency of positive lymph nodes in various nodal regions summarized in Figs 25 to 27 emphasizes the importance of radical resections in most patients with T2-4 tumors. Tumors of the cardia, lying 2 to 5 cm below the GE junction, deserve special mention. These tumors are typically high grade and have a tendency to invade the esophagus. In Western surgical series, between 26% and 63% have esophageal invasion with risks being greater in linitus plastica, or diffuse type T3-4 tumors.157
FIG 25. Frequency of node-positive zones for distal gastric cancers. (From Sutherland DA. The
Lymphatic Spread of Gastric Cancer. In: McNeer G, Pack GT, editors. Neoplasms of the Stomach. Philadelphia: Lippincott; 1967:408-15. Reproduced with permission.)
Nodal Drainage. The extent of lymphadenectomy and hence the extent of the gastric resection is frequently inuenced by the nodal drainage of the tumor and the intraoperative ndings.158 For example, T3 tumors along the lesser curve with suspicious lymph nodes frequently require extensive dissection of the left gastric artery and celiac axis. This dissection may compromise the viability of the proximal stomach and appropriateness of subtotal gastrectomy for some distal tumors. Perioperative Morbidity and Long-Term Gastrointestinal Function. Survival is equivalent after subtotal gastrectomy or total gastrectomy for patients with cancers of the antrum. Total gastrectomy is associated with an increased risk for splenectomy, longer hospital stay, longer impairment of caloric intake, and greater long-term nutritional sequelae when compared with subtotal gastrectomy. What is the preferred operation for patients with proximal gastric cancers? In our opinion, these patients are best served with total gastrectomy. A proximal gastrectomy with esophagogastrostomy can be
FIG 26. Frequency of node-positive zones for midgastric cancers. (From Sutherland DA. The Lymphatic Spread of Gastric Cancer. In: McNeer G, Pack GT, editors. Neoplasms of the Stomach. Philadelphia: Lippincott; 1967:408-15. Reproduced with permission.)
achieved with adequate margins and lymphadenectomy.157 However, this operation results in unacceptable long-term morbidity and should, in our opinion, never be performed. Gastroesophageal reux is severe after this operation, and it is not treatable medically. Gastric emptying is usually impaired; the reuxate is composed of pancreaticobiliary secretions that are very irritating to the esophageal mucosa, and patients usually do not respond to antisecretory medications. Furthermore, a tension-free anastomosis is easier with a Roux-en-Y esophagojejunal reconstruction, thus reducing the temptation to compromise the esophageal resection and margin. In summary, the factors above should govern the extent of gastric resection. Well-conducted studies have established that subtotal gastrectomy is equivalent to total gastrectomy in patients with distal or antral cancers.159,160 In experienced hands, elective total gastrectomy does not increase postoperative mortality, but there is no improvement in survival. Bozzetti and colleagues randomized 618 patients with cancers of the
FIG 27. Frequency of node-positive zones for proximal gastric cancers. (From Sutherland DA. The Lymphatic Spread of Gastric Cancer. In: McNeer G, Pack GT, editors. Neoplasms of the Stomach. Philadelphia: Lippincott; 1967:408-15. Reproduced with permission.)
distal stomach: 315 underwent subtotal gastrectomy (SG) and 303 underwent total gastrectomy (TG).161,162 There were 4 operative deaths in the SG group and 7 in the TG group. The 5-year survival probability was 65% for SG and 62% for TG. The authors concluded that SG, which is associated with better nutritional status and quality of life, should be the procedure of choice in patients with distal gastric cancers, provided that the 6-cm proximal margin of resection is in healthy tissue. In their study, 6 of 315 SG patients had positive margins (4 with clearance less than 6 cm), but only 1 of 303 TG patients had a positive margin (with a 10 cm clearance). These latter data suggest that a subtotal gastrectomy mindset can affect intraoperative decision making and potentially increase the likelihood of settling for inadequate proximal margins. Of note, 13 patients in the study had distal margins inltrated by the tumor. Virtually all patients with T2-4 tumors of the body of the stomach or proximal stomach should undergo total gastrectomy.
Preoperative Evaluation
National Comprehensive Care Network guidelines indicate the following preoperative workup and/or evaluation in all patients: (1) multidisciplinary evaluation, (2) history and physical examination, (3) CBC and SMA-12, (4) abdominal and pelvic CT, (5) chest radiograph, (6) esophago-gastroduodenoscopy (EGD), and (7) laparoscopy. We believe that the majority of patients should also undergo EUS evaluation to better dene the T stage of the tumor. Although tumor markers have no role in screening, we believe that preoperative measurement of CEA and CA 19-9 is warranted, as it may help with postoperative follow-up in those with elevated levels (approximately 35% of patients). Preoperative preparation routinely includes cathartic bowel preparation the day before operation, with admission to the hospital on the day of operation. Because of concerns regarding the association between perioperative blood transfusion and decreased cancer-related survival, transfusion is avoided, if at all possible. Patients with preoperative anemia are treated with iron repletion (orally or intravenously) and operation delayed if necessary. Prophylactic antibiotics (cefazolin [2 g] or a quinalone in penicillin-allergic patients) are administered within 30 minutes before the surgical incision. Redosing of antibiotics is appropriate approximately every 2 half-lives during operation, or approximately every 3 to 4 hours for cefazolin. No postoperative antibiotics are needed. Aggressive measures should be taken to prevent deep vein thrombosis (DVT), with at least 2 interventions. In our practice, we place graded compression stockings plus sequential compression devices and also administer low dose heparin in most patients. Similarly, we believe the data support the routine use of thoracic epidural anesthesia and postoperative patientcontrolled epidural analgesia (PCEA). Improved outcomes in patients undergoing major cancer operations treated with epidural techniques have been reported. The initiation of thoracic epidural anesthesia with local anesthetics before the surgical stimulus blunts the surgical stress response, thereby decreasing the risk for DVT and improving myocardial performance. Postoperative patient-controlled epidural analgesia likely decreases the length of hospital stay, shortens postoperative ileus, and improves pain control.
Surgical Technique
Gastric Resection
Subtotal or total gastrectomy is initiated in an identical fashion. The decision to perform a subtotal gastrectomy in patients with antral cancers
FIG 28. The entire greater omentum is detached from the transverse colon (hepatic exure to the
splenic exure) using electrocautery. (From Brennan MF. Total gastrectomy for carcinoma. In Baker RJ, Fischer JF, editors. Mastery of Surgery. Philadelphia: Lippincott Williams & Wilkins; 2001:997-1006. Reproduced with permission.)
is not made until the latter stages of the procedure. We use a midline incision in virtually all cases, although an upper bilateral subcostal incision (Chevron incision) provides excellent exposure as well. Exposure is enhanced with a self-retaining retractor. The abdominal contents are explored in search of metastatic disease and to assess the mobility of the stomach and feasibility of resection. The decision to proceed with a palliative resection (eg, in patients with grossly positive para-aortic nodes or peritoneal metastasis) is complex and reviewed elsewhere in this article. Once curative resection is planned, further exposure is necessary. Exposure of the esophageal hiatus is enhanced by verticalization of the diaphragm. We routinely disarticulate the xiphoid from its costal attachments and/or remove the xiphoid. This allows several additional centimeters of distraction of the costal margin by a self-retaining retractor that then makes the diaphragm vertical under the xiphoid and provides direct visualization of the gastroesophageal junction. The suspensory ligament of the left lateral segment of the liver is divided. The areolar tissue of the suspensory ligament is dissected to the right of the
FIG 29. Exposure of lesser sac. The short gastric and left gastroepiploic vessels are divided close to the spleen using the Harmonic Scalpel. (From Brennan MF. Total gastrectomy for carcinoma. In Baker RJ, Fischer JF, editors. Mastery of Surgery. Philadelphia: Lippincott Williams & Wilkins; 2001:997-1006. Reproduced with permission.)
esophageal hiatus, taking care to identify and avoid the inferior phrenic vein. This permits retraction of the left lobe to the patients right with an additional blade attached to a self-retaining retractor. The formal operation should commence with dissection of the omentum from the transverse colon (Fig 28). The avascular plane at the junction with colon permits this to be achieved with scissors or the electrocautery. Mobilization of the hepatic and splenic exures of the colon facilitates this dissection laterally. We believe the use of the Harmonic Scalpel (Ethicon, Endo Surgery, Inc., Cincinnati, OH) or similar devices enhances the speed and safety of this dissection. At this point, the lesser sac is widely opened permitting careful inspection and assessment of extent of disease (Fig 29). The classic D2 resection proceeds with dissection of the anterior leaf of the transverse colon and the peritoneal surface of the pancreas at the base of the lesser sac. In our opinion, this maneuver adds nothing to the operation in terms of clearance of cancer or potential cure of the patient. This tissue
FIG 30. The left gastric artery is suture ligated and divided at its origin. Exposure is usually best achieved with cephalad retraction on the divided stomach. (From Brennan MF. Total gastrectomy for carcinoma. In Baker RJ, Fischer JF, editors. Mastery of Surgery. Philadelphia: Lippincott Williams & Wilkins; 2001:997-1006. Reproduced with permission.)
represents a trivial peritoneal surface in terms of the peritoneal surface area at risk and does not signicantly facilitate lymphadenectomy of important nodal basins. The next maneuver should be the dissection and suture ligation of the right and left gastroepiploic arteries and veins. This adds mobility to the specimen and facilitates duodenal transection and dissection of zone II and III nodes. The duodenum is dissected circumferentially just distal to the pylorus in proximal cancers and approximately 3 cm distal to the pylorus in antral cancers. We typically divide the duodenum with a stapler. The staple line is not routinely inverted. Dissection of the areolar tissue and lymph nodes of the porta is commenced from above at the level of the bifurcation of the hepatic artery, reecting the tissue toward the
midline. This dissection is thus taken along the hepatic artery to the celiac axis and the origin of the left gastric artery. The left gastric artery is suture ligated at its origin (Fig 30). Exposure may be best achieved from below, lifting the stomach anteriorly and cephalad, or from above, retracting the lesser curve caudally and to the patients left. At this time, the greater curve is dissected. The Harmonic Scalpel facilitates safe division of the short gastric and left gastroepiploic arteries as close as possible to the splenic hilum (Fig 29). For reasons reviewed above, splenectomy is avoided if at all possible. If subtotal gastrectomy is planned, 1 or 2 short gastric vessels should be preserved. The dissection on the lesser curve should be within 2 cm of the esophagogastric junction and include the nodal tissue of zone Ia (see Fig 26). The stomach can be divided with a heavy wire 90-mm stapler. If total gastrectomy is planned, the greater curve dissection should include removal of all tissue to the level of diaphragm. Similarly, the lesser curve dissection should include division of the hepatic branch of the anterior vagal nerve as well as all tissue below the diaphragm to the level of the right crus. Since the vagus nerves tether the tissue cephalad, the proximal dissection is facilitated by bilateral truncal vagotomy (Fig 31). This should be performed early in the proximal dissection. The vagus nerves are divided at the GE junction and dissected for 3 to 4 cm to divide branches to the distal esophagus and proximal stomach. To achieve 6-cm margins in patients with proximal tumors, we believe exposure is frequently enhanced by a modied Dragstedt maneuver (Figs 32 to 35). The central tendon of the diaphragm is carefully incised with a knife. Blunt dissection permits grasping the divided edges with Allis clamps, followed by further division. The original Dragstedt maneuver, described to facilitate exposure of the distal esophagus during vagotomies, involved a short transverse incision. A vertical incision of the diaphragm to the hiatus is routinely added. The inferior phrenic vein is suture ligated. With this maneuver, the hiatus, inferior mediastinum, and the distal 10 cm of the esophagus is exposed widely. After completion of the anastomosis, the diaphragmatic incision is closed with interrupted horizontal mattress sutures. In some cases, it may also be appropriate to place tacking sutures between the Roux limb and the diaphragm. Lessons learned performing Roux-en-Y gastric bypass procedures in morbidly obese patients have facilitated the safety of construction of the Roux limb. Standard texts describing Roux limb construction illustrate division of the jejunum 8 to 12 cm distal to the ligament of Treitz. However, the jejunal mesentery is short and the mesenteric vasculature is complex close to the ligament of Treitz. In virtually all patients, the
FIG 31. The phreno-esophageal bundles and lymphatic tissue surrounding the esophagogastric
junction are dissected caudally before division of the esophagus. Bilateral truncal vagotomy facilitates this dissection. (From Brennan MF. Total gastrectomy for carcinoma. In Baker RJ, Fischer JF, editors. Mastery of Surgery. Philadelphia: Lippincott Williams & Wilkins; 2001:997-1006. Reproduced with permission.)
mesentery lengthens and the mesenteric vasculature simplies approximately 25 cm distal to the ligament of Treitz. We routinely divide the jejunum at this point with a stapler. A single arcade vessel is divided and suture ligated and the Roux limb will then reach the mediastinum in a tension-free fashion in all patients. A retrocolic Roux-en-Y esophagojejunostomy is then performed. The length of the Roux limb to the jejuno-jejunostomy should be 45 to 50 cm to prevent bile reux.
FIG 32. The central tendon of the diaphragm is exposed through an upper-midline incision with
routine excision of the xiphoid. The length of the transverse incision in the diaphragm (arrow) averages 10 cm. In most cases, the incision is Td through the hiatus. (From Thirlby RC, Kraemer SJM, Hill LD. Transdiaphragmatic approach to the posterior mediastinum and thoracic esophagus. Arch Surg 1993;128:897. Reproduced with permission.)
There are many methods of reconstruction or restoration of intestinal continuity, none of which have been proven superior. Randomized and cohort studies have concluded that the safety and function of stapled and hand-sewn jejuno-esophageal anastomoses are equivalent.163-166 Our preference is to perform a hand-sewn anastomosis after subtotal gastrectomy and a stapled Roux-en-Y esophageal anastomosis after total gastrectomy. An additional unresolved issue is the value of incorporating a jejunal pouch into the Roux-en-Y reconstruction. Small randomized studies have reported greater meal size and less weight loss in patients reconstructed with Hunt-Lawrence pouches compared with those reconstructed with standard Roux-en-Y limbs.167-170 In these series, weight loss at 1 year was approximately 20% of preoperative weight in the Roux-en-Y groups and approximately 12% in the Hunt-Lawrence groups, a difference that reached statistical signicance. However, the long-term
FIG 33. Intraoperative photograph shows incision in diaphragm (upper arrow, Defect in Diaphragm) and esophageal hiatus (lower arrow, Hiatus). The bridge of diaphragm between these structures can be divided to improve exposure.
benets of the pouch procedures are likely not clinically signicant and we continue to perform a standard Roux-en-Y reconstruction. Subtotal Gastrectomy. As mentioned above, subtotal gastrectomy is possible in many patients with antral cancers. Bilateral truncal vagotomy also is routinely performed because a Roux-en-Y reconstruction is ulcerogenic. We prefer a hand-sewn anastomosis, using a double-armed Prolene suture for the seromuscular layer. As mentioned below, we still frequently place nasogastric tube during the procedure, which is left in place for 1 to 3 days. Total Gastrectomy. Our preferred anastomotic technique is a stapled end-esophagus to side-Roux limb anastomosis using a 25-mm EEA stapler (USSC, Norwalk, CT). Alternatively, a single layer running anastomosis using monolament suture (polydioxanone or polypropylene) is acceptable. However, with the proximal progression of cancers and resultant increased esophageal resections necessary in our practice, we feel more comfortable with a double-staple technique as illustrated in Figs 36 to 39.171,172 In this technique, a heavy Prolene suture is attached
FIG 34. Using blunt dissection, the pericardium and heart are retracted cephalad, and the lower esophagus and posterior mediastinum are exposed. (From Thirlby RC, Kraemer SJM, Hill LD. Transdiaphragmatic approach to the posterior mediastinum and thoracic esophagus. Arch Surg 1993;128:89. Reproduced with permission.)
to the anvil of the stapler before passing the anvil into the midesophagus through a small gastrotomy. The esophagus is then stapled at least 6 cm proximal to palpable tumor with a 30-mm stapler. The esophagus is carefully divided taking care not to divide the Prolene tag sutures. After placement of lateral stay sutures (needles left in place), the Prolene suture is then used to pull the anvil through the staple line. A standard EEA anastomosis is then constructed. The anastomosis is reinforced with the 2 stay sutures. Using this technique, together with the modied Dragstedt maneuver described previously, we have been able consistently to accomplish total gastrectomies with clear margins in patients with proximal gastric cancers. To our knowledge, there are no well-controlled data showing lower leak rates of high risk anastomoses reinforced with brin glue products. Regardless, we have increasingly been reinforcing our esophageal anastomoses with brin glue. We perform a stapled jejuno-jejunostomy with a 50-cm Roux limb.
FIG 35. Anterior view of exposure of posterior mediastinum achieved via a transdiaphragmatic approach. (From Thirlby RC, Kraemer SJM, Hill LD. Transdiaphragmatic approach to the posterior mediastinum and thoracic esophagus. Arch Surg 1993;128:897. Reproduced with permission.)
622
FIG 36. Anvil, with spike and heavy polypropylene suture attached, are passed to the mid-esophagus
via a proximal gastrotomy. (From Cebrian ET, Gimenez TR, Fernandez LF, Herroros AT, Sanchez EJ. Double-stapling technique for mechanical circular oesophageojejunal anastomosis after total gastrectomy. Br J Surg 1994;81:408. Reproduced with permission.)
Frozen Sections
What is the role of frozen section in operations for gastric cancer? There are 2 issues. First, is an anastomosis with microscopic tumor in the wall safe? The answer, based on multiple studies is yes. Second, what is the effect of positive microscopic margins on overall survival? Based on a review of 47 patients with positive margins in a series of 572 patients, Kim and colleagues concluded that the signicance of a positive microCurr Probl Surg, Aug/Sept 2006 623
FIG 37. Esophagus is stapled with a 30 mm stapler taking care to place the suture centrally in the staple line. (From Cebrian ET, Gimenez TR, Fernandez LF, Herroros AT, Sanchez EJ. Double-stapling technique for mechanical circular oesophageojejunal anastomosis after total gastrectomy. Br J Surg 1994;81:408. Reproduced with permission.)
scopic margin is dependent on the extent of disease.94 In patients with more than 5 positive lymph nodes, there was no relationship between margin status and survival. On the other hand, in patients with fewer than 5 positive lymph nodes, survival was negatively affected by the presence of a positive microscopic margin. The obvious practical problem with this conclusion is that the operating team does not know the denitive nodal status at the time of resection. Others have also found that residual disease after surgery is an important negative factor for survival.173 Regardless, in patients in whom curative resections are being performed, we believe
FIG 38. The esophagus is divided, leaving the polypropylene suture intact. (From Cebrian ET, Gimenez TR, Fernandez LF, Herroros AT, Sanchez EJ. Double-stapling technique for mechanical circular oesophageojejunal anastomosis after total gastrectomy. Br J Surg 1994;81:408. Reproduced with permission)
frozen sections of margins should be obtained. Consistent with the experience of others, we have found that clearing the distal (duodenal) margin is a more frequent and difcult problem than clearing the esophageal margin.156
Extended Resections for T4 Disease

Aggressive surgery with multiorgan resections is frequently indicated in patients with T4 gastric cancers. Several studies have reported long-term
FIG 39. Stay sutures are placed laterally. The anvil with spike is pulled through the staple line and docked to the stapler. (From Cebrian ET, Gimenez TR, Fernandez LF, Herroros AT, Sanchez EJ. Double-stapling technique for mechanical circular oesophageojejunal anastomosis after total gastrectomy. Br J Surg 1994;81:408. Reproduced with permission.) 626 Curr Probl Surg, Aug/Sept 2006
survival in this subset of patients that is equivalent to that in T3 patients.174-176 In patients with clear margins (RO resections), 5-year survival rates of 37% have been reported.175,176 However, recent studies suggest that 5-year survival rates may be as low as 16% with median survival times of only approximately 1 year.177 In this recent series from Japan, 5-year survival rates in patients who had noncurative resections of T4 tumors were only 10% and median survival time was only 8 months, leading the authors to conclude that noncurative resections should be avoided in patients with T4 gastric cancers. The assessment of adjacent organ invasion by preoperative CT or intraoperative assessment is unreliable. In 1 series of 21 patients undergoing multiorgan resections for gastric cancers, only 8 (38%) had pathologically conrmed T4 disease.178 In other words, preoperative staging and intraoperative assessment tends to suggest adjacent organ invasion when it does not exist. Preoperative CT is inaccurate in assessing T4 lesions, with a positive predictive value of only 50%. Regardless, aggressive multiorgan resections can be performed with little increased morbidity with the expectation that long-term survival is possible in approximately one third of patients with RO resections.
Naso-Jejunal Tubes
Placement of a naso-jejunal tube after total gastrectomy is routine. However, there are few if any data to support this practice.179 In fact, a recently published randomized trial suggests that this practice is unnecessary, with equivalent leak rates in patients with or without tubes.180 The protocol used by the surgeons in this trial included NPO status for 7 days. In the few patients who developed leaks in the no tube group, tubes were placed with uoroscopic guidance. Virtually all patients with leaks in both groups were managed conservatively with bowel rest and drainage. Only 1 patient actually required operation. On the basis of this study, we do not believe that routine naso-jejunal tube placement after total gastrectomy is necessary.
Feeding Jejunostomy
The role of enteral feeding after total gastrectomy is controversial. Conicting studies have concluded that routine enteric feedings (through a feeding jejunostomy placed in the operating room) are and are not associated with better outcomes. Ferlay and colleagues1 randomized 195 patients undergoing major upper gastrointestinal cancer operations to enteral feeding via jejunostomy tubes or control. Complications and median length of hospital stay were not signicantly different between the
2 groups. Another similar randomized study of patients undergoing esophagectomy or pancreatoduodenectomy reported impaired respiratory mechanics and decreased mobility in the enteral feeding group and concluded that routine immediate postoperative tube feeding should not be used in a routine fashion.181 On the other hand, several studies support the safety and efcacy of routine immediate postoperative enteral nutrition after major upper gastrointestinal surgery for cancer. Protocols with slow progression of volume have been shown to be safe and well tolerated.182 Randomized studies suggest that the hospital length of stay is shorter in those managed with enteral nutrition.183 Furthermore, prospective randomized studies suggest that complications and cost are decreased.184 Finally, a meta-analysis of randomized controlled trials of enteral nutrition in patients undergoing upper gastrointestinal cancer operations demonstrated a lower risk of infectious complications and a shorter overall hospital length of stay in treatment arms.185 NCCN guidelines concluded that the surgeon should consider placing a feeding jejunostomy tube. Our practice has been to place feeding catheters in most patients undergoing total gastrectomy and begin feeding at a slow rate on the rst postoperative day. The motility of the Roux limb is poor for several weeks, and we believe that hospital stay is shortened and short-term recovery is enhanced in a majority of patients treated with this protocol. In addition, the majority of patients are now receiving adjuvant chemoradiotherapy that further impairs functional status for weeks after surgery. In some of these patients, nutritional and functional status during adjuvant treatment can be better maintained with supplemental tube feedings.
Cholecystectomy
At least 30% of patients who undergo total gastrectomy will develop gallstones within 1 to 2 years.186 Gallbladder contraction is impaired due to both decreased vagal tone and to decreased cholecystokinin (CCK) secretion (CCK-stimulated gallbladder contraction is triggered by nutrients in the duodenum). Weight loss also is associated with increased lithogenicity of bile. Total gastrectomy (vs. subtotal) and hepatoduodenal lymph node dissection are independent predictors of gallbladder formation. Presumably, excision of the lymphatics of the hepatoduodenal ligament results in disruption of essential neural pathways related to gallbladder function. Therefore, there may be a role for prophylactic cholecystectomy as part of most operations for gastric cancer. Is there a downside to performing cholecystectomy? First, although the risk of cholelithiasis is high, the risk of symptoms may be low, at less than
1% in 1 series. Cholecystectomy has also been linked to increased risk for postgastrectomy syndromes in patients undergoing gastric resections, especially bile reux and diarrhea. Since virtually all gastric cancer patients are reconstructed with Roux-en-Y anatomy, the risk for bile reux is nil. However, cholecystectomy could increase the risk of diarrhea and aggravate the symptoms of dumping syndrome. In our experience, signicant dumping syndrome is unusual after total gastrectomy for cancer. In summary, a strong case for prophylactic cholecystectomy during gastrectomy for cancer cannot be made. However, we tend to perform cholecystectomy in young patients and in those with early stage tumors in whom prolonged survival is anticipated.
Drains
Prophylactic drain placement during total gastrectomy (near the duodenal stump and/or the esophageal anastomosis) is common. We are not aware of any studies justifying this practice and do not routinely place drains during operations for gastric cancer. A recently published randomized study found no difference in outcomes in drained and no drain groups and concluded that prophylactic drain placement does not add any benet in patients undergoing gastrectomy with extended lymph node dissection.187
Postoperative Management
There is little good evidence regarding the optimal postoperative care of patients undergoing gastric resection. Traditionally, naso-jejunal tubes have been used for 3 to 7 days and oral alimentation has been postponed for 5 to 7 days. Increasingly, perhaps based on successful fast-tracking of other patient groups undergoing major gastrointestinal operations, more aggressive progression of diet is being incorporated safely into postoperative care. Our program is outlined below. Postoperative Analgesia. We routinely use patient-controlled epidural analgesia for 48 to 72 hours. This practice is associated with shorter intensive care unit (ICU) stay, fewer complications (eg, DVT), decreased postoperative ileus, and probably shortened length of hospital stay. In addition, we believe routine use of ketorolac (unless contraindicated) for 48 to 72 hours followed by scheduled oral ibuprofen for the duration of the hospital stay improves postoperative pain management, decreases narcotic requirements, and improves patient satisfaction. Diagnostic Studies. In total gastrectomy patients, our practice continues to include a diagnostic radiographic study to rule out anastomotic leak on
the third postoperative day. If this study is normal, oral intake is commenced immediately. Alimentation. In patients in whom jejunal feeding catheters were placed intraoperatively, we begin infusion of full-strength tube feedings at a slow rate (eg, 30 mL/hr) on the rst postoperative day. Infusion rates are not increased aggressively, with the intent to achieve goal rates by the third or fourth postoperative day. Oral intake is commenced on the third postoperative day with frequent low volume liquids. We use a standardized protocol of 30 mL every 10 to 15 minutes. At discharge, volumes are restricted to 4 ounces at a time and liquids are maintained for 10 to 14 days. Our goal is hospital discharge in 5 to 7 days. To achieve this, many patients require supplemental (nocturnal) tube feedings at home for 2 to 3 weeks. The diet is progressed to a soft or pureed diet at 10 to 14 days and then advanced as tolerated to regular food over the next month. In our opinion, the feeding catheter should be left in place until the patient demonstrates adequate alimentation through the initial stages of adjuvant treatment.
Postoperative Complications and Outcomes

A large review of surgical series published in 1989 reported an average operative mortality rate of 22% in patients undergoing gastrectomy for cancer.188 Similarly, the Assessment of Stomach and Esophageal Cancer Outcomes from Treatment (ASCOT) database, representing patients from 32 hospitals in England and Wales, demonstrated a postoperative surgical complication rate of 18.3% and medical complication rate of 32.4%. The in-hospital mortality rate was 10.3% (61 patients). Anastomotic leaks (3.2%) or intra-abdominal abscesses (3.1%) were the most common surgical complications, with 10.2% of these patients requiring a second operation.189 However, advancements in anesthesia, surgical technique, and perioperative care have decreased the overall 30-day morbidity and mortality rates of surgery for gastric cancer. In a recent retrospective case series at Seoul National University in Korea, the overall morbidity and mortality rates were 17% and 0.6%, respectively.190 The most common complications were intra-abdominal uid collections (4.5%) and wound infections (3.7%). Morbidity was increased in older patients who underwent multiorgan resections (eg, splenectomy; pancreatectomy and splenectomy).190 Another large series of 700 gastric cancer patients reported that postoperative deaths occurred in 5.7%40 of patients.191 For patients who underwent operations for recurrent gastric cancer or cancer in the gastric remnant, reoperation rates were 30%. Complications were also common
after palliative procedures. Surgical reintervention for complications was required in 20% of palliative total gastrectomies and 16.7% of those undergoing palliative subtotal gastrectomies.191 The leading cause for relaparotomy was anastomotic leak. The most common site of leakage was the esophago-jejunostomy. The National Cancer Center Hospital in Tokyo and the Dutch Gastric Cancer Trial have reported leak rates of 7% and 8%, respectively. A major risk factor for leakage of an esophagojejunostomy is an intrathoracic anastomosis. More recent reports suggest that leak rates should be as low as 1%.192 Most anastomotic leaks manifest early (eg, third postoperative day) as peritonitis or with abnormal drain output. On the other hand, many leaks manifest later (eg, 7 to 9 days) with intra-abdominal abscesses.191 Reoperation or percutaneous drainage can be used to control leaks. Large reviews suggest that outcomes in patients with leaks at the esophagojejunostomy are better if they are managed with conservative percutaneous drainage (vs. surgical intervention). However, these data do not control for the severity of disease and no randomized controlled studies have examined this issue.193 Regardless, wide drainage, either percutaneous or surgical, is the cornerstone of treatment. Many leaks can be managed with percutaneous techniques, avoiding reoperation. Operative repair of an esophago-jejunostomy is a challenge, with poor tissues preventing effective suture placement at the anastomosis. In the setting of an intrathoracic anastomosis, cervical esophagostomy in addition to wide drainage permits diversion of oropharyngeal secretions and prevents further contamination of the pleural space. Successful management of anastomotic leakage with percutaneous drains requires expertise in the percutaneous techniques usually only available to interventional radiologists. Sequential exchange or upsizing of the drainage tubes should be guided by drain output and uid collections determined by serial CT. Additional percutaneous drainage tubes should be considered if drainage is not adequate. Tube checks, the injection of contrast into the drainage tube, is an inexpensive method of monitoring and characterizing abscesses and adjusting drain position.192 Novel stenting techniques for managing esophago-jejunostomy leaks have been reported in recent years.194,195 Self-expanding covered plastic or metal stents can be placed endoscopically to seal a leak that is less than one third of the anastomosis circumference. Langer and colleagues reported successful stenting of 89% of patients who presented with esophageal anastomotic leakage.194 Unfortunately, stenting techniques are particularly challenging with a Roux-en-Y anastomosis, requiring placement of the guide wire at least 15 cm past the leak. In addition, this
invasive technique can also result in further injury and complete dehiscence of the anastomosis. In the Langer series, enlargement of the leak occurred in 8%2 of patients. Reintervention is also common with stenting procedures. Most commonly, the stent is dislodged or migrates, requiring endoscopic removal or adjustment. Endoscopic and interventional techniques continue to evolve and will undoubtedly have a role in the management of postoperative complications of gastric cancer. Although no current randomized controlled trials exist to show a signicant outcome improvement with stenting, this technique is very appealing and is being adopted in hospitals worldwide.194
Nutritional Complications
Pathophysiology
Virtually all patients who undergo operation for gastric cancer have signicant gastrointestinal side effects. It is imperative that surgeons not only understand the pathophysiology of the sequelae of gastric surgery, but also take active measures in directing the postoperative care of their patients. Although many patients do not have major postgastrectomy symptoms, all patients have nutritional sequelae and most have symptoms that affect their quality of life. All too frequently, the physicians assuming care of these patients (eg, medical oncologists, internists) have little understanding of the many important complications of gastrectomy. Therefore, it is imperative that surgeons understand these outcomes and guide the nutritional education and care of their patients. The side effects of gastric surgery can be divided into 2 categories: postcibal symptoms and nutritional deciencies. Postcibal symptoms include anorexia or decreased hunger in the fasted state, early satiety, and early and/or late dumping syndrome. Nutritional deciencies include maldigestion of polymeric foods with malabsorption of calories, iron deciency, and osteomalacia. This review will focus on the pathophysiology of the postgastrectomy state and provide insight into its treatment. Why do patients lose weight after gastrectomy and how much weight do they lose? Clearly, restriction of meal size is the key factor in determining weight loss after gastrectomy. Meal size is probably less restricted in patients with a gastric remnant. Hence, weight loss is less in patients who have subtotal gastrectomy than in those undergoing total gastrectomy. Weight loss may be less in total gastrectomy patients reconstructed with jejunal pouches. In addition, caloric consumption is decreased in many patients because of postcibal symptoms related to the dumping syndrome
and malabsorption. Dumping syndrome results in avoidance of rened carbohydrates. Some patients avoid fatty foods because malabsorption of fats causes postprandial gas, bloating, and diarrhea. Total gastrectomy also affects hunger. The pathophysiology of hunger and satiety is very complex. Scores of gastrointestinal and neural peptides affecting satiety have been linked to the control of body weight and/or the pathophysiology of human fatness.196,197 More recently, peptides affecting hunger have been identied. For example, ghrelin is a gastric peptide that signicantly affects hunger and initiation of meals.198 Empirically, most gastrectomy patients (and most gastric bypass patients) claim that they rarely get hungry. It is very likely that most, if not all, total gastrectomy patients have a physiologic impairment of the signals that trigger hunger and/or initiation of meals. In our opinion, this factor is an underappreciated side effect of gastrectomy. It should be reviewed during the nutritional counseling of all patients. Patients should understand that they will not experience normal hunger and that they should avoid the tendency to skip meals. In summary, the net effect of these factors is decreased calorie consumption and weight loss in most total gastrectomy patients in the range of approximately 10% over the rst year. Several studies have reported that weight loss is less in total gastrectomy patients reconstructed with jejunal pouches.199 Nozoe and colleagues compared nutritional outcomes in 16 gastric cancer patients reconstructed with simple Roux-en-Y to 14 patients with jejunal pouches.169 Body weight decreased 20% and 12% at 1 year in the simple and pouch patients, respectively. Another small randomized study (n 10 in each group) reported that body weights 2 years after operation were approximately 85% and 90% of preoperative weights in simple and pouch Roux-en-Y patients, respectively. However, most reports from North America suggest that weight loss at 1 year in gastric cancer patients after curative resections is approximately 10% of preoperative weight and actually results in an end weight that is near ideal body weight. Others have reported insignicant differences in body composition among different operative types.200 We continue to perform simple Roux-en-Y reconstructions in virtually all patients. Steatorrhea follows all gastric operations for gastric cancer.201-203 Many patients also demonstrate abnormal absorption of carbohydrates. Absorption of nitrogen is within normal ranges in virtually all patients.202 The cause of malabsorption is complex but is largely due to derangements in digestive balance.202 This refers to the ratios between nutritional substrates and digestive enzymes. Pancreatic enzyme secretion occurs in response to cephalic vagal stimulation and reexes triggered by food in the gastric antrum and the duodenum. Not surprisingly, there is marked
impairment of pancreatic enzyme secretion after total gastrectomy.201 Furthermore, the mixing of substrates and enzymes is disturbed by the asynchrony of the food bolus and pancreatic enzymes entering the jejunum. Finally, many of the digestive enzymes can only attack water-insoluble, polymeric foods when they have been broken down. Whenever there is defective gastric sieving, digestion is impaired. That is, the lack of gastric grinding or trituration of solid foods probably impairs absorption.202 Intrinsic factor secretion from the parietal cells is eliminated by resection of the proximal stomach. Vitamin B12 deciency with pernicious anemia thus follows total gastrectomy in 2 to 7 years after total gastrectomy if the vitamin is not administered parenterally. Folate and iron are absorbed most effectively from the duodenum and proximal jejunum. Hence, iron and folate deciency is also common in gastric cancer patients. Bone disease with loss of bone mineral content and osteomalcia occurs after total gastrectomy and becomes clinically signicant with time.202,204-207 Postgastrectomy patients studied years postoperatively have abnormal bone biopsies, elevated serum alkaline phosphatase and parathyroid hormone levels, and decreased serum 25-hydroxy vitamin D levels.208 Pathologic fractures have been reported to occur in approximately 10% of patients with long-term follow-up after peptic ulcer surgery.202 The severity of decreased bone density has been reported to correlate with weight loss but not serum alkaline phosphatase or calcium levels.204 Bone density has been correlated with vitamin 1,23-(OH)2D levels, but several studies have reported that there are no highly sensitive serum markers for the development of osteomalacia after gastric surgery.202 The assumption is that decreased bone density is related to the previously discussed malabsorption of fats and fat-soluble vitamins. However, there is no consistent relationship between the presence or absence of bone disease and steatorrhea in postgastrectomy patients.202 Absorption of calcium has been shown to be normal in most patients with gastric resections. In summary, the cause of postoperative osteomalacia is unknown.202
Treatment
Weight Loss. In our experience, weight loss is not a major problem in most patients. Nutritional counseling and encouragement counteracts the negative effects of early satiety, depressed hunger, and food avoidances. Patients are advised to eat multiple small meals regardless of hunger and
to modify dietary composition to minimize symptoms of dumping or carbohydrate, lactose, or fat malabsorption. Iron, Folate, and Vitamin B12. Deciencies of iron, folate, and vitamin B12 are preventable with proper supplementation. Iron replacement should probably be administered as solutions or chewable formulations of ferrous salts, not large tablets. Vitamin B12 supplementation should be 1000 micrograms monthly administered by intramuscular injection.202 Osteomalacia and Malabsorption of Polymeric Foods. Treatment and/or prevention of osteomalacia and malabsorption of polymeric foods after gastrectomy are problematic. We believe the standard of care includes supplemental calcium and vitamin D in postgastrectomy patients.204 Tablets of calcium carbonate should be pulverized by chewing or be administered as solution. However, we would emphasize that we are not aware of any studies that have demonstrated convincingly that this program will decrease the likelihood of developing bone disease.202,206 Similarly, malabsorption of polymeric foods is multifactorial and no treatment has been proven to be effective. For example, there is little or no evidence that supplemental exogenous pancreatic enzymes affect fecal fat excretion or symptoms of fat malabsorption after gastrectomy.202 A single study reported that the bisphosphonate alendronate improves vitamin D-resistant osteopenia in postgastrectomy gastric cancer patients.209 Thirteen patients with progressive osteopenia despite treatment with vitamin D were studied after initiation of alendronate. Statistically signicant improvements in parameters such as bone mineral density and parathyroid hormone levels were reported. If these ndings are conrmed in larger studies, alendronate may become routine in postgastrectomy patients.
Special Considerations
Gastric Stump Cancer
Gastric stump cancer is dened as a gastric carcinoma occurring 5 or more years after gastric surgery for benign disease.210 The association between surgery for peptic ulcer and the subsequent development of gastric cancer has been noted for decades. Original reports suggested that the incidence was highest after partial gastrectomy with Billroth II reconstruction.211 However, more recent studies suggest that the incidence is similar in patients undergoing Billroth I reconstruction or pyloroplasty. Cases of gastric cancer after proximal gastric vagotomy are now being reported.210 A causal relationship between the surgical procedure and the eventual
cancer was supported by well-controlled animal experiments that concluded that the combination of pancreaticobiliary reux produced by operations for peptic ulcer and decreased gastric acid secretion was carcinogenic.210,212 N-Nitroso compounds are recognized as important carcinogens and the relationship between bile reux and gastric cancer becomes more relevant in this patient population. The hypochlorhydric stomach with high pH promotes bacterial overgrowth, which then converts dietary nitrates and nitrites to carcinogenic N-nitroso compounds. Furthermore, bile acids degrade gastric mucous, facilitating transmucosal ow of large intraluminal molecules and causing atrophy of the mucosal cells. Bacterial deconjugation of reuxed bile acids may also generate cocarcinogens. Several human cohort studies, comparing populations of patients who had undergone surgery for peptic ulcer to a population of age- and sex-matched persons who had not undergone operations for peptic ulcer, also suggest a causal relationship between operations and the subsequent development of gastric cancer.211,213,214 Risk factors for cancer included female gender, Billroth II reconstruction, and age at time of operations.210,211,214 In most studies, the risk becomes statistically signicant after 15 to 20 years and increases with longer follow-up.211 Is the risk for gastric cancer increased in patients who have had operations for peptic ulcer? Several series from Europe have concluded that the answer is yes.211,213-215 For example, data from the Swedish Cancer Registry show that the average adjusted risk for gastric cancer increased 28% for each successive 5-year interval after operation.211 The adjusted risk was greater in women and in those who had undergone Billroth II operations for gastric ulcer. The relative risk in those followed for more than 30 years was approximately 3-fold. On the other hand, 2 large cohort studies have concluded that there is not an increased risk.178,216 A study of 338 residents of Olmsted County, Minnesota, who had operation for peptic ulcer between 1935 and 1959 found only 2 gastric cancers: a relative risk of 0.8 (95% CI, 0.1-2.7).217 These investigators concluded that there was not an association. Similarly, a larger cohort study from North Carolina calculated a relative risk of 0.7.178 Regardless, we believe the bulk of the literature supports the positive association between surgery for peptic ulcer and the subsequent development of gastric cancer. Is there a causal relationship between operations for peptic ulcer and the development of cancer? We believe the answer to this question is probably not. The aw in all human cohort studies suggesting a causal relationship is that the control groups did not have peptic ulcer disease. In
these studies, patients with peptic ulcers severe enough to warrant operation were compared with a population of individuals who did not have operations for peptic ulcer.218 These studies antedated the understanding of the relationship between H. pylori, peptic ulcer, and gastric cancer. Most studies now suggest that the relationship between surgery for peptic ulcer and cancer is probably due to the presence of H. pylori in the stomach of the operated cohort.219 For example, data from the Inpatient Registry of the Swedish National Board of Health and Welfare suggest that there is an increased risk for stomach cancer in patients with gastric ulcers and that there are likely etiologic factors in common (eg, atrophic gastritis induced by H. pylori).219 In conclusion, recent studies suggest that although the risk of gastric cancer is likely increased in patients who have had operations for peptic ulcer more than 15 to 20 years ago, there is probably not a clinically signicant causal relationship between the physiologic changes produced by the operation and the development of gastric cancer. What is the clinical signicance of gastric stump cancer? The role of screening for gastric cancer in patients who have had operations for peptic ulcer in the remote past is controversial.220,221 There is good evidence that there is a dysplasia-cancer sequence in these patients.222,223 Offerhaus and colleagues from the University of Leiden, Netherlands, reported long-term follow-up of 504 asymptomatic patients 15 to 46 years after partial gastrectomy.224 At rst endoscopy, there were 7 malignancies identied, mild dysplasia was found in 58 patients, and severe dysplasia was identied in none. Follow-up biopsies identied severe dysplasia in 6 patients, 3 of whom eventually were diagnosed with cancers. Of 34 patients with severe atrophy on random stomal biopsies, 2 manifested early stump cancer during follow-up.224 Similarly, another report that reviewed the results of a screening program in 354 gastric remnant patients concluded that patients with moderate or severe dysplasia required close follow-up.225 These investigators identied 22 patients in their screening program with moderate dysplasia; 3 were diagnosed with stump cancers at 2, 2, and 6 years after the rst endoscopy. Seven (41%) of 17 patients with severe dysplasia had stump cancers within a median time of 2 years. These authors recommended close surveillance in these patients.225 In the United States, Greene and colleagues reported similar results in a screening program in 163 patients who had previous gastric resections for peptic ulcer.221 Of the 15 patients with severe dysplasia, 9 (60%) had associated microscopic cancers. Four additional macroscopic cancers were identied. All 13 patients were reportedly asymptomatic. Greene has concluded that patients who are at least 20
years postpartial gastrectomy for benign disease should be considered for annual endoscopic surveillance.226 However, well-conducted hypothetical cohort studies in the United States have appropriately concluded that screening in American patients is probably not justied.227 Given the relatively low risk of gastric cancer in postpartial gastrectomy patients in the United States, any benet of endoscopic screening becomes nil if the postoperative 5-year survival rate of patients treated for gastric stump cancers falls below 80%.227 Since the majority of cancers detected in most screening programs are at the index procedure and are frequently advanced, this 80% survival cutoff seems unlikely to be achieved. We believe, therefore, that wholesale screening of asymptomatic patients is not justied. On the other hand, endoscopy with random biopsies of the stomach (and especially peristomal gastric mucosa) is indicated in any patient with a history of surgery for peptic ulcer who has a change in symptoms related to his/her upper gastrointestinal tract. An interesting concept, which has not, to our knowledge, been addressed adequately, relates to the concept of H. Pylori eradication in this patient population. We would propose evaluation of H. Pylori cytologies and H. Pylori eradication in all H. Pylori-positive patients with a remote history of an operation for peptic ulcer. What are the surgical implications in patients with gastric stump cancers? Stage for stage, patients with the diagnosis of gastric stump cancers should be evaluated and undergo surgical resection using the same principles as those used for patients with primary gastric cancers.227-230 However, for reasons elucidated below, diagnostic laparoscopy may not be warranted. The largest surgical series was reported by Viste and colleagues from the University of Bergen, Oslo, Norway.231 In a series of 819 patients, the median age was 69 years and the median interval from index operation to cancer diagnosis was 29 years. The majority of patients had a short duration of symptoms. Twenty-one percent of patients had localized disease, 25% had regional disease, and 39% had metastatic disease; resectability rate was only 41% and the overall 5-year survival rate was only 10%. In patients with localized disease, the 5-year survival rate was approximately 40%. These investigators concluded that the apparent poor prognosis relative to patients with primary gastric cancers was due to differences in patient characteristics.231 On the other hand, a large series from Japan suggests that the resectability rate in gastric stump cancer patients is approximately 90%, and that 5-year survival rates in all patients approaches 40%. An interesting study from Japan also suggests that there are clinicopathologic differences between gastric stump cancers and primary gastric cancers.232
Whereas the 5-year survival rates were similar (52% in gastric stump cancers and 62% in primary cancers), there was a distinct difference in terms of patterns of recurrence. The gastric stump cancer patients did not develop peritoneal metastases. The percentages of peritoneal and hematogenic (eg, liver) metastases were 41% and 31% in primary cancers and 0% and 83% in stump cancers, respectively.232 The practical implication of this nding is that diagnostic laparoscopy would seem not to be warranted in this patient group. Finally, as operations for peptic ulcer become uncommon, the clinical entity of gastric stump cancer likely will become rare over the next 2 decades.209
Early Gastric Cancer

In 1962, the Japanese Endoscopy Society described early gastric cancer (EGC) as gastric cancer limited to the mucosa and submucosa independent of lymph node metastasis.71,233 Early gastric cancer has several gross manifestations and EGC historically has been managed differently than advanced gastric cancer. In the early 1970s, the Japanese Endoscopic Society outlined a macroscopic classication system for EGC. This classication system was adopted by the Japanese Research Society for Gastric Cancer71 (Fig 3). Like other forms of gastric cancer, the incidence and presentation varies between countries. In Japan, EGC comprises 40% to 50% of gastric cancers at time of presentation. In the United States and Europe, EGC is uncommon. Only 28 (18%) of 213 gastric cancers resected from 1970 to 1979 at Columbia-Presbyterian Hospital in New York were EGC.234 The NCDB data suggest that only approximately 10% of gastric cancers in the United States are EGC. In a French study over 25 years, 102 (15%) cases of EGC were identied (mean age of 60).235 Early gastric cancer is associated with peptic ulcer disease.234 Twenty-ve percent of patients have been diagnosed with peptic ulcer disease, Barretts esophagus, or pernicious anemia before being diagnosed with EGC.236 The majority of EGC manifests as epigastric pain, less frequently as dyspepsia, and more than 50% of patients have seen a physician within 2 months of their diagnosis. EGC is typically located at the gastric antrum along the lesser curve near the angularis.14 In Japan, lymph nodes are positive in 10% of EGC. Large series have suggested that lymph node metastasis does not have signicant impact on survival of patients with EGC.234 In a French study, lymph node metastases were more frequent (18%) but more than one half of the tumors were 2 to 5 cm in size.235 The depth
of invasion also correlates with lymph node metastasis. More recent data suggest that size, depth, and lymph node metastasis directly impact survival.236 In Japan, the 5-year survival rate for patients with EGC is 85%.237 A cohort of EGC patients at Memorial Sloan-Kettering Cancer Center conrmed these excellent outcomes in the United States.236 A German cohort of 130 patients had an overall 10-year survival rate of 91%.238 However, most other reports have found worse outcomes. In a Columbia University study, the 5-year survival rate for patients with EGC was only 68%, with 29% having positive lymph nodes.234 EGC can be managed with minimally invasive techniques. Endoscopic mucosal resection (EMR) is used widely in Japan. This approach is becoming more common in the United States as surgeons and gastroenterologists become more familiar with the technique. EMR is indicated in (1) mucosal tumors; (2) type I, IIa, and IIc EGC without evidence of ulcer or scar; (3) well or moderately differentiated EGC; and (4) tumors smaller than 2 cm.239 EMR is contraindicated in large, poorly differentiated tumors that invade the submucosa. In our opinion, other treatment options such as local injection with 5-uorouracil and endoscopic neodymiumTAG laser ablation are not appropriate.240,241
Sentinel Lymph Node Biopsy

Although several case series and reports describe the use of sentinel lymph node biopsy in gastric cancer, its role is still being dened. Most published reports demonstrate the feasibility of sentinel lymph node biopsy in gastric cancer. Japanese studies suggest that the majority of patients have predictable metastasis with easy detection of sentinel lymph nodes. The frequency of false-negative sentinel lymph node evaluation, or skip metastasis, is controversial. A large study from Japan reported that the sentinel lymph node is not in the rst level nodes in 5% of the patients.242 With this potential skip in lymphatic metastasis, negative sentinel lymph nodes and a failure to complete a lymphadenectomy may result in undertreatment. On the other hand, a German case series of 135 patients demonstrated no skip nodes in their application of sentinel lymph node biopsy. With preliminary data suggesting sentinel lymph node biopsy is feasible, how can it be applied? Ideally, it should be applied to patients with T1N0M0 (stage 1) tumors who plan to undergo minimally invasive procedures. No randomized controlled trials have been conducted. An observational study with short-term follow-up showed no adverse outcomes with local gastric resection and sentinel lymph
node biopsy for EGC.243 In this study, indocyamine green was used to facilitate sentinel lymph node biopsy. We look forward to the results of randomized trials to help us understand the role of this novel technique. For now, sentinel lymph node biopsy should be limited to trials and management of gastric cancers should follow the standard guidelines outlined previously.
Minimally Invasive Techniques

A Japanese surgeon, Kitano, reported the rst laparoscopic-assisted distal gastrectomy (LADG) in 1991.244 Between 1991 and 2001, 4552 patients underwent laparoscopic surgery for stomach cancer in Japan.244 The use of laparoscopy in gastric cancer is more common in Japan and other Asian countries compared with Western countries. The procedures described include the following: laparoscopic local resection without lymph node dissection, laparoscopic gastrectomy with lymph node dissection, and laparoscopic gastrectomy with extensive lymph node dissection.244 The role of minimally invasive approaches to early and late stage gastric cancer is not well established despite numerous case reports and case-control studies. Patients with EGC who are not eligible for EMR are likely the best candidates for laparoscopic local resection. Laparoscopic wedge resection and intragastric mucosal resection are the 2 techniques described to remove early gastric cancers. It has been estimated that 1428 local wedge resections were completed between 1991 and 2001.244 Laparoscopic gastrectomy has been accomplished using totally laparoscopic, laparoscopic-assisted, or hand-assisted techniques.244 Laparoscopic-assisted distal gastrectomy is the most common procedure. Short-term outcomes from randomized controlled trials examining open versus laparoscopicassisted gastrectomy suggest similar complication rates and operative times.244 The reported benets of laparoscopic techniques are shorter hospital stay, fewer complications, and fewer days off work. From 1992 to 1996, a case series of 59 patients randomized to laparoscopic distal gastric resections or open techniques showed similar morbidity and mortality rates.245 Long-term outcomes have not been reported.
Palliative Surgery
Few indications exist for palliative surgery in patients with gastric cancer. The intent of palliative surgery is to relieve pain and suffering without increasing a patients morbidity or mortality. Palliative surgery should relieve pain, obstructive symptoms, or hemorrhage.246 Numerous palliative procedures have been reported and include
gastroenterostomy (enteric bypass), partial gastrectomy, total gastrectomy, esophagogastrectomy, gastrostomy, jejunostomy, and stenting. Gastric resection, endoscopic techniques (laser argon ablation, epinephrine injection) and arterial embolization can be used to treat acute refractory hemorrhage. No controlled trials have investigated the most effective approach to palliate gastric cancer. Selection bias and heterogeneity of the patient population makes interpretation of published studies difcult. What is clear is that palliative gastric surgery carries high morbidity and mortality rates.247 Is there a role for palliative resection? Several studies suggest a small survival benet with noncurative resections.248,249 In a retrospective review of gastric cancer patients from 1941 to 1987 at MD Anderson, palliative total gastrectomy was performed in 45 of 219 patients scheduled to undergo total gastrectomy.250 Another 21 of the 219 patients underwent only exploratory laparotomy or bypass procedure. Patients undergoing palliative total gastrectomies had improved survival compared with the group undergoing exploratory laparotomy with or without bypass (10.4 months vs. 3.4 months). Clearly, these groups of patients are not matched with respect to extent of disease. The degree of palliation was examined in this study on a scale of good, fair, or poor. In this group, no patients experienced good palliation, but 86% of the palliative resections had fair palliation. Observational data representing 503 patients who underwent palliative treatment in the Norwegian Stomach Cancer Trial suggest a doubling of mean survival time with palliative resections.248 Thirty-day mortality, however, was 11% to 13% for patients who underwent resection. In patients who did not undergo an operation, the 30-day mortality rate was only 2%. An Italian case series demonstrated similar improved mean survival with resection (3 to 8 months) but high operative mortality (10% to 15%).251 There probably is a role for palliative total gastrectomy. In a retrospective chart review of palliative total gastrectomy at the Mayo Clinic, the majority of patients (59%) felt this procedure improved their quality of life based on the ability to maintain adequate oral intake, ability to do normal daily activities, absence of dysphagia, and ability to maintain weight.249 However, the in-hospital mortality rate was 8%. What is the role of palliative bypass procedures in patients with gastric cancer? In our opinion, palliation is infrequently provided by bypass procedures and the perioperative mortality is high. In a Mayo Clinic series, only 19% of patients who underwent a bypass gastroenterostomy actually felt they beneted from the operation.246
Gastrostomy and jejunostomy have traditionally been felt to have little role in patients with gastric cancer. A gastrostomy tube may benet the patient requiring frequent nasogastric suction for gastric outlet obstruction. A jejunostomy can be used for nutritional supplementation, thereby avoiding total parental nutrition and hydration. Feeding jejunostomy should be limited to patients who are to undergo adjuvant or neoadjuvant chemotherapy and in patients with slowly progressive tumors to facilitate hospice care, thereby avoiding prolonged hospitalization.246 Feeding tubes are not without complications, however. More than 20% of patients will require general anesthesia for feeding tube placement. Approximately one third will need replacement due to malfunction. Thirteen percent of patients will have a major complication such as aspiration, bleeding, infection, or peritonitis. On the other hand, procedure-related death is rare (less than 1%).252 With the emergence of self-expanding metal stents (SEMS), endoscopic palliative techniques are replacing surgical intervention.253 Placement of a SEMS is an effective alternative to surgical bypass in gastric outlet obstruction. Many different stent congurations are available to accommodate varying anatomic situations.253 Perforation and bleeding are potentially lethal but occur in less than 1.2% of procedures. Obstruction after stent placement, due to progression of disease or technical failure (insufcient stensosis cover, stent fracture, stent migration, or collapsed stent), can occur in approximately 18% of cases.253 More recent series suggest that noncurative gastric resections should be avoided if possible. Between 1993 and 2002, 165 patients were treated at Memorial Sloan-Kettering Cancer Center with metastatic disease identied at laparoscopy.254 There were no upfront resections in this cohort of patients. Eventually, interventions were necessary in 33% of patients for obstruction, 8% for bleeding, and only 1% for perforation during chemotherapy. The median survival time was 10 months; virtually all patients received chemotherapy and many received radiation. Obstructions were usually treated with stents, gastrostomy, and/or jejunostomy. No patient had a gastric resection for obstruction, although 12% of patients did have laparotomy (eg, for small bowel obstruction, jejunostomy tubes). Consistent with previous reports, the authors found that less than one half of the patients with intestinal obstruction due to peritoneal carcinomatosis were improved with operation. Several recent reports suggest a potential role for laparoscopic surgical techniques in palliative surgery. Laparoscopic gastroenterostomy and cholecysto-jejunostomy are possible palliative options.147 However, these
reports are only small case series without comparison with open techniques.
Neoadjuvant and Adjuvant Chemoradiation Therapy

Gastric cancer displays a strong propensity for systemic involvement from the time of initial presentation (or even before). As a result, maximum therapeutic success for all stages of gastric cancer ultimately is determined by the effectiveness of drug therapies applied to this disorder. Unfortunately, advances in the drug therapy of gastric cancer have been much slower than desired. A variety of reasons are possible, including (1) a relatively low incidence of gastric cancer in countries most able to advance clinical chemotherapeutic research, (2) the frequent presence of advanced disease at clinical presentation, (3) the importance of coordinated multidisciplinary participation (often lacking) in the optimum management of gastric cancer, (4) patient comorbidity, and (5) therapeutic nihilism. Fortunately, the tempo of progress in the drug therapy of gastric cancer has accelerated in recent years, both in terms of breadth of agents and options for their integrated usage with other therapeutic modalities.
Single-Agent Drug Therapy

Beginning with 5-uorouracil (5-FU), a variety of chemotherapeutic agents have been found to display at least a 10% objective response rate in advanced gastric cancer. Key agents used initially included 5-FU, mitomycin-C, doxorubicin, epirubicin, methotrexate, etoposide, and cisplatin. More recently, a variety of contemporary agents have also shown single-agent activity in gastric cancer, especially oxaliplatin, paclitaxel, docetaxel, and irinotecan. This latter group of agents in particular have expanded the range of possible drug combinations for the treatment of gastric cancer. Single-agent response rates in advanced gastric are typically between 15% and 25%. These agents are shown with their dosage as applied in gastric cancer, along with common side effects in Table 4. Results for the use of systemic therapy in advanced gastric cancer can be compared against outcomes from best supportive care 3to 5-month median life expectancy, with 1-year survival rates lower than 10%, and no survivors at 2 years from diagnosis.
Combination Drug Therapy

Given the limited response rates of single-agent therapies, combinations of chemotherapeutic agents were an obvious strategy for advanced gastric
TABLE 4. Chemotherapeutic agents in gastric cancer Agent 5-Fluorouracil Dose Wide variety of doses and schedules used 10 mg/m2 3050 mg/m2 50 mg/m2 1,500 mg/m2 100120 mg/m2 60100 mg/m2 85130 mg/m2 175 mg/m2 75100 mg/m2 75100 mg/m2 15002500 mg/m2 orally divided dosage over 2 weeks Major toxicities mucositis, diarrhea, hand-foot syndrome
Mitomycin C Doxorubicin Epirubicin Methotrexate Etoposide Cisplatin Oxaliplatin Paclitaxel Docetaxel Irinotecan Capecitabine
myelosuppression, renal toxicity myelosuppression, nausea/vomiting, cardiac toxicity myelosuppression, nausea/vomiting, cardiac toxicity mucositis, hepatic/renal toxicity myelosuppression, peripheral neuropathy neutropenia, nausea/vomiting, renal toxicity neutropenia, peripheral neuropathy neutropenia, musculoskeletal pain, peripheral neuropathy mucositis, neutropenia, musculoskeletal pain myelosuppression, nausea/vomiting, diarrhea mucositis, hand-foot syndrome
cancer to improve patient response rates and overall survival. The rst combination chemotherapy which received broad attention was FAM (5-FU, doxorubicin, and mitomycin-C), rst reported in 1980.255 In the initial report, 26 of 62 patients (42%) achieved a response. The survival duration for the entire patient population was 9 months, although responders lived signicantly longer than nonresponders (12.5 months vs. 5.5 months). This regimen thus became a mainstay of treatment, particularly in the United States in the 1980s and into the 1990s. The FAM regimen, like other chemotherapeutic regimens in advanced gastric cancer, had progressively disparate results after the initial experience, however. In a review of more than 650 U.S. patients receiving FAM, the overall response rate using FAM was 30% (2% complete responses); the overall survival of treated patients typically varied between 5 and 10 months.256 As with other regimens, the response to combination chemotherapy in advanced gastric cancer appeared superior in the hands of Japanese investigators. Using the similar regimen of 5-FU, cytarabine, and mitomycin-C, Ogawa reported an overall response rate of
36%, and median survival times of 16 to 20 months in a review of more than 350 patients.257 The initial modest promise of combination regimens was dampened, however, by results from 2 randomized trials. In 1982, Cocconi and colleagues reported no difference between 5-FU and 5-FU, cytarabine, and mitomycin-C in response rate, response duration, and overall survival.258 In 1985, the North Central Cancer Treatment Group compared 5-FU to FAM in 100 patients.259 Although response rates were higher in the combination treatment arm (27% vs. 17%), overall survival was identical in both arms (7 months). These 2 combinations cast signicant doubt as to the value of drug combinations in advanced gastric cancer. Subsequently, chemotherapy for advanced gastric cancer began to evolve in 2 different directions. The rst was to attempt to improve the FAM regimen by adding additional drugs. Foremost among these attempts was experience with FAMTX, which substituted high-dose methotrexate for mitomycin-C in the regimen.260 FAMTX was formally compared with FAM by the European Organization for the Research and Treatment of Cancer (EORTC).261 Response rates were much higher with FAMTX versus FAM (41% vs. 9%, P 0.0001) as were median survival (42 weeks vs. 29 weeks, P 0.004) and 1- and 2-year survival rates (41% and 9% vs. 22% and 0%, respectively). Serious toxicity was similar in the 2 arms. FAMTX thus became a new standard for treatment for advanced gastric cancer in the early 1990s. The second major therapeutic direction was to employ cisplatin for the treatment of advanced gastric cancer. Beginning with the cisplatin/ etoposide combination (EP), a variety of drug combinations containing cisplatin were employed in advanced gastric cancer, including cisplatin, doxorubicin, and cisplatin (EAP).262 The EAP regimen produced high response rates: typically 50% to 70% with complete response rates anywhere from 5% to 20%.263 The overall survival was typically 8 to 10 months for the treatment population. The EAP regimen was also associated with signicant toxicity, particularly in elderly patients; treatmentrelated mortality was reported at 10% or more. Owing to the toxicity of EAP, Wilke and colleagues created a regimen with etoposide added to 5-FU and leucovorin (ELF), a regimen specically designed for patients older than 65.264 In 51 patients, the response rate was 53%, including 12% complete responses. Response rates were 70% and 49%, respectively, in patients with locally advanced versus metastatic disease; the overall survival was 9.5 months. Signicant toxicity was largely limited to myelosuppression.
TABLE 5. Major chemotherapeutic regimens in gastric cancer Regimen FAM FAMTX EAP ELF CF ECF DCF Drugs 5-FU, adriamycin, mitomycin C 5-FU, adriamycin, mitomycin C, methotrexate Etoposide, adriamycin, cisplatin Etoposide, 5-FU, leucovorin Cisplatin, 5-FU Epirubicin, cisplatin, 5-FU Docetaxel, cisplatin, 5-FU
Given the synergistic cytotoxicity of cisplatin and 5-FU in a variety of in vitro tumor models and clinical studies, cisplatin was also combined with 5-FU in patients with advanced gastric cancer. The EORTC subsequently tested this regimen (CF) against the FAMTX and ELF regimens described previously.265 In this study of 274 patients, no signicant difference was found in toxicity, response rates (which ranged from 20% to 27%), and median survival (7 to 8 months). The identity of the best regimen for advanced gastric cancer remained uncertain. Cisplatin was also tested as a substitute for mitomycin-C (remembering the high degree of myelosuppression of the latter drug) in the FAM regimen to create FAP. This regimen produced a 34% response rate, with 5% complete responses.256 Cunningham and colleagues then substituted epirubicin, an anthracycline analog of doxorubicin popular in Europe, for doxorubicin to create the ECF regimen. In a trial of 52 patients, a 37% response rate was achieved, with 17% complete responses.266 A subsequent randomized clinical trial solidied the importance of the ECF regimen. The rst, conducted by the MRC, randomized 256 patients between FAMTX and ECF, with ECF clearly proving to be the superior regimen.267 Response rate (46% vs. 21%), median survival (8.7 months vs. 6.1 months), and 2-year survival rates (14% vs. 5%) all clearly favored patients receiving ECF. Based on this trial, ECF became the standard of care for advanced gastric cancer entering the twenty-rst century, at least with respect to tumor response. Since 2000, clinical research has centered on the use of the newer chemotherapeutic agents proven active in advanced gastric cancer. Docetaxel is foremost among these agents at this time. Exemplary is the phase III trial reported by Moiseyenko and colleagues that compared docetaxel, cisplatin, and 5-FU (DCF) with CF only.268 In this large study involving 457 patients, DCF produced a superior
response rate (37% vs. 25%, P 0.01), time to progression (5.6 months vs. 3.7 months, P 0.01), and 2-year survival rate (18% vs. 9%). However, the benet of DCF was less clear in patients older than 65 years, particularly with a 4% to 8% toxic death rate estimated for DCF. Overall grade III-IV toxicity rates for these regimens were between 75% and 80%. Signicant combination chemotherapy regimens employed during the historical evolution of drug treatment for advanced gastric cancer are listed in Table 5. At present, the DCF and ECF regimens have produced the highest tumor response rates, but they are also the most toxic. As such, no single best treatment for advanced gastric cancer exists, and the choice of therapy ideally is individualized to particular patient circumstances. Present benchmark statistics for chemotherapy regimens in advanced gastric cancer are response rates of 30% to 40%, complete response rates of 10% to 20%, time to tumor progression of 5 to 6 months, overall survival time of 8 to 10 months, 1-year overall survival rates of 40% to 50%, and 2-year overall survival rate of 15% to 20%. Therapeutic toxicity remains a signicant issue. The most recent meta-analysis on this subject concludes the following: (1) chemotherapy signicantly improves survival over best supportive care, (2) combination chemotherapy improves survival to single-agent 5-FU, although the effect size is smaller, and (3) the best results are achieved with regimens containing 5-FU, anthracyclines, and cisplatin (eg, ECF).269
Future Directions in Drug Therapy

Future research in this area is evolving along 3 separate lines. The rst examines the role of other, newer, chemotherapeutics (particularly oxaliplatin, irinotecan, and oral 5-FU prodrugs such as capecitabine and S-1), that have proven valuable in other gastrointestinal malignancies. The second examines the role of so-called targeted therapies, drugs designed to inhibit the function of a particular molecular target critical to cancer cell growth. Major examples of therapies presently under investigation at present include cetuximab, an epidermal growth factor inhibitor, and bevacizumab, a vascular epidermal growth factor inhibitor, both given in conjunction with chemotherapy. Finally, there is growing emphasis on clinical and molecular predictors of chemotherapeutic responsiveness in advanced gastric cancer. Such considerations are particularly important given the relatively modest benet/toxicity ratios of present chemotherapy programs for gastric cancer, as well as the expense of the agents themselves. Examples of the
former might include such features as patient performance status, presence or absence of pain, extent of visceral involvement (eg, liver), and nature of prior therapy. For example, low tissue levels of expression of thymidine synthetase (critical to intracellular 5-FU metabolism), p53 (related to chemotherapeutic resistance), and BCL2 (important to cellular apoptosis) have been found to correlate with superior survival in gastric cancer.270 More sophisticated techniques for prediction of therapeutic response (eg, molecular proling of individual tumors) are also an active area of research throughout oncology, including gastrointestinal oncology.
Radiation Therapy for Locoregional Disease

In the American population, 80% to 90% of patients with locoregional gastric cancer are at risk for recurrence following surgery. The risk is signicant for all but patients with T1-2N0M0 disease. Recurrence risk is local, systemic, or both. Thus, the use of radiotherapy and chemotherapy as (neo)adjuvant treatment for resected gastric cancer nds obvious potential application. With respect to radiation therapy, the tissues near the stomach (liver, small intestine, kidney, and spinal cord) limit the amount of radiation that can be delivered as an adjuvant treatment. The stomach itself is also radiosensitive, with bleeding and ulceration an important complication at radiation doses greater than 5000 cGy. Consequently, radiation therapy for gastric cancer is typically administered at a dose of 4500 cGy using 180 cGy/day fractions. Radiation therapy is not generally used without chemotherapy (see following discussion) and the exact optimum integration of radiation therapy and chemotherapy with respect to radiation and chemotherapeutic dose, schedule, and timing are not known. Radiation elds used to treat gastric cancer must consider typical patterns of cancer spread. For cancers originating in the gastric antrum, it is not necessary to radiate the entire cardia, but radiation of periduodenal lymph nodes is mandatory. For cancers originating in the cardia, coverage of the cardia and distal esophagus is important owing to the potential for local spread, but periduodenal lymph node irradiation is not necessary. In all cases, posterior penetration and cancer extension to the pancreas or other retroperitoneal structures must be considered; appropriate eld coverage of these areas is essential. Radiation elds are typically constructed anteroposterior, although both lateral and oblique elds are useful for the nal dose
boost. When oblique elds are used, care must be taken to limit the dose to the liver to 2500 cGy or less. The delivery of adjuvant chemoradiation to patients with resected gastric cancer requires complex and dedicated supportive care. Key potential complications of such therapy typically include weight loss, mucositis, dehydration, nausea and vomiting, and diarrhea. These complications are potentially serious enough to produce interruption of therapy, hospitalization, or even death. The wise clinician considers these complications in advance of chemoradiation and takes steps to mitigate their severity, throughout and even before chemoradiation begins. Virtually no studies have evaluated radiation therapy as a sole adjuvant modality to surgery in the adjuvant treatment of resected gastric cancer. Such an approach would be expected to have an impact on disease outcome; however, given the high propensity for occult metastatic disease in resected gastric cancer. Experience with radiation therapy thus is largely conned to its concomitant use with chemotherapy, typically 5-FU.
Postoperative Chemotherapy
Discouragingly, adjuvant chemotherapy alone (usually 5-FU or 5-FU based) failed to show with condence a survival advantage to surgery alone when applied to resected gastric cancer for many years. An initial report by the Gastrointestinal Study Group (GITSG) randomizing 142 patients to chemotherapy using 5-FU plus methyl CCNU produced a statistically signicant survival advantage at 5 years (50% vs. 31%, P 0.03).271 However, additional studies employing the identical drug combination failed to produce statistically signicant differences in overall survival in similar patient groups.272 Several additional studies comparing postoperative chemotherapy to observation likewise failed to demonstrate a role for chemotherapy alone in the adjuvant treatment of gastric cancer. Exemplary of this point is a study reported by Lise and colleagues of behalf of the European Organization for Research and Treatment of Cancer (EORTC) in which 314 patients were randomized between an intensied version of 5-FU, adriamycin, and mitomycin C (FAM2) versus surgery only.273 Although the time to disease progression was improved in the chemotherapy arm (P 0.02), median survival was not statistically different between the 2 arms (42 vs. 36 months, P 0.30). Similar results were obtained when FAM was applied as an adjuvant treatment to gastric cancer by the Southwest Oncology Group (SWOG).274
Japanese investigators, however, came to quite different conclusions when analyzing their data on adjuvant chemotherapy for gastric cancer in Japan. Collected experiences analyzed by Imanaga and Nakazato275 and Nakjima and colleagues276 using mitomycin C, either individually or in combination with other agents, displayed (1) higher overall survival rates than seen in the Western experiences, and (2) a statistically superior outcome to surgery alone when chemotherapy was used. These data form the basis for the routine use of systemic chemotherapy following resection of gastric cancer in Japan today. A meta-analysis performed by Hermans and colleagues in 1993 attempted to answer the question of the role of adjuvant chemotherapy following curative surgery for gastric cancer.277 Using 11 randomized trials with complete clinical data encompassing more than 2000 patients, the odds ratio for recurrence following surgery and adjuvant chemotherapy was 0.88 versus surgery alone, a trend that favored adjuvant chemotherapy, but not to a point that achieved statistical signicance (95% CI, 0.78-1.08). A second meta-analysis performed in 1998 on this subject produced similar results (odds ratio recurrence with adjuvant chemotherapy, 0.81; 95% CI, 0.67-0.98).278 Thus, postoperative adjuvant chemotherapy had not been shown to improve survival in resected gastric cancer (at least in Western patients) before 2000.
Postoperative Combined Modality Therapy

Another line of research emanating from the United States for the adjuvant therapy of gastric cancer involved the combined use of radiation therapy with uorinated pyrimidines (usually 5-FU) as radiation sensitizers. Although postoperative radiation therapy by itself seems to have a modest favorable benet on local control, no survival benet has been detected in randomized trials. Integration of radiation therapy with 5-FU, however, had shown survival benet in randomized trials, although the patient numbers were small. Noteworthy in this regard is the study from Moertel and colleagues at the Mayo Clinic.279 In this study involving 62 patients, treatment with radiation therapy (3750 cGy in 24 fractions over 4 to 5 weeks), plus chemotherapy (concomitant bolus 5-FU 15 mg/kg/day 3) was compared with surgery only. Although both radiation therapy and chemotherapy dosing would be regarded as inferior to todays methodologies, improvement for the treatment group was seen with locoregional control (61% vs. 46%), disease-free survival (17 months vs. 9 months), and overall survival (20 months v s. 12 months, P 0.05). The use of combined modality radiation and chemotherapy with 5-FU
FIG 40. The United States Intergroup Trial. Randomization of adjuvant chemoradiation with
5-urouracil and leucovorin versus docetaxel, cisplatin, and 5-FU. Study is ongoing.
was also of benet in esophageal cancer, resulting in prolonged disease-free survival for this disease without the need for surgical resection.280 Since the demonstrated benet of integrated radiation therapy and 5-FU in patients with known residual gastric and esophageal cancer, the United States Intergroup study was initiated in 1991 to test the value of the 5-FU/leucovorin chemotherapy regimen coupled with radiation therapy in patients with resected gastric cancer. This study enrolled 603 patients and was published in 2001.281 Eighty-ve percent of patients were node positive. Sixty-four percent of patients assigned to the chemoradiation arm were able to complete all therapy. Reasons for failure to complete therapy included therapeutic toxicity (17%), patient choice (8%), disease progression or death (6%), and other reasons (4%). Seventy-three percent of patients experienced grade III or higher toxicity by common toxicity criteria (CTC) (42% grade III, 31% grade IV). There were 3 toxic deaths (1%) in the treatment arm. Both disease-free and overall survival rates were signicantly improved in the combined modality study arm. The median time to relapse was 30 months in the treatment arm versus 19 months in the control arm (P 0.001). Overall survival was 36 months in the treatment arm versus 27 months in the control arm (odds ratio 0.65, P 0.005). The 3-year disease-free survival rate was 48% in the chemoradiation arm versus 31% in the surgery arm. Local relapse rates were 29% in the surgery arm and 19% in the control arm. This landmark study demonstrated for the rst
time (1) the ability to carry out large-scale clinical trials for the adjuvant therapy of gastric cancer in the United States, and (2) a survival advantage for the adjuvant therapy of gastric cancer in Western patients. As a result of this trial, a follow-up Intergroup Trial was initiated in the United States randomizing the above regimen to the more contemporary pre- and post-chemotherapy regimen of DCF (Fig 40). This trial is presently ongoing.
The MAGIC Trial

While the aforementioned Intergroup Trial was being conducted in the United States, efforts to use some of the newer, more active chemotherapy regimens for the adjuvant therapy of gastric cancer were being employed in Europe. In particular, these regimens were being employed from a neoadjuvant standpoint, in an attempt to improve patient tolerance of adjuvant therapy, to improve resectability rates (downstage) in patients, and to improve patient survival. Most notable among such trials is the MRC Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial reported recently.282 Between 1994 and 2002, 503 patients (74% of whom had gastric cancer, the remainder esophageal cancer) were randomized to 6 cycles of ECF chemotherapy (3 administered preoperatively, 3 administered postoperatively) versus surgery only. Sixty-four percent of patients completed all 6 planned therapy cycles. Preoperative chemotherapy improved curative resection rates. With more than 3 years of follow-up, the 5-year survival rates for the 2 study arms were 36% (ECF) versus 23% (surgery only), representing a 25% reduction in hazard for recurrence (P 0.009). This large-scale trial further establishes the importance of systemic therapy in addition to surgery for the curative treatment of gastric cancer, and emphasizes the potential for neoadjuvant approaches in this setting.
Future Directions for Neoadjuvant Therapy

Multiple directions for future clinical research in locoregional gastric cancer now present themselves. The success of the MAGIC trial encourages new approaches to neoadjuvant therapy for gastric cancer, as well as comparison with conventional postoperative combined modality treatment. As exemplied by the current United States Intergroup Trial, superior chemotherapy regimens must be integrated into (neoadjuvant) therapy programs as they prove successful in more advanced disease, perhaps even without the use of radiation therapy. Novel chemoradiation methods beyond the simple use of 5-FU require immediate consideration.
Finally, revisitation of intraperitoneal chemotherapy (not convincingly shown benecial to date in Western trials), or integration of immunotherapy with adjuvant therapy techniques may eventually nd fruition in this setting.
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Current Problems in Surgery: Gastric Cancer

Curr Probl Surg, Aug/Sept 2006

Pathophysiology of Gastric Cancer

Tumor suppressor genes

DNA repair Metastasis and invasion genes

Screening Laboratory Tests

ysis of gene expression (SAGE), differential display, and subtractive hydridization.65-68

Upper Gastrointestinal Barium Examination (UGI)

Curr Probl Surg, Aug/Sept 2006

Staging and Histologic Classication

Survival and Patterns of Recurrence

Stage IIIB Stage IV

Curr Probl Surg, Aug/Sept 2006

Curr Probl Surg, Aug/Sept 2006

Curr Probl Surg, Aug/Sept 2006

Magnetic Resonance (MR)

Positron Emission Tomography

FIG 21. Extent of lymph node dissection for D1 (

FIG 22. Extent of lymph node dissection for D1 (

FIG 23. Extent of lymph node dissection for D1 (

Extent of Gastric Resection

Curr Probl Surg, Aug/Sept 2006

Extended Resections for T4 Disease

Postoperative Complications and Outcomes

Early Gastric Cancer

Sentinel Lymph Node Biopsy

Minimally Invasive Techniques

Neoadjuvant and Adjuvant Chemoradiation Therapy

Single-Agent Drug Therapy

Combination Drug Therapy

Future Directions in Drug Therapy

Radiation Therapy for Locoregional Disease

Postoperative Combined Modality Therapy

The MAGIC Trial

Future Directions for Neoadjuvant Therapy

132. 133. 134.

135. 136. 137. 138. 139. 140.

Curr Probl Surg, Aug/Sept 2006

176. 177. 178. 179. 180.

187. 188. 189.

Curr Probl Surg, Aug/Sept 2006

Curr Probl Surg, Aug/Sept 2006

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