08 - 09. gastric cancer

GmtgETdBtbo

sEpSiw1etHifJhc

u

C0d

5

Current Problems in Surgery:Gastric Cancer

astric cancer is the fourth most common cancer worldwide. Approxi-ately 600,000 new cases are diagnosed each year; almost two thirds of

hese individuals will die of their disease.1 Most cases (65% to 75%) ofastric cancer occur in developing countries.1 In many regions of Easternurope and East Asia, gastric cancer is the leading cause of cancer death.he countries with the highest incidence rates (more than 40 newiagnoses per 100,000 individuals per year) are Korea, Japan, Chile,elarus, Kazakhstan, China, and Costa Rica. Within many countries,

here is also regional variation emphasizing the differences in physical,iological, social, and environmental factors involved in the pathogenesisf 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

teadily declined for the last 60 years. Surveillance Epidemiology andnd Results (SEER) data have reported a decrease in incidence from 11.7er 100,000 in 1975 to 8.8 per 100,000 in 2002.4 Within the Unitedtates, there is a regional difference in incidence (the highest incidence is

n Hawaii). Similarly, there are racial and gender differences in incidence,ith higher rates in men and blacks: 15.4 cases of gastric cancer per00,000 black males versus 6 per 100,000 white women.4 In Los Angeles,thnic variation in incidence is pronounced, with the highest incidence inhe Korean population and lowest in the Hispanic-white population.2

owever, with each successive generation, the incidence in Asianmmigrants approaches their host country, suggesting that environmentalactors play a greater role than genetic factors.5 Even first generationapanese residents of Hawaii and São Paulo, Brazil, have been found toave decreased rates of gastric cancer compared with their nativeountries.5,6

The precise cause of the overall decline in stomach cancer worldwide is
nknown. Many experts attribute the decline to the advent of refrigeration
urr Probl Surg 2006;43:566-670.011-3840/2006/$30.00 � 0oi:10.1067/j.cpsurg.2006.06.003

66 Curr Probl Surg, Aug/Sept 2006

arugusc1r

lgdiOooaplpolocpt

P

eRppvc

1(a1

C

nd the increased access to fresh fruits and vegetables.3 However, theelationship between refrigeration and the etiology of stomach cancer isnproven. Studies from England, Germany, and Venezuela have sug-ested that there is a decreased risk of gastric cancer if refrigeration issed for greater than 30 years.7-9 In contrast, a Polish cohort studyhowed no association between long-term refrigerator use and stomachancer.10 More recently, the large Netherlands Cohort Study representing20,852 men and women showed no association between the duration ofefrigerator use and stomach cancer.11

In addition to decreased incidence of gastric cancer, recent epidemio-ogic studies suggest a changing anatomic pattern in the incidence ofastric cancer. Although the incidence of distal cancers has greatlyecreased, the incidence of cardia or proximal stomach cancers hasncreased.12 The Rochester Epidemiology Project, a longitudinal study oflmsted County, Minnesota, in residents from 1941 and 1990, showed anverall decline in gastric cancer, but found that the decline representednly distal and intestinal-type gastric cancers. The incidence of proximalnd diffuse-type gastric cancers remains stable.13 The shift from distal toroximal location of gastric cancers has been noted in many studies andikely represents a change in environmental factors that play a role in theathogenesis of cancer of the stomach.14-16 In summary, the lifetime riskf gastric cancer for current U.S. residents is approximately 1% and theifetime risk of dying from gastric cancer is 0.6%. The mean age at timef diagnosis is 72 years. Approximately 24% of stomach cancersurrently diagnosed in the United States are localized at the time ofresentation, 32% have spread to regional lymph nodes or directly beyondhe primary site, and 32% are associated with metastatic disease.

athophysiology of Gastric CancerDevelopment of stomach cancer is a complex process involving

nvironment factors, host susceptibility, and a viral or bacterial infection.isk factors include male gender; family history; polyposis syndromes;ickled foods; diets high in nitrates and salts; gastric adenomas; previousartial gastrectomy, and Menetrier’s disease. Aspirin, a fresh fruit andegetable diet, selenium, and vitamin C may decrease the risk for gastricancer3,14,17,18 (Table 1).Familial Gastric Cancer. Hereditary gastric cancer represents only0% of gastric cancers. Hereditary nonpolyposis colorectal cancerHNPCC), familial adenomatous polyposis (FAP), and BRCA2 mutationsre all associated with gastric cancer in addition to colon cancer.19-22 In
964, familial gastric cancer was identified in a large kindred of Maori
urr Probl Surg, Aug/Sept 2006 567

fEod

iap

giprdp

T

HEIGIP

At

T

PMOCC

NE

T

DM

At

5

rom New Zealand and recently identified as a germline mutation in-cadherin.23 Loss of function or low levels of E-cadherin is seen in 50%f diffuse-type stomach cancers.24 Loss of E-cadherin function mayisrupt cell-cell adhesion thus altering growth-control signals.23

Genetic Alteration. Numerous other genetic alterations have beendentified in gastric cancers. They include gene deletion, suppression,mplification, overexpression, microsatellite instability, and DNA aneu-loidy25 (Table 2).Environment. The dramatic reduction in the incidence and mortality ofastric cancer worldwide has been attributed to environmental factorsncluding improvement in socioeconomic status, refrigeration, and im-roved access to fresh fruits and vegetables. The relationship betweenefrigeration and the decreased incidence of gastric cancer is likely due toecreased use of salt and other nitrate-based preservatives in food

ABLE 1. Risk factors for gastric cancer

igh salt and pickled food dietxogenous chemicalsntragastric synthesis of carcinogens (converting nitrates to nitrites)enetic factors

nfectious agents (Helicobacter pylori, Epstein-Barr virus)athologic conditions of the stomach (atrophic gastritis, intestinal metaplasia)

dapted with permission from Shang and Pena. Multidisciplinary Approach to Understandhe Pathogenesis of Gastric Cancer. World J Gastroenterol 2005;11:4131–9.

ABLE 2. Genetic alternations identified in gastric cancer

olymorphism Interleukin-1icrosatellite instabilityncogenes K-sam, c-met, c-erbB-2ell proliferation and apoptosis bcl-2, Cyclin D1, E2F-1, SC-1ell-cell interaction ICAM-1, VCAM-1, E-cadherin (CDH1),

beta-catenin, MMPseoangiogenesis VEGF, HIF-alpha, ECM1pigenetic changes Hyper- or hypomethylation by DNA

methyltransferases (DNMTs)Repress chromatin states by

histone deacetylase (HDAC)umor suppressor genes p16INK4a, p15INK4b, p73, p14ARF,

p73, adenomatous polyposis coli(APC), BRCA1

NA repair hMLH1etastasis and invasion genes E-cadherin (CDH1), TIMP3, DAPK

dapted with permission from Chen et al. Recent advances in molecular diagnosis andherapy of gastric cancer. Dig Dis 2004;22:381.

reservation and the increased availability of fresh vegetables and fruit.


sbacmaecaC

vt20mt(vsi

obfpsadghr(iag

egr

C

Salt, pickled foods, and smoked foods are “probable” risk factors fortomach cancer according to a WHO/FAO expert panel.26 Establishing a linketween cancer and diet is complex given the difficulties in measuring dietnd the lag time between exposure and diagnosis. Most research is based onase-control and cohort studies.27 The carcinogenic effect of dried and curedeat, pickled foods, and smoked fish is likely due to the high content of salt

nd nitrates. Early animal models from the 1960s support the carcinogenicffect of N-nitroso compounds (N=-nitro-N-nitrosoguanidine).28 Nitrates areonverted to carcinogenic nitrite compounds in the stomach. Low gastric pHnd antioxidants vitamin C and �-carotene inhibit this endogenous process.29

onversely, high gastric pH facilitates the process.Based on these findings, randomized controlled trials have studieditamin supplementation and its role in cancer prevention. The results ofhese studies have been mixed. A Chinese study of 29,584 men found a1% reduction (relative risk [RR], 0.79; 95% confidence interval [CI],.64-0.99) in stomach cancer mortality in a group using a diet supple-ented with vitamin E, �-carotene, and selenium.30 On the other hand,

he Finnish Alpha-Tocopherol, Beta-Carotene, Cancer Prevention StudyATBC) of 29,133 middle-aged smokers showed no risk reduction withitamin supplementation.31 A follow-up study to the ATBC studyuggested that there are no benefits and that �-carotene may actuallyncrease the risk of lung cancer in smoking patients.32

Diets high in raw and fresh vegetables are inversely related to the incidencef gastric cancer.3 Cohort and case-control studies show raw, fresh vegeta-les to be the most protective. However, the anticarcinogenetic properties ofruits and raw vegetables have yet to be proven, and it may be thatopulations with higher fruit and vegetable consumption have lower con-umption of animal products. Research has focused on finding the activenticarcinogens in fruits and vegetables. Potential candidates include antioxi-ants, coumarins, flavonoids, isoflavones, isothiocyanates, phytosterols, anducosinolates.3 Like the vitamin studies described above, there are no gooduman studies to support the positive findings of in vitro studies. Futureeports by the European Prospective Investigation into Cancer and NutritionEPIC) study representing over 500,000 individuals will help outline thempact of diet on stomach cancer (see http://www.iarc.fr/epic). It is likely that

combination of foods or overall dietary habits impact the incidence ofastric cancer rather than specific foods or nutrients.Tobacco and Alcohol. The carcinogenetic effect of tobacco is well

stablished in oropharyngeal and lung cancer. The link between smoking andastric cancer has not been as clear. In 1997, Tredaniel and colleagues33

eviewed multiple cohort studies and 40 case-control studies and found an


http://www.iarc.fr/epic

icmasacGs

1trgHprediAtgo

pswv

PliNinace

a

5

ncreased risk (�1.5) of gastric cancer among smokers. These investigatorsoncluded that 11% of all gastric cancers are due in part to smoking.33 In aulticenter, case-control study of esophageal and gastric cancer, Gammon

nd colleagues showed an increased risk of gastric adenocarcinoma inmokers.34 These studies make a convincing case for a link between smokingnd stomach cancer. On the other hand, an association between alcoholonsumption and gastric cancer is unlikely. The case-control study byammon and colleagues showed no association between the two.34 Other

tudies have found no association.35,36

Helicobacter Pylori. H. pylori was described by J. Robin Warren in983.37 H. pylori is a microaerophilic, sheathed bacteria with 7 flagellahat infects the gastric mucosa. H. pylori is now known to play a centralole in the pathogenesis of gastric cancer and considered to be carcino-enic by the International Agency for Research on Cancer at the Worldealth Organization (WHO).38 There is a strong association between H.ylori infection and stomach cancer.39 However, not all regions with highates of H. pylori colonization have high rates of gastric cancer,mphasizing the fact that H. pylori is only 1 of many contributors to theevelopment of stomach cancer. For example, there is a very highncidence of H. pylori infection (70% to 80% of population) in Westfrica but a low incidence of gastric cancer (less than 2% of malignant

umors)—the “African enigma.”40 Most studies suggest that the carcino-enic effect of H. pylori infection is subtle, requiring chronic exposurever more than 40 years.41

H. pylori infects a majority of people worldwide at an early age,articularly in developing countries and regions with low socioeconomictatus.41,42 In developing countries, 80% to 90% of children are infectedith H. pylori.29 Although H. pylori infection varies with ethnicity, thisariability may actually be a reflection of socioeconomic status.41,43

H. pylori is a chronic infection that rarely resolves spontaneously.29

rolonged exposure to H. pylori and the associated inflammatory reactioneads to cancer. Tahara has outlined the combined effect of H. pylorinfection and the genetic alterations that lead to gastric cancer25 (Fig 1).umerous inflammatory factors are upregulated by a H. pylori infection

ncluding: interleukin 1-beta (IL-1�), IL-6, IL-8, IL-18, and tumorecrosis factor-alpha (TNF-�).14 Polymorphisms in the IL-1 gene clusterre associated with H. pylori-induced hypochlorhydria and gastric can-er.44 The genetic variability caused by these polymorphisms mightxplain the increased incidence in specific families.Specific variable virulence factors of H. Pylori, such as cytotoxin-

ssociated gene A (cagA) and vaculating toxin A (vacA), appear to


iiHiv

F

C

ncrease the likelihood of cancer.45 Family history and cagA-positivenfection results in a 16-fold increase in risk for gastric cancer.14

owever, the risk still increases 4-fold if there is a cagA-positivenfection and no family history.29 These factors may partially explain the

IG 1. Different pathways in the carcinogenesis of intestinal (A) and diffuse-type (B) gastric cancer.

ariable incidence of gastric cancer in specific populations. H. pylori


icNca

owciwirmrsmap

taiAapicEcwrod

C

S

ev

5

nfection also acts synergistically with nitrate infections to induce gastricancer in animal models. The combination of H. pylori and N-methyl--nitrosurea has been shown to induce gastric cancer, suggesting that

ombinations of environmental factors act in concert with H. pylori toffect one’s risk of gastric cancer.46

What is the significance of H. pylori infection? In a case-control studyf 7498 Japanese Hawaiians, the odds ratio of developing gastric cancerith H. pylori infection was 6.0 (95% CI, 2.1-17.0).47 In another

ase-control study involving 186 gastric cancer patients, H. pylorinfection was found to be associated with an increased risk for cancerith an odds ratio of 3.6 (95% CI, 1.8-7.3).48 The EUROGAST study,

nvestigating 17 populations in 13 countries, reported a significantelationship between H. pylori infection and gastric cancer incidence andortality, with coefficients of 2.68 (P � 0.001) and 1.79 (P � 0.002),

espectively. This study indicated that populations with 100% H. pylorieropositivity have a 6-fold increased risk of gastric cancer.49 In aeta-analysis of 19 studies with 2491 patients and 3959 controls, Huang

nd colleagues demonstrated an odds ratio for gastric cancer in H.ylori-infected patients to be 1.92 (95% CI, 1.32-2.78).39

Is there justification for eradication of H. pylori? Several studies suggesthat eradication of H. pylori will affect the incidence of gastric cancer.38,50 In5-year study of 67 patients with early gastric cancer, eradication of H. pylori

nfection made a significant impact on the development of gastric cancer.51

s of 2001, 8 interventional studies were investigating the effects of treatingH. pylori infection on the development of stomach cancer and regression ofrecancerous lesions (intestinal metaplasia, atrophic gastritis).52 In a random-zed controlled trial of 1630 healthy adult carriers of H. pylori, Wong andolleagues showed mixed results with the eradication of H. pylori.53

radication of H. pylori was not associated with an overall decrease of gastricancer in the entire population. However, in subgroup analysis of patientsithout precancerous lesions, no patient developed gastric cancer. Until

esults from the other prospective randomized trials are available, expertpinion recommends testing for and treatment of H. pylori infection in firstegree relatives of patients with gastric cancer.54

linical Presentation

igns and SymptomsStomach cancer usually does not become symptomatic until there is

xtensive disease. Early symptoms are nonspecific. Weight loss, nausea,
omiting, anorexia, and fatigue frequently present at the time of diagnosis

aamPsw(

tcesue

w(tKthNbf

ginfm

P

cspislg

C

nd manifest late in the disease process. The location or type of tumor mayffect the symptoms at presentation. Dysphagia is associated with proximalasses whereas distal tumors manifest with gastric outlet obstruction.atients with scirrhous-type (linitis plastica) lesions will complain of earlyatiety due to loss of stomach distensibility. Typical symptoms in patientsith 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 presenta-ion is rare, occurring in only 1% to 4% of cases.56 Although moreommon in T3 and T4 gastric cancer patients, perforation can occur inarly gastric cancers, emphasizing the importance of biopsy and frozen-ection analysis during emergency operations for perforated gastriclcers. Palliative gastric resection should be considered at the time ofmergency exploratory laparotomy.56

Upper Gastrointestinal Bleeding. Upper gastrointestinal bleeding is aell-described presentation of gastric cancer. However, a minority

approximately 2%) of patients presenting with acute upper gastroin-estinal bleeding will have cancer. For example, in a large Unitedingdom study, only 27 of 1105 patients with acute upper gastroin-

estinal bleeding had gastric cancer. More than 70% of these patientsad stage IV gastric cancer with a dismal median survival of 9 months.o patient in this series required emergency resection to controlleeding and those treated nonoperatively (8 patients) did not haveurther acute bleeding.57

Paraneoplastic Syndromes. Paraneoplastic syndromes associated withastric cancer are not common. Cutaneous systemic manifestationsnclude diffuse seborrheic keratoses (sign of Leser-Trelat) and acanthosisigricans (velvety, dark pigmented lesions) involving the axilla and skinolds. Hematologic abnormalities including Trouseau’s syndrome andicroangiopathic hemolytic anemia have been described.

hysical ExaminationThe physical examination is unremarkable until the late stages of gastric

ancer. Classic physical findings represent metastatic lesions of incurabletage IV patients. Virchow’s supraclavicular node, Sister Mary Joseph’seriumbilical node, Blumer’s shelf, and Krukenberg’s tumor representncurable lymphatic and/or peritoneal metastases. End-stage physicaligns include hepatosplenomegaly, jaundice, ascites, hematemesis, me-ena, and cachexia. Late complications include perforation, bleeding,
astrocolic fistulae, and obstruction.

D

P

Jspsda4SrcwTdgi

S

foCngusggsbtsan

ooc

5

iagnosis

opulation ScreeningWith gastric cancer being a leading cause of cancer-related deaths in

apan, double-contrast barium studies have been used as the maincreening tool since the 1960s. However, only 10% to 20% of the targetopulation was represented in these screening programs. In 1983, a masscreening program was implemented in Japan. Age-adjusted death ratesuring this period show a decrease in gastric mortality and have beenttributed to this screening program. The Japanese 5-year survival rate is0% to 60%, compared with only 20% in other developed countries.58

tudies suggest mass screening does decrease mortality; however, noandomized controlled trials exist to support this conclusion.59 In aase-control study of postgastrectomy patients, no significant differenceas noted between those screened and not screened for gastric cancer.60

he possible ineffectiveness of screening programs may be due toifferences in the pathophysiology of early gastric cancer and advancedastric cancer.61 Mass screening should be limited to countries with highncidence.

creening Laboratory TestsCarcinoembryonic antigen (CEA) and CA 19-9 serum levels are

requently elevated in patients with advanced gastric cancers. However,nly approximately one-third of all patients have abnormal CEA and/orA19-9 levels.62 With low sensitivity and specificity, these markers haveo role as a screening test in high risk patients. The tumor-associatedlycoprotein antigen, TAG-72 (commercially CA 72-4 assay), may be aseful postresection tumor marker. In 1 study, CA 72-4 demonstrated apecificity of 40% to 50% and a sensitivity of 100%.62 The E-cadherinene, recognized in familial forms of gastric cancer, may be a usefulenetic marker for recurrent disease. It has a sensitivity of 59% andpecificity of 75%.63 Vascular endothelial growth factor (VEGF) has alsoeen proposed as a postoperative marker.64 A serum VEGF level greaterhan 533 pg/mL was found to be an independent factor for cancer-specificurvival (hazard ratio, 2.9; 95% CI, 1.3-6.4; P � 0.007). Analysis ofberrant methylation of key genes involved in gastric cancer may be aovel molecular marker system for detecting early cancer.65

No single laboratory test yet exists to facilitate diagnosis and detectionf recurrent gastric cancer. New techniques are emerging for the detectionf individuals at increased risk for gastric cancer based on their genetic
omposition. These technologies include cDNA microarray, serial anal-

yh

U

tedtcbd

bdwmrsotcPss

fipas

Sa((mWbic

C

sis of gene expression (SAGE), differential display, and subtractiveydridization.65-68

pper Gastrointestinal Barium Examination (UGI)Endoscopy and the upper gastrointestinal barium examination (UGI) are

he primary modalities for the detection of gastric cancer. Althoughndoscopy offers the advantage of immediate biopsy and expeditediagnosis, a UGI remains a viable alternative initial diagnostic examina-ion due to its less invasive nature, lack of need for sedation, and lowerost.69 In addition, a gastric neoplasm may be a fortuitous finding on aarium examination performed for unrelated symptoms or on a studyirected at the evaluation of the esophagus or small bowel.Technical Considerations. A combination of techniques is optimal forarium evaluation of the stomach. The examination should include aouble-contrast technique, in which thick barium is used in combinationith effervescent CO2 granules for gas distention, thereby producing aucosal relief image. The double-contrast examination is the single best

adiologic technique for the detection of early gastric cancer (Fig 2). In 1tudy of 80 patients with gastric cancers, 99% were detected successfullyn a double-contrast examination.70 During a double-contrast examina-ion the patient must perform rolling maneuvers for optimal mucosaloating. The patient must also be able to retain the ingested CO2 gas.atients with limited mobility or those with patulous lower esophagealphincters may not be able to perform this portion of the examinationuccessfully.The radiographic examination should also include a single-contrast orlled evaluation with compression views. This technique requires lessatient assistance and may be the only method of evaluation possible indebilitated patient. A single-contrast examination alone has an overall

ensitivity of only 75% in diagnosing gastric cancer.70

Corresponding to morphologic types described by the Japan Researchociety of Gastric Cancer, early gastric cancers may be detected on UGIs small polyps (type I), superficial lesions that are minimally elevatedtype IIa), or flat (type IIb), slight depressions (type IIc), or shallow ulcerstype III)71 (Fig 3). Advanced gastric cancer may present as a polypoidass, an ulcer, or an infiltrative process (linitis plastica pattern) (Fig 4).ith the double-contrast technique, a mass will be etched in white by the

arium, or be recognized by abnormal nodularity or curvilinear linesnterrupting the normal background of areae gastricae. On a single-ontrast image, the mass will be seen as a filling defect in the barium pool.
An ulcer is a common finding on an UGI examination. However, only

FC

5

IG 2. Double contrast UGI study showing polypoid adenocarcinoma of the cardia and fundus.
ourtesy of Dr. Felicia Cummings, Department of Radiology at Virginia Mason Medical Center.

3pulub

mtuitAoa

FN

C

% to 5% of gastric ulcers are malignant.72,73 Although earlier studieserformed between 1955 and 1975 suggested that up to 16% of gastriclcers thought to be benign on single-contrast turned out to be malignant,ater studies using double-contrast technique have shown that virtually alllcers demonstrating unequivocally benign appearances are in factenign.74,75

Benign ulcers have a round or oval shape, a smooth rim representing aound of edema with folds radiating to the edge of the ulcer crater, and

end to project beyond the expected lumen of the stomach. A malignantlcer, on the other hand, will be associated with a mass, have anrregularly shaped crater, nodular or clubbed folds that do not extend tohe edge of the ulcer crater, and project inside the lumen of the stomach.

benign ulcer should demonstrate significant healing after 6 to 8 weeksf therapy. Any ulcer that has a mixed pattern is not unequivocally benign

IG 3. Five types of early gastric cancer. Reproduced with permission from Sleisenger and Fordtran.eoplasms of the Stomach. Gastrointestinal Disease. 4th Edition. Philadelphia: Saunders, 1989: 747.

nd warrants biopsy.


aspmUunwTa

S

H

dg

FsD

5

Limitations of Examination. There are operator-dependent factors thatffect the performance and interpretation of a UGI. For demonstration ofubtle lesions, the UGI requires meticulous technique. In addition,erceptual errors may occur, most commonly due to overlooking orisinterpreting shallow depressions in early cancers.76 The number ofGIs ordered has decreased in the past 2 decades due to greatertilization of endoscopy, diluting the experience for trainees. The diag-ostic accuracy for detection of early lesions is likely greater in countriesith large screening programs, such as Japan, than in the United States.he sensitivity is likely decreased in postgastrectomy patients due tonatomic distortion of the surgical reconstruction.

taging and Histologic Classification

istologyAn understanding of the anatomy of the stomach and its lymphaticrainage is essential to understanding the modern staging systems for

IG 4. Double contrast UGI study showing lack of distensibility and abnormal contour of most of thetomach due to infiltrative adenocarcinoma (linitis plastica pattern). Courtesy of Dr. Felicia Cummings,epartment of Radiology at Virginia Mason Medical Center.

astric cancer. The stomach is divided into 5 major areas: cardia, fundus,


bsdanp

gescasuc1srtr

Fc

C

ody, antrum, and pylorus (Fig 5). The 5 layers of the stomach are serosa,ubserosa, muscularis, submucosa, and mucosa (Fig 6). The lymphaticrainage system of the stomach has been well described by the Japanesend is comprised of 33 regional lymph node stations. Regional lymphode stations are classified into 3 groups based on the location of therimary tumor.77

Numerous histologic classification systems have been proposed forastric cancer. In 1926, Borrmann identified 5 types using simple grossxamination: superficial spreading, polypoid, fungating, ulcerative, andcirrhous-infiltrating (linitis plastica). The WHO has outlined a histologiclassification system with 9 subtypes: papillary adenocarcinoma, tubulardenocarcinoma, mucinous adenocarcinoma, signet-ring cell carcinoma,quamous cell carcinoma, adenocanthoma, undifferentiated carcinoma,nclassified carcionoma, and carcinoid tumor. Ming proposed a classifi-ation system based on expanding or infiltrating growth pattern.78 In965, Lauren described a simple and widely accepted classificationystem: diffuse gastric cancer, intestinal gastric cancer, and other.79 In aecent Western series, approximately 70% of patients have diffuseumors; 30% have intestinal type tumors.80 The simplicity and clinical

IG 5. Anatomic divisions of the stomach. Reproduced with permission from Townsend andolleagues. Sabiston Textbook of Surgery. 17th Edition. Philadelphia: Elsevier, 2004: 1266.

elevance of the Lauren histology classification is emphasized in a recent


rKhstd

ceT

FT

5

eview of the long-term survivors of gastric cancer at Memorial Sloan-ettering Cancer Center (Fig 7). After multivariate analysis, Laurenistologic type had the highest statistical association with long-termurvival of all the variables analyzed. Furthermore, as described below,he Lauren histologic type frequently affects surgical management and/orecision making.The distinction between diffuse (glandular) and intestinal-type stomach

ancer assumes greater importance given the current changes in thepidemiology of and debates regarding the pathogenesis of gastric cancer.

IG 6. Layers of the stomach. Reproduced with permission from Townsend and colleagues. Sabistonextbook of Surgery. 17th Edition. Philadelphia: Elsevier, 2004: 1268.

he worldwide decline in gastric cancer is restricted to intestinal-type


ss

lcePpfiGm

F5mHs

C

tomach cancers, whereas the incidence of diffuse-type tumors remainstable.Tahara outlined the carcinogenetic pathways of these 2 distinct histo-

ogical types of gastric cancer.25 Intestinal-type tumors demonstrate alassic progression of carcinogenesis similar to colon cancer. Initialnvironmental exposures (eg, high salt and low vitamin C/E diet, H.ylori infection) result in a chronic superficial gastritis. There is then arogression from atrophic gastritis to intestinal metaplasia, dysplasia, andnally cancer. Intestinal-type tumors are more common in elderly males.enetic alternations unique to intestinal-type include the following gene

IG 7. Importance of Lauren classification. T stage and N stage determine the prognosis within the firstyears after resection. Shown above is the survival of the subset of patients who survived 5 years. Onultivariate analysis, Lauren classification becomes the strongest predictor of long-term survival. (Fromochwald SN, Kim S, Klimstra DS, Brennan MF, Karpeh MS. Analysis of 154 actual five-year

urvivors of gastric cancer. J Gastrointest Surg 4:520, 2000. Reproduced with permission.)

utations: microsatellite instability, DCC (deleted in colorectal cancer),


aappi

qaplaoftdg

FcSN

5

nd APC (adenomatous polyposis coli).81 Precancerous lesions, liketrophic gastritis and intestinal metaplasia, are major targets for therevention of intestinal-type gastric cancer. Detection, treatment, andrevention of these lesions may play an important role in reducing thencidence of gastric cancer.Diffuse-type gastric cancer is a disease of young and more fre-uently female patients.82 Familial forms have been identified. Anssociation with blood type A is recognized. Diffuse-type tumors areoorly differentiated with signet-ring cells (Fig 8). Transmural andymphatic spread is more common. Metastases occur early and there is

worse overall prognosis.25 Overexpression of c-met, a proto-ncogene, is greater in diffuse-type tumors, especially advancedorms.81 Decreased function and expression of E-cadherin (CDH1), aransmembrane protein involved in cell-cell adhesion, is unique toiffuse-type stomach cancers. In contrast to intestinal-type tumors,

IG 8. Diffuse-type gastric cancer with scattered signet ring cells. Cytokeratin (bh11) immunohisto-hemistry staining (100X). Reproduced with permission from Balch CM, et al: Cancer Staging fortomach. In: Greene FL, Page DL, Fleming ID, et al, editors. AJCC Cancer Staging Manual, 6th Edition.ew York: Springer-Verlag, 2002: 101.

astritis is uncommon.


S

cas(JJTifaloa

tctnissE(Frs

S

rim(uSvst

C

tagingThere are currently 2 major staging systems for patients with gastric

ancer. The Japanese use an elaborate system that focuses on a complexnatomic nodal classification scheme. Western countries have adopted aystem developed jointly by the American Joint Committee on CancerAJCC) and the International Union Against Cancer (UICC). Theapanese Gastric Cancer Association’s most recent staging system,apanese Classification of Gastric Carcinoma, 2nd English Edition, usesand M staging similar to the AJCC system. However, the nodal staging

s significantly different (see http://www.jgca.jp). The Japanese systemocuses on detailed description of the lymphatic spread of gastric cancernd outlines different nodal stations (echelons). Staging is thus based onymphatic spread in relation to the primary tumor (versus the total numberf positive nodes). That is, anatomic distribution of metastatic spreadssumes importance over quantitative extent of nodal metastatic disease.In 2002, the AJCC and UICC agreed on a common staging system with

he release of the AJCC 6th Edition (Table 3). The UICC and AJCChanged from a nodal staging system based on distance from the primaryumor to a staging system based on the number of positive nodes. Thisew approach to handling lymph nodes requires a minimum of 15 nodesn the resection specimen. Although understanding the Japanese stagingystem is useful for research purposes, the AJCC/UICC classificationystem is more practical and more widely used in the United States andurope. The AJCC stage of patients in the National Cancer Database

NCDB) presenting with gastric cancer in this country is shown in Fig 9.or comparison, a recently published large U.S. single-institution studyeported the following distribution of presenting stages: stage 1, 20%;tage 2, 19%; stage 3, 34%; and stage 4, 27%.80

urvival and Patterns of RecurrenceCancer of the stomach continues to have 1 of the worst 5-year survival

ate statistics of any cancer (Fig 10). Due to geographic variation inncidence within the United States, there is wide geographic variation inortality 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 Fornexplained reasons, survival rates are improving in the United States.EER data have shown consistent improvement in overall 5-year sur-ival: 16% in the mid-1970s to 23% by 2001.4 Similarly, the 5-yearurvival rate in Sweden has improved from 13% in the 1970s to 19% in
he mid-1980s.83 No cause for improved survival was identified in the

http://www.jgca.jp

Src5

DWo

T

PTTT

TTTT

TRNNNNNDMMMSSSS

S

S

SS

RS

5

wedish cohort. The Italian Trials in Medical Oncology has recentlyeported results of a randomized trial of patients with T3-4 gastricancers. In this series, the 7-year overall survival rate was approximately0%.84

The survival by stage in U.S. patients entered into the National Canceratabase is illustrated in Fig 10. Five-year survival data from more recentestern series suggest that these data are representative of current

ABLE 3. TNM classification and staging of stomach cancer

Category Criteria

rimary tumor (T)X Primary tumor cannot be assessed.0 No evidence of primary tumor.is Carcinoma in situ: intraepithelial tumor without invasion of

the lamina propria1 Tumor invades lamina propria or submucosa2a Tumor invades muscularis propria2b Tumor invades subserosa3 Tumor penetrates serosa (visceral peritoneum) without

invasion of adjacent structures4 Tumor invades adjacent structuresegional lymph nodes (N)X Regional lymph node(s) cannot be assessed0 No regional lymph node metastasis1 Metastasis in 1 to 6 regional lymph nodes2 Metastasis in 7 to 15 regional lymph nodes3 Metastasis in more than 15 regional lymph nodesistant metastasis (M)X Distant metastasis cannot be assessed0 No distant metastasis1 Distant metastasistage groupingtage 0 Tis N0 M0tage 1A T1 N0 M0tage 1B T1 N1 M0

T2a/b N0 M0tage II T1 N2 M0

T2a/b N1 M0T3 N0 M0

tage IIIA T2a/b N2 M0T3 N1 M0T4 N0 M0

tage IIIB T3 N2 M0tage IV T4 N1-3 M0

T1-3 N3 M0Any T Any N M1

eproduced with permission from Greene et al. American Joint Committee on Cancertaging Handbook. 6th Edition. New York: Springer; 2001.

utcomes. For example, 5-year survival rates for patients treated at Johns


FCSN

FCM

C

IG 9. AJCC stage of U.S. patients presenting with gastric cancer. Based on American Jointommittee on Cancer data. Reproduced with permission from Balch CM, et al: Cancer Staging fortomach. In: Greene FL, Page DL, Fleming ID, et al, editors. AJCC Cancer Staging Manual, 6th Edition.
ew York: Springer-Verlag, 2002: 100.
IG 10. Gastric cancer survival by AJCC stage. Reproduced with permission from Balch CM, et al:ancer Staging for Stomach. In: Greene FL, Page DL, Fleming ID, et al, editors. AJCC Cancer Staging
anual, 6th Edition. New York: Springer-Verlag, 2002: 101.

H2

pyncg(b

bswatTclahmTsOemt

sccCtohsSpll

5

opkins University between 1984 and 2002 were: stage 1, 63%; stage 2,8%; stage 3, 18%; stage 4, 10%; and all patients, 26%.Many factors affect prognosis in gastric cancer patients. The number ofositive lymph nodes is the most consistent prognostic indicator. Five-ear survival rates in patients with 1-6, 7-15, and greater than 15 positiveodes are 43%, 21%, and 13%, respectively.85 Further supporting theurrent AJCC staging system, a multicenter observational study of 477astric cancer patients in the German Gastric Cancer Study GroupGGCS) demonstrated that the number of positive lymph nodes was ofetter prognostic value than the location of the involved nodal basin.86

Positive peritoneal cytology is also associated with decreased survivalut is currently not part of the AJCC staging system.87 Recent studiesuggest that the sensitivity of peritoneal cytologic evaluation is enhancedith real-time reverse transcriptase-polymerase chain reaction (RT-PCR)

mplifying CEA.88 Cytologic evaluation for malignant cells using thisechnique was positive in 10%, 29%, 66%, and 81% of patients with T1,2, T3, and T4 tumors, respectively. Positive tests were stronglyorrelated with eventual peritoneal carcinomatosis and survival. Simi-arly, metastasis to the bone marrow is correlated with poor survival in T1nd T2 patients.89 Decreased survival has been reported in patients withistologically negative but immunohistochemically positive lymph nodeicrometastasis. In a Japanese prospective study of node-negative T2 or3 patients, the 5-year survival rate in those with lymph nodes thattained positive with anticytokeratin antibody (CAM 5.2) was only 66%.n the other hand, there was a 95% survival rate in patients with no

vidence of immunohistochemical micrometastasis. Detection of micro-etastases of gastric cancer may find a role in staging before neoadjuvant

herapy.90

Other systems have been proposed to guide treatment and/or predicturvival of patients with gastric cancer. Maruyama has developedomputer software (Maruyama Program) based on 7 demographic andlinical features of 3834 gastric cancer patients at the National Cancerenter Hospital in Tokyo. The software can be used to guide surgeons in

he extent of lymphadenectomy in a specific patient.91 A Maruyama Indexf Unresected Disease (MI) can be derived from this software model andas been shown to be an independent predictor of survival.92 The clinicalignificance of the Maruyama Program and MI has yet to be established.imilarly, nomograms or scoring systems have been developed thatredict survival based on weighted importance of sex, age, tumorocation, Lauren histologic type, T stage, N stage, and extent of
ymphadenectomy.93-95 The results of a nomogram developed at Memo-

rLolr

rertTnftposlenm

S

detus

E

roeiosfua

C

ial Sloan-Kettering Cancer Center, combining sex, age, tumor location,auren histotype, number of positive and negative nodes, as well as depthf invasion is illustrated in Fig 11. A recent study has shown thatymphovascular invasion is also a strong independent predictor ofecurrence.96

What are the patterns of recurrence? Recent case series suggest that theatio of distant to locoregional recurrence rates is approximately 2:1. Forxample, in the Italian Trials in Medical Oncology study, distant and localecurrences occurred in 34% and 16% of patients, respectively. Chemo-herapy had no effect on this recurrence pattern or on survival rates.84

umor factors affect patterns of recurrence. Gastric remnant cancers tendot to develop peritoneal metastasis. There are also established riskactors for the development of liver metastasis. In 1 series, intestinal-typeumors were much more likely to recur as liver metastases.97 Only 9% ofatients with diffuse-type tumors developed liver metastasis versus 36%f patients with intestinal tumors. In addition, preoperative positivity forerum tumor markers and lymph node involvement are risk factors foriver metastasis. Eighty-five percent of patients with liver metastasis hadlevated tumor markers preoperatively. In contrast, only 1 patient withegative tumor markers developed liver metastasis. Virtually all liveretastases developed within 2 years of surgical resection.

taging ModalitiesOnce the diagnosis of gastric cancer is established, further studies areirected at staging to assist with therapeutic decisions. Neither routinendoscopy nor the UGI examination can assess the depth of invasion ofhe primary tumor, which is the sole criterion for T staging. Endoscopicltrasound (EUS) and computed tomography (CT) are the current primarytaging modalities for gastric cancer.

ndoscopic UltrasoundThe era of EUS, or endosonography, began in the early 1980s when

esearchers at the Mayo Clinic welded an ultrasound transducer to the tipf an endoscope.18 Despite the rise in sophistication and availability ofxtracorporal imaging techniques over the last 3 decades, concurrentmprovements in EUS technology have positioned EUS as an integral partf the diagnosis and staging of gastric cancers. Transabdominal ultra-ound utilizes low frequency signals. Lower frequency signals travelurther, but provide lower resolution. Since the target organ in EUS issually close to the transducer, higher frequencies can be used, producing
high resolution image.

5

sLesaba�sgowcn

mecceopumod

tcuav

FCntcR

C

Tumors tend to be denser than other tissues and can be detected as darktructures that obliterate the normal interfaces between tissue layers.arger tumors that extend into adjacent organs and vessels obliterate thendosonographic interfaces between these structures. Endosonographic Ttaging is based on the number of visceral wall layers that are disrupteds well as the preservation or destruction of sonographic interfacesetween adjacent organs and vessels. N staging is based on the presencend location of perivisceral lymph nodes that fit certain criteria (diameter

10 mm, round shape, uniform hypoechoic structure, well-circum-cribed margins) or that are found to harbor malignant cells by EUS-uided transvisceral fine needle aspiration (FNA). Due to its limited depthf penetration, endosonography is less useful for M staging. However,ith low frequency options on newer echoendoscopes, much of the liver

an often be surveyed and even sampled from the stomach and duode-um.98

Three types of EUS devices are currently available. The workhorse ofost diagnostic EUS imaging in the stomach is the radial scanning

choendoscope. This device employs either a multifrequency transducingrystal attached to a mechanically rotating shaft, or a series of smallerrystals mounted in a fixed, circular array, mounted at the tip of anndoscope. This generally creates a cross-sectional image of the hollowrgan into which it is passed, although angulation changes the imaginglane. These images usually show the visceral wall and adjacent organs,p to as far as 12 cm with a 5-MHz transducer. Frequencies of 20 MHzay penetrate only 2 or 3 cm. The endoscope itself houses standard

ptics, a light source, an accessory channel, and 4-point cables forirectional manipulation.The second type of device, a curved linear array (CLA) echoendoscope

akes the same basic endoscope design, but places a series of transducingrystals on a curved head of the scope. This produces a wedge-shapedltrasound image oriented along the axis of the endoscope. This designllows for the incorporation of Doppler imaging to show flow in bloodessels and, more importantly, to track the passage of a needle from the

IG 11. Nomogram, developed based on 1039 gastric cancer patients at Memorial Sloan-Ketteringancer Center, factors sex, age, tumor location, Lauren histotype, number of positive and negativeodes, and tumor depth. Survival in patients in 4 quartiles of nomogram (A, top) are compared withhat determined by AJCC stage (B, bottom). (From Novotny AR, Schuhmacher C, Busch R, andolleagues, Predicting individual survival after gastric cancer resection. Ann Surg. 243:74, 2006.
eproduced with permission.)

aew

pppfvb

stifbcrpTsncbeasAb(ticuaE

ccg

5

ccessory channel into the image field. These 2 characteristics make CLAndosonography ideal for sampling submucosal and extraluminal tissueith either FNA or, in some cases, core biopsy technique.The third device is a simple, rotating ultrasound probe that can beassed through the accessory channel of most standard endoscopes. Theserobes are small, easy to use, and relatively inexpensive. Their lowerower and small size, however, enables them to produce only higherrequency, low depth images, making them useful only for visualizing theisceral wall and directly adjacent structures. In this capacity, probes cane quite useful for defining submucosal nodules.Although the initial diagnosis of gastric cancer is usually made with

tandard endoscopy, it is of limited value in assessing the T stage and unableo assess the N or M stage. Computed tomography scanning is useful fordentifying distant metastases, especially in the liver, but demonstrates onlyair accuracy in T and N staging. Accuracy for T staging of gastric cancersy spiral CT is approximately 64%, with much lower accuracy for early stageancers.99 Nodal staging by spiral CT scan is also unreliable, with sensitivityates ranging from 24% to 43%.100 Endoscopic ultrasound adds to thereoperative staging of gastric cancers in several ways. Accuracy of EUS for

staging in gastric cancer is approximately 82%, with a sensitivity andpecificity of 70% to 100% and 87% to 100%, respectively.101-103 Unfortu-ately, even in experienced hands, differentiating T2 and T3 gastric canceran be difficult. Desmoplastic reaction associated with a tumor that does notreach the serosa can, on EUS, sometimes look like T3 invasion because thedema distorts the interface between the stomach and adjacent tissue. N-stageccuracy has been shown to be approximately 70%, with sensitivity andpecificity that ranges from 69.9% to 100% and 87.5% to 100%, respectively.ddition of FNA of suspicious nodes increases the accuracy even further,ringing specificity to 100%.18 In addition, EUS-guided FNA or Tru-Cut®

Baxter, Deerfield, IL) biopsy of submucosa can provide a tissue diagnosis inhe setting of linitis plastica where carcinoma spreads along the submucosalnterfaces and leaves the overlying mucosa intact (Figs 12 and 13). In theseases, simple pinch biopsies often show only normal mucosa.104 Endoscopicltrasound can also identify some liver metastases and early ascites associ-ted with stage 4 gastric cancers, both of which can be sampled safely byUS-guided FNA across the gastric or duodenal wall.105,106

Endoscopic ultrasound can be particularly useful in early stage gastricancer where identification of disease limited to the mucosa (intramucosalarcinoma) can sometimes allow for endoscopic resection rather than
astrectomy107,108 (Fig 14). Although rare outside of Japan, endoscopic

rJ

mgssc

C

p

FaGp

C

esection has become the standard of care in many major medical centers inapan.The ability of EUS to provide images and tissue in a quick andinimally invasive manner will likely keep EUS as a major tool for

astric cancer for the foreseeable future. Better resolution echoendo-copes and improved techniques for endoscopic mucosal resection andubmucosal dissection will broaden the treatment options for early gastricancer as well.

omputed TomographyComputed tomography scanning provides critical information in treatment

IG 12. Endoscopic view of linitis plastica in the body of the stomach. Despite the thickenedppearance of gastric folds, the mucosa is normal. Courtesy of Dr. Drew Schembre, Department ofastroenterology at Virginia Mason Medical Center. Note Figs 12 and 13 are imaging from the sameatient.

lanning for gastric cancer patients. Data obtained from CT complement as


FdlCN

FDi(oD

5

IG 13. EUS image of linitis plastica. Double-headed arrow represents the thickened submucosal areaue to tumor infiltration. Thin single-headed arrow indicates hypertrophied muscularis propria with

ikely tumor infiltration extending beyond the gastric wall into peri-gastric fat (thick white arrow).ourtesy of Dr. Drew Schembre, Department of Gastroenterology at Virginia Mason Medical Center.
ote: Figs 12 and 13 are imaging from the same patient.
IG 14. (A) Endoscopic image of early gastric cancer at the incisura. Courtesy of Dr. Drew Schembre,epartment of Gastroenterology at Virginia Mason Medical Center. (B) Endoscopic ultrasound (EUS)

mage of T1 cancer. Thick dark arrow demonstrates mucosal tumor invading the broad white layerhypoechoic) of hyperechoic submucosa (white arrow) but not disrupting the dark layer (hypoechoic)f the muscularis propria (thin dark arrow) in the same patient. Courtesy of Dr. Drew Schembre,
epartment of Gastroenterology at Virginia Mason Medical Center.

C

wiit

bioSWgrad

TaCps

snl81i

iaDosaettaawo

5

ell as reinforce findings on EUS. Computed tomography can providenformation about the primary tumor, detect lymphadenopathy, and predictnvasion of adjacent organs, with some limitations. Computed tomography ishe single best noninvasive means of detecting metastatic disease.T Staging. Evaluation of intramural tumor involvement and extensioneyond the wall is critical in therapeutic planning. The depth ofnvolvement is directly related to prognosis. The role of CT in T stagingf gastric cancer has been controversial and is in rapid evolution.tandard CT techniques are notoriously poor at evaluating the stomach.all thickness is difficult to judge without distention and parts of the

astric wall that are coplanar with the axial scan angle (the gastric cardiacegion in particular) may appear artifactually thickened. A pseudomassppearance of the gastroesophageal (GE) junction on standard CT wasescribed in 23% of 100 patients with normal GE junctions.109

Endoscopic ultrasound has been the most accurate method available forstaging of gastric cancer. A study from 1991 demonstrated 92%

ccuracy of EUS for depth of tumor penetration compared with 42% forT.110 Many technical advances in CT scanning have occurred over theast 15 years and this gap has narrowed. A more recent study demon-trated CT T-staging accuracy of 76% compared with 86% for EUS.111

Enhancing mucosal lesions may be subtle or obscured when adjacent totandard high density positive oral contrast, and the use of water as aegative oral contrast agent has increased the conspicuity of enhancingesions.112-117 Distention achieved with the use of water filling (300 to00 mL) is important for an accurate assessment of wall thickness (Fig5). Hypotonic agents such as glucagon or scopolamine may be admin-stered to assist in maintaining distention throughout the examination.Helical CT scanning made possible by slip-ring technology was

ntroduced in the early 1990s and permitted faster scanning with reducedrtifact from motion compared with incremental CT scanners. In 1999,ux and colleagues evaluated 115 gastric carcinomas using water as theral contrast and single-slice helical CT with conventional 5-mm-thicklices at 8-mm intervals and reported a disappointing 51% overallccuracy in T staging.112 More recently, multidetector CT (MDCT) hasnabled even faster scanning with simultaneous acquisition of multiplehin slices. Use of thin slice collimation decreases partial volume artifacthat enables more accurate assessment of the wall in a curved organ. Thecquisition of volumetric high resolution data made possible by MDCTlso allows multiplanar reconstructions (MPR) to be performed on aorkstation, depicting most segments of the gastric wall in the optimal
rthogonal plane with enhanced anatomic detail. In 2005, Shimizu and

csU9(s

io2cfi

Fr

C

olleagues published data demonstrating an 85% accuracy of CT for Ttaging, using MDCT with 1.25-mm multiplanar reconstructed images.126

sing the MPR technique, Shimizu and colleagues were able to detect6% of advanced gastric cancers and 41% of early gastric cancerscompared with 20.5% detection rate for early gastric cancers by usingtandard 5-mm-thick collimation).Some authors have advocated the use of 2 or 3 phases of scanning

ncluding arterial, equilibrium, and delayed phases to optimize detectionf the wall layers.115-117 Optimized CT techniques allow visualization ofor 3 layers of the gastric wall, and several studies have been performed

orrelating the CT appearances of wall involvement with histologic

IG 15. CT performed with water distention of the stomach demonstrates a mass in the gastric cardiacegion. Courtesy of Dr. Patrick Freeny and Dr. Gita Rabbani at the University of Washington.

ndings.113-119


ucsdTtm

m1

FaV

5

Kumano reported 93% accuracy in assessment of serosal invasion bysing MDCT compared with previous reports of 80% to 87% by usingonventional techniques.114 In this study, CT tended to understagecirrhous-type tumors, which do not enhance as well in general asifferentiated tumors.114 T3 scirrhous tumors also may be understaged as2 due to the relative smooth outer surface of the wall and tendency of the

umor to infiltrate perigastric adipose tissue without an observableass.114

Invasion of adjacent organs such as liver, pancreas, and transverseesocolon is suspected when intervening fat planes are lost on CT (Fig

IG 16. CT demonstrates T4 gastric carcinoma of proximal body with extension into perigastric fatnd involvement of splenic artery. Courtesy of Dr. Felicia Cummings, Department of Radiology atirginia Mason Medical Center.

6). However, fat planes may be lost without tumor invasion due to


bff(g

idnn1n5nNpawlHfspi

lrTtpp

amnm

M

cm

C

enign inflammation and in cachectic patients with little intra-abdominalat. Conversely, tumor infiltration may be sufficiently subtle to preserveat planes on CT. Halvorsen and colleagues reported only 27% sensitivity3 of 11 patients) in the detection of pancreatic invasion by adjacentastric cancer.69

Nodal Staging. Accuracy of CT for nodal involvement by gastric cancers limited. The limitation is due to the fact that size remains the primaryiagnostic criteria for determining tumor involvement. The cutoff forormal nodal size is 8 to 10 mm, but metastases may be found in lymphodes smaller than 8 mm. In a study of 58 patients with gastric cancer and082 histologically sampled lymph nodes, cancer was found in 82.6% ofodes larger than 14 mm, 23.0% of nodes 10 to 14 mm, 21.7% of nodesto 9 mm, and 5.1% of nodes smaller than 5 mm.120 The same study alsooted that lymph nodes smaller than 5 mm were rarely detected by CT.odes may be difficult to detect in cachectic patients with little fat, anderigastric lymph nodes may be incorporated into the primary tumor massnd be difficult to isolate. In a series of 85 patients with gastric cancerho had histologic correlation, Dux and colleagues reported a majority of

ymph nodes containing metastases were between 2 and 10 mm.112

alvorsen and colleagues reported 67% sensitivity and 61% specificityor nodal metastasis in a series of 75 patients with gastric cancer.69 Inummary, CT has a tendency to understage nodal disease despite theotential for low specificity due to enlarged lymph nodes due tonflammation rather than metastatic disease.111

Metastases. Hematogenous metastases most commonly arise in theiver, lung, and adrenals, and uncommonly bone, kidneys, and brain. CTemains the single best modality for detection of metastatic disease.echnical advances in the past 10 years have included contrast bolus

racking, which enables imaging of the liver in optimal phases of organerfusion. Liver metastases are well visualized on the equilibrium orortal venous phase of CT (Fig 17).Signs of peritoneal carcinomatosis include ascites, omental stranding,

nd peritoneal studding. Metastases to the ovaries (Krukenberg’s tumor)ay be seen as enhancing ovarian enlargement (Fig 18). However, when

o ascites is present and peritoneal implants are small, carcinomatosisay be below the resolution of CT.

agnetic Resonance (MR)Currently, MR is used primarily when CT iodinated contrast is

ontraindicated due to a significant contrast allergy or renal failure. MR
ay also be used to confirm the presence of equivocal liver masses seen

omasFbr

P

r

FC

5

n CT. With respect to T staging of gastric cancer, MR is comparable orinimally superior to CT.121,122 CT and MR are comparable when

ssessing nodal staging.121,122 Due to the cost, longer scanning times, andusceptibility to motion, CT remains the imaging technique of choice.urther developments in MR may include the use of endoluminal coils foretter definition of the gastric wall layers and improved T staging andegional nodal staging accuracy.

ositron Emission TomographyPotential uses of PET in gastric cancer patients are in staging, detecting

IG 17. CT demonstrates extensive liver metastases from gastric carcinoma. Courtesy of Dr. Feliciaummings, Department of Radiology at Virginia Mason Medical Center.

ecurrence, determining prognosis, and measuring therapy response. The


mslMTfai

rs

F(M

C

ajor advantage of PET over anatomic modalities, such as CT, isubstantially greater contrast resolution. For example, PET can detectymph node metastases before lymph nodes are enlarged on CT (Fig 19).

any pathologic lesions are much more conspicuous on PET than on CT.he limitations of PET are lower sensitivity for small lesions and

alse-positive results from infectious or inflammatory processes. Inddition, PET studies are relatively expensive compared with othermaging modalities.Combined PET and CT (PET/CT) scanners have been introduced

ecently. These scanners perform both a PET and CT scan in the same

IG 18. CT demonstrates large pelvic masses representing drop metastases to bilateral ovariesKrukenberg’s tumor). Courtesy of Dr. Felicia Cummings, Department of Radiology at Virginia Masonedical Center.

ession and fuse the images. A PET/CT scanner combines the excellent


cNwhw

cpi9dthutuF

FlR

6

ontrast resolution of PET with the excellent spatial resolution of CT.umerous studies have shown improved accuracy of PET/CT comparedith PET alone.123 However, the accuracy of PET/CT in gastric canceras not been well defined. PET has been reported to have poor sensitivityith signet-ring cell and mucinous tumors.124,126

Although PET does not have a role in the primary detection of gastricarcinoma, the degree of uptake in a known gastric carcinoma hasrognostic value. Moderately intense fluorodeoxyglucose (FDG) uptaken the gastric wall is a normal variant. Despite this, the majority (60% to6%) of primary gastric neoplasms are detected by PET.125,126 A greateregree of FDG uptake is associated with greater depth of invasion, size ofumor, and lymph node metastases.127 The survival rate in patients withigh FDG uptake is significantly lower than in patients with low FDGptake.127 However, the degree of the primary tumor uptake is related toumor histology and tumors with poor prognoses can have low FDGptake. In particular, signet-ring cell and mucinous carcinomas have lowDG uptake.124,126

IG 19. Axonal positron emission tomography (PET) image of gastric cancer. Short arrow is gastricesion. Long arrows represent nodal metastases. Courtesy of Dr. Felicia Cummings, Department ofadiology at Virginia Mason Medical Center.

PET has potential value in staging gastric cancer. Yoshioka and


cictdtoPstsdbm

rpP6w

c4dsrs

L

pSdo1fuMl1m

C

olleagues reported an overall sensitivity of 71% and specificity of 74%n a group of 42 patients with advanced, metastatic, or recurrent gastricancer.128 The reported sensitivities for nodal metastases vary substan-ially (23% to 73%).127,128 Positron emission tomography is limited in theetection of perigastric nodes that can be obscured by activity in the primaryumor. Positron emission tomography is particularly insensitive for detectionf nodal metastases from signet-ring cell carcinoma.125 The primary value ofET in the detection of nodal metastases from gastric carcinoma is itspecificity (78% to 96%).125,128,129 The overall accuracy of PET and CT forhe detection of local and distant nodes is similar.124 Although CT is moreensitive than PET for detection of lymph node metastases in N1 and N2isease, PET is more specific.124,125,129 Positron emission tomography maye more sensitive for the detection of nonnodal sites such as liver and lungetastases but not bone, peritoneal, and pleural metastases.124,128

Limited data are available regarding the value of PET in evaluatingecurrent gastric carcinoma. De Potter and colleagues130 evaluated 33atients for recurrence after surgical treatment with curative intent.ositron emission tomography had a sensitivity of 70% and specificity of9% in this group of patients.130 A negative PET scan was associatedith a significantly longer survival than a positive PET scan.PET may also have value in the prediction of response to preoperative

hemotherapy in gastric cancer. Ott and colleagues prospectively studied4 patients with locally advanced gastric carcinomas at baseline and 14ays after the initiation of cisplatin-based polychemotherapy.131 Re-ponse on the PET scan 14 days after therapy predicted histopathologicesponse 3 months after therapy and was positively correlated withurvival.

aparoscopyLaparoscopy now plays a fundamental role in guiding management ofatients with gastric cancer felt to be eligible for resection. In 1985,handall and Johnson reported that routine use of laparoscopy resulted inetection of metastatic disease to the liver or peritoneum and avoidancef laparotomies in 29% of patients.138 Subsequent studies confirmed that2% to 52% of patients felt to be appropriate for gastric resection wereound to have metastatic lesions at the time of laparoscopy and thusnnecessary laparotomies were avoided.132-137 Burke and colleagues atemorial Sloan-Kettering Cancer Center (MSKCC) demonstrated that

aparoscopy has 100% sensitivity and 84% specificity. Twenty-four of the10 patients who underwent laparoscopy in the MSKCC study had occult
etastatic disease. None of these patients required palliative surgery.138

paieCacp

lmucscis

FC5psv

6

With the emergence of laparoscopic ultrasound, nodal staging is nowossible with laparoscopy. Unfortunately, like endoscopic ultrasound, it isspecialized technique with operator variability. Finch and colleagues

ndicate that laparoscopic ultrasound is 84% accurate in TNM staging ofsophageal cancers.139 This study compared laparoscopy ultrasound toT and laparoscopy and showed a clear benefit for ultrasound inssessing gastrointestinal cancers.135 Controlled studies specific to gastricancer comparing laparoscopy with and without ultrasound have yet to beublished.Confirming the importance of staging laparoscopy, the practice guide-

ines provided by the National Comprehensive Cancer Network recom-end that patients with gastric cancer and locoregional disease (M0)

ndergo laparoscopy to guide further management140 (Fig 20). Laparos-opy should not be restricted to the patients felt to be resectable. Accuratetaging even in unresectable patients will help determine if combinedhemoradiation will be beneficial, since radiation may not be appropriaten patients with metastatic disease.140 Laparoscopy can also be used in

IG 20. Clinical management of gastric cancer. Adapted with permission from National Comprehensiveancer Network Clinical Practice Guidelines in Oncology, 2005. 1Radiation Therapy, 45-50 Gy �

-FU-based radiosensitization. 2Salvage therapy guided by Karnofsky performance score and ECOGerformance score and includes chemotherapy, clinical trial participation, or supportive care. 3Peritonealeeding, distant metastases, inability to perform complete resection, or invasion/encasement of majorascular structure(s). Available at http://www.nccn.org/professionals/physician_gls/PDF/gastric.pdf

taging before entry into neoadjuvant trials.141 Laparoscopy is not


http://www.nccn.org/professionals/physician_gls/PDF/gastric.pdf

nFpt

S

E

crsitJptNbrbfdlcdcrapian

tptepeS

C

ecessary in T1 or T2 lesions given the low incidence of metastases.141

urthermore, as discussed below, laparoscopy may not be indicated in thereoperative evaluation of patients with gastric remnant cancers, sincehey do not tend to develop peritoneal metastasis.

urgical Treatment

xtent of Lymph Node DissectionThe optimal extent of lymphadenectomy in a patient with potentially

urable gastric cancer has been debated for decades. The Japanese firsteported large cohort studies suggesting that disease-free and overallurvival is increased in patients treated with extended resections, includ-ng radical lymphadenectomies.142 Unfortunately, a variety of nomencla-ures (Japanese vs. AJCC) make understanding this literature difficult.apanese nodal staging categorizes nodal basins into 4 groups: N1erigastric nodes in proximity to the stomach; N2 nodes associated withhe major gastric vessels (eg, left gastric, splenic, and common hepatic);3 nodes in the hepatoduodenal ligament, the celiac plexus, and at thease of the superior mesenteric artery; and N4 nodes in the para-aorticegion. Similarly, Japanese nomenclature describes R0-R4 resectionsased on the extent of lymph node and gastric resection versus margin-ree or positive resections in the AJCC nomenclature. Over the lastecade, however, most series have settled on designations of D1 or D2ymphadenectomies when describing surgical procedures for gastricancer. In our opinion, the best description of D1 and D2 lymph nodeissections is the simplest: D1 resections remove lymph nodes within 3m of the tumor en bloc with the greater omentum and stomach; D2esections also include the omental bursa and lymph nodes of the celiacxis, hepatoduodenal, splenic and retroduodenal nodes. To resect com-letely the nodes in the splenic hilum, the classic D2 resections alsoncluded splenectomy and distal pancreatectomy. The differences in D1nd D2 resections are nicely illustrated in Figs 21 to 23 (using the “R”omenclature).The controversy surrounding the relationship between radical opera-

ions and oncologic outcomes has been reviewed in several recentublications. As mentioned above, initial studies from Japan suggestedhat cure rates were improved in patients with gastric cancer treated withxtended lymph node dissections or radical operations. Cure rates foratients in the radical surgical cohorts approximated 50% to 60%, farxceeding the 15% to 30% cure rates reported in series from the United
tates. Subsequent large series from Western centers confirmed these

rbasil

Fcts

F(c

6

eports.143,144 However, these studies have been appropriately criticizedecause of the inevitable “stage migration effect,” which compromisesny study comparing survival in patients treated with extensive versustandard lymph node dissections. That is, the more lymph nodes exam-ned, the greater the probability of positive nodes. Some patients in the

IG 21. Extent of lymph node dissection for D1 (� R1) or D2 (� R2) resections for distal gastricancers. (From Smith JW, Shiu MH, Kelsey L, Brennan MF. Morbidity of radical lymphadenectomy inhe curative resection of gastric carcinoma. Arch Surg 1991;126:1469. Reproduced with permis-ion.)

IG 22. Extent of lymph node dissection for D1 (� R1) or D2 (� R2) resections for mid-gastric cancers.From Smith JW, Shiu MH, Kelsey L, Brennan MF. Morbidity of radical lymphadenectomy in theurative resection of gastric carcinoma. Arch Surg 1991;126:1469. Reproduced with permission.)

imited lymph node dissection group are inaccurately labeled node


ntfWCmti

bsrfShi3a

pC

Fcts

C

egative and will have lower survival rates than node-negative patients inhe extended lymph node group. When the 2 groups are compared stageor stage, survival rates will be better in the extended lymph node group.

ill Rogers once said, “When the Okies left Oklahoma and moved toalifornia, they raised the intellectual level in both states.” Stageigration, also called the Will Rogers phenomenon, shifts stage 2 patients

reated with extensive lymph node dissection to stage 3, thereby resultingn a false finding of treatment advantage in stage-matched patients.Since conventional staging cannot be used to compare 2 treatment armsecause of the stage migration effect, the best method to assess effect ofurgery on survival is to compare intermediate stage patients (T3 tumors)egardless of the nodal status. This group would be most likely to benefitrom extended lymph node resections. For example, the Memorialloan-Kettering Cancer Center reviewed their results in 774 patients whoad undergone curative gastric resections.144 They reported survival ratesn patients with T3 tumors treated with D2 and D1 dissections of 54% and9%, respectively. They concluded, “D2 dissection offered a survivaldvantage for T3 tumors.”144

Two large randomized studies have compared D1 and D2 resections inatients with gastric cancer. In the first study, the Medical Research

IG 23. Extent of lymph node dissection for D1 (� R1) or D2 (� R2) resections for proximal gastricancers. (From Smith JW, Shiu MH, Kelsey L, Brennan MF. Morbidity of radical lymphadenectomy inhe curative resection of gastric carcinoma. Arch Surg 1991;126:1469. Reproduced with permis-ion.)

ouncil (MRC) trial, 400 patients were randomized.145 The Dutch


Gatratrpdwacao

rscmdwrcbantps

crtisf

cmap

6

astric Cancer Group randomized 711 patients.146 In the Dutch trial, theuthors calculated that stage migration occurred in approximately 30% ofhe D2 group. Both groups reached nearly identical conclusions that D2esections: (1) offered no survival advantage and (2) were accomplishedt the expense of greater operative morbidity and mortality. In the Dutchrial, 5-year survival rates in D1 and D2 patients were 45% and 47%,espectively.146 However, major complications were more likely in D2atients than in D1 patients (43% vs. 25%, P � 0.001). Perioperativeeath rates were also higher (10% vs. 4%, P � 0.004). These findingsere duplicated in the MRC trial.145 Both groups reported a strong

ssociation between splenectomy/distal pancreatectomy and poor out-ome. Although many have challenged the conclusions of these studies,ll experts agree that splenectomy should be avoided in nearly allperations for gastric cancers.147-151

What were the systematic flaws of these studies and what is the currentole of extended lymphadenectomy? A recent Cochrane Review nicelyummarizes the status quo and makes the following observations andonclusions.152 First, a frequently cited problem with both studies is thatost participating surgeons had little or no pretrial experience with D2

issections. Furthermore, the mean within-study case volume per surgeonas low (mean 4.7 D2 procedures per surgeon per year.) In addition, both

andomized studies validated the extent of lymph node dissections byounting retrieved lymph nodes. There was likely considerable overlapetween treatment groups. In the Dutch study, 36% of D1 patients haddditional lymph nodes resected, whereas 51% of D2 cases had lymphodes missing in specific designated nodal specimens.146 In our opinion,hese criticisms ignore the importance and variability of diligence of theathologist in retrieving lymph nodes and of patient body habitus on theuccess of nodal retrieval.The second important systematic flaw in the randomized trials was the

lear and significant excess mortality in the D2 resections, with a riskatio of 2.23 (95% CI, 1.45-3.45). This suggests that death is more thanwice as often after D2 surgery. Subgroup analysis showed a strongndependent association between postoperative death and resection of thepleen and tail of pancreas (combined risk ratio for splenectomy, 5.5, andor pancreatic resection, 5.8).The Cochrane Review concludes that modified D2 resections can be and

urrently are being performed with much lower operative morbidity andortality.152 Whereas operative mortality rates were approximately 10%

fter D2 resections in the Dutch and MRC trials, weighted mean
ostoperative mortality rates for 9 recent cohort studies of D2 resections

ptCgsr

fFssloTcat

esfmg

cedKorcrmsap1tpmi

C

erformed at high volume centers is only approximately 4%. Consideringhe potential sources of systematic bias in these 2 randomized trials, theochrane authors concluded that they were not “confident that the trialsave a reliable estimate of treatment outcome.”152 In other words, thesetudies neither proved nor disproved an advantage for extended or D2esections.Interestingly, follow-up publications and subgroup analyses of the data

rom these 2 studies have claimed advantages for D2 resections.151-154

irst, the modern version of the D2 operation, in which resection of thepleen and pancreas are avoided, is safer.150 The Dutch, MRC, andeveral prospective studies have demonstrated the safety of extendedymph node dissection with splenic preservation.147,150,151 Preservationf the spleen is associated with better survival and local failure rates.here are few indications for splenectomy during operations for gastricancer.147,149 A D2 lymphadenectomy can be performed with postoper-tive morbidity and mortality equivalent to limited lymph node dissec-ion.Improved outcomes with D2 resections first described in Japan are

merging. The Cochrane Review and others have estimated, based onubgroup analyses, that there is approximately a 30% survival advantageor patients with T3 cancers undergoing D2 surgery.152 Examination ofature results of the Dutch trial noted recurrence rates in D1 and D2

roups of 41% and 29%, respectively (P � 0.02).Prospective cohort studies from the United States have also con-

luded that an absolute number of lymph nodes retrieved and/orxamined are a reasonable means to assess the adequacy of surgicalissection and resection. Karpeh and colleagues at Memorial Sloan-ettering Cancer Center have concluded that survival estimates basedn the number of involved or positive lymph nodes are betterepresented when at least 15 lymph nodes are examined.155 That is,orrect staging requires that at least 15 lymph nodes be examined. Thisequires dedicated cooperation with the surgical pathology depart-ent. The 10-year results of the German Gastric Cancer Study also

upport the notion that increased numbers of lymph nodes removednd examined has an effect on survival86 (Fig 24). In this study, 1654atients with gastric cancer undergoing operation between 1986 and989 were followed prospectively. D1 or D2 operations were arbi-rarily determined by numbers of lymph nodes examined, with a breakoint of less than or greater than 25 lymph nodes. As expected,ultivariate analysis confirmed that nodal status was the major

ndependent prognostic factor for survival. However, the extent of


l1sfiIgUam

mwtgfr

FraS

6

ymph node dissection had a significant and independent effect on the0-year survival rates in patients with stage 2 tumors. Since thisubgroup effect was seen even in patients with pT3N0 tumors, thisnding appears not to be due to the phenomenon of stage migration.86

n addition, a recently published prospective comparison of 118astric cancer patients undergoing D1 or modified D2 resections in thenited Kingdom reported 5-year survival rates of 32% and 59% in D1

nd D2 resection patients, respectively.151 Operative morbidity andortality were the same.In conclusion, whereas the benefits of D2 resections are unproven, theodern (splenic preservation) D2 resection is an acceptable procedurehen performed at high volume centers. It is likely the preferred

reatment for patients with T3 tumors and/or intermediate stage (2 to 3)astric cancers.143 Finally, modern quality assessment process measuresor surgeons and pathologists should require 15 or more nodes in the

IG 24. Cumulative survival in patients with resected T3N0 gastric cancers. Number of lymph nodesemoved (and by inference D2 versus D1 resection) strongly correlates with survival. (From Siewert JRnd the German Gastric Carcinoma Study Group. Relevant prognostic factor in gastric cancer. Annurg 1998;228:457. Reproduced with permission.)

esected specimens.


E

wtt

etbwLcmcasc1reapua

sdwm

lbdleTjabi

C

xtent of Gastric ResectionAt least 6 factors determine the extent of gastric resection in patientsith potentially curable gastric cancers: tumor stage, tumor histology or

ype, tumor location, nodal drainage, perioperative morbidity, and long-erm gastrointestinal function.Tumor Stage. The extent of surgical resection is dictated largely by the

xtent of microscopic spread of the tumor beyond palpable or visibleumor. Recent studies suggest that the extent of operation can be modifiedased on tumor stage. Early gastric cancer (T1a lesions) may be treatedith endoscopic techniques and/or limited wedge gastric resections.arger tumors require greater surgical margins. Most studies haveoncluded that for T2-3 tumors, a 6-cm length of proximal margin,easured in the operating room, results in clear margins in virtually all

ases. These measurements are obtained during intraoperative assessmentnd need not be adjusted for retraction of the esophagus once thepecimen has been delivered to the pathologist. Margins between 3 and 6m are associated with positive microscopic margins in at least 5% to0% of cases. In T2 tumors, a 3-cm clearance may be adequate. This latterecommendation is not valid for poorly differentiated, diffuse tumors. Theffect of T stage on ideal surgical margins emphasizes the importance ofccurate preoperative staging, preferably with endoscopic ultrasound. Ifreoperative staging suggests a T3-4 tumor, preoperative laparoscopy issually warranted and a modified D2 resection with 6-cm margins isppropriate.Tumor Histology. The extent of tumor and tumor histology affects the

urgical margin and therefore the extent of resection. Diffuse, poorlyifferentiated tumors require 6-cm proximal margins.156 Superficial,ell-differentiated intestinal-type tumors may be treated with lesserargins.Tumor Location. The extent of gastric resection is affected by the

ocation of the tumor. As shown in Figs 25 to 27, tumors of the antrum,ody, or proximal stomach have different nodal drainage and henceifferent requirements for lymphadenectomy. The frequency of positiveymph nodes in various nodal regions summarized in Figs 25 to 27mphasizes the importance of radical resections in most patients with2-4 tumors. Tumors of the cardia, lying 2 to 5 cm below the GE

unction, deserve special mention. These tumors are typically high gradend have a tendency to invade the esophagus. In Western surgical series,etween 26% and 63% have esophageal invasion with risks being greater
n linitus plastica, or diffuse type T3-4 tumors.157

otaeda

Spaoc

cg

FLP

6

Nodal Drainage. The extent of lymphadenectomy and hence the extentf the gastric resection is frequently influenced by the nodal drainage ofhe tumor and the intraoperative findings.158 For example, T3 tumorslong the lesser curve with suspicious lymph nodes frequently requirextensive dissection of the left gastric artery and celiac axis. Thisissection may compromise the viability of the proximal stomach andppropriateness of subtotal gastrectomy for some distal tumors.Perioperative Morbidity and Long-Term Gastrointestinal Function.urvival is equivalent after subtotal gastrectomy or total gastrectomy foratients with cancers of the antrum. Total gastrectomy is associated withn increased risk for splenectomy, longer hospital stay, longer impairmentf caloric intake, and greater long-term nutritional sequelae whenompared with subtotal gastrectomy.What is the preferred operation for patients with proximal gastric

ancers? In our opinion, these patients are best served with total

IG 25. Frequency of node-positive zones for distal gastric cancers. (From Sutherland DA. Theymphatic Spread of Gastric Cancer. In: McNeer G, Pack GT, editors. Neoplasms of the Stomach.hiladelphia: Lippincott; 1967:408-15. Reproduced with permission.)

astrectomy. A proximal gastrectomy with esophagogastrostomy can be


aoooiartrm

rtciB

FLP

C

chieved with adequate margins and lymphadenectomy.157 However, thisperation results in unacceptable long-term morbidity and should, in ourpinion, never be performed. Gastroesophageal reflux is severe after thisperation, and it is not treatable medically. Gastric emptying is usuallympaired; the refluxate is composed of pancreaticobiliary secretions thatre very irritating to the esophageal mucosa, and patients usually do notespond to antisecretory medications. Furthermore, a tension-free anas-omosis is easier with a Roux-en-Y esophagojejunal reconstruction, thuseducing the temptation to compromise the esophageal resection andargin.In summary, the factors above should govern the extent of gastric

esection. Well-conducted studies have established that subtotal gastrec-omy is equivalent to total gastrectomy in patients with distal or antralancers.159,160 In experienced hands, elective total gastrectomy does notncrease postoperative mortality, but there is no improvement in survival.

IG 26. Frequency of node-positive zones for midgastric cancers. (From Sutherland DA. Theymphatic Spread of Gastric Cancer. In: McNeer G, Pack GT, editors. Neoplasms of the Stomach.hiladelphia: Lippincott; 1967:408-15. Reproduced with permission.)

ozzetti and colleagues randomized 618 patients with cancers of the


dut6apt6ccslpas

FLP

6

istal stomach: 315 underwent subtotal gastrectomy (SG) and 303nderwent total gastrectomy (TG).161,162 There were 4 operative deaths inhe SG group and 7 in the TG group. The 5-year survival probability was5% for SG and 62% for TG. The authors concluded that SG, which isssociated with better nutritional status and quality of life, should be therocedure of choice in patients with distal gastric cancers, provided thathe 6-cm proximal margin of resection is in healthy tissue. In their study,

of 315 SG patients had positive margins (4 with clearance less than 6m), but only 1 of 303 TG patients had a positive margin (with a 10 cmlearance). These latter data suggest that a “subtotal gastrectomy mind-et” can affect intraoperative decision making and potentially increase theikelihood of settling for inadequate proximal margins. Of note, 13atients in the study had distal margins infiltrated by the tumor. Virtuallyll patients with T2-4 tumors of the body of the stomach or proximal

IG 27. Frequency of node-positive zones for proximal gastric cancers. (From Sutherland DA. Theymphatic Spread of Gastric Cancer. In: McNeer G, Pack GT, editors. Neoplasms of the Stomach.hiladelphia: Lippincott; 1967:408-15. Reproduced with permission.)

tomach should undergo total gastrectomy.


P

ipSetds1w

tooftipsefslsdrcubaspdi

S

G

d

C

reoperative EvaluationNational Comprehensive Care Network guidelines indicate the follow-

ng preoperative workup and/or evaluation in all patients: (1) multidisci-linary evaluation, (2) history and physical examination, (3) CBC andMA-12, (4) abdominal and pelvic CT, (5) chest radiograph, (6)sophago-gastroduodenoscopy (EGD), and (7) laparoscopy. We believehat the majority of patients should also undergo EUS evaluation to betterefine the T stage of the tumor. Although tumor markers have no role increening, we believe that preoperative measurement of CEA and CA9-9 is warranted, as it may help with postoperative follow-up in thoseith elevated levels (approximately 35% of patients).Preoperative preparation routinely includes cathartic bowel preparation

he day before operation, with admission to the hospital on the day ofperation. Because of concerns regarding the association between peri-perative blood transfusion and decreased cancer-related survival, trans-usion is avoided, if at all possible. Patients with preoperative anemia arereated with iron repletion (orally or intravenously) and operation delayedf necessary. Prophylactic antibiotics (cefazolin [2 g] or a quinalone inenicillin-allergic patients) are administered within 30 minutes before theurgical incision. Redosing of antibiotics is appropriate approximatelyvery 2 half-lives during operation, or approximately every 3 to 4 hoursor cefazolin. No postoperative antibiotics are needed. Aggressive mea-ures should be taken to prevent deep vein thrombosis (DVT), with ateast 2 interventions. In our practice, we place graded compressiontockings plus sequential compression devices and also administer lowose heparin in most patients. Similarly, we believe the data support theoutine use of thoracic epidural anesthesia and postoperative patient-ontrolled epidural analgesia (PCEA). Improved outcomes in patientsndergoing major cancer operations treated with epidural techniques haveeen reported. The initiation of thoracic epidural anesthesia with localnesthetics before the surgical stimulus blunts the surgical stress re-ponse, thereby decreasing the risk for DVT and improving myocardialerformance. Postoperative patient-controlled epidural analgesia likelyecreases the length of hospital stay, shortens postoperative ileus, andmproves pain control.

urgical Technique

astric ResectionSubtotal or total gastrectomy is initiated in an identical fashion. The
ecision to perform a subtotal gastrectomy in patients with antral cancers

iiiiespoa

dactdlt

FsFR

6

s not made until the latter stages of the procedure. We use a midlinencision in virtually all cases, although an upper bilateral subcostalncision (Chevron incision) provides excellent exposure as well. Exposures enhanced with a self-retaining retractor. The abdominal contents arexplored in search of metastatic disease and to assess the mobility of thetomach and feasibility of resection. The decision to proceed with aalliative resection (eg, in patients with grossly positive para-aortic nodesr peritoneal metastasis) is complex and reviewed elsewhere in thisrticle. Once curative resection is planned, further exposure is necessary.Exposure of the esophageal hiatus is enhanced by “verticalization of theiaphragm.” We routinely disarticulate the xiphoid from its costalttachments and/or remove the xiphoid. This allows several additionalentimeters of distraction of the costal margin by a self-retaining retractorhat then makes the diaphragm “vertical” under the xiphoid and providesirect visualization of the gastroesophageal junction. The suspensoryigament of the left lateral segment of the liver is divided. The areolar

IG 28. The entire greater omentum is detached from the transverse colon (hepatic flexure to theplenic flexure) using electrocautery. (From Brennan MF. Total gastrectomy for carcinoma. In Baker RJ,ischer JF, editors. Mastery of Surgery. Philadelphia: Lippincott Williams & Wilkins; 2001:997-1006.eproduced with permission.)

issue of the suspensory ligament is dissected to the right of the


eva

fwMt(t

ircso

FtB2

C

sophageal hiatus, taking care to identify and avoid the inferior phrenicein. This permits retraction of the left lobe to the patient’s right with andditional blade attached to a self-retaining retractor.The formal operation should commence with dissection of the omentum

rom the transverse colon (Fig 28). The avascular plane at the junctionith colon permits this to be achieved with scissors or the electrocautery.obilization of the hepatic and splenic flexures of the colon facilitates

his dissection laterally. We believe the use of the Harmonic Scalpel®

Ethicon, Endo Surgery, Inc., Cincinnati, OH) or similar devices enhanceshe speed and safety of this dissection.At this point, the lesser sac is widely opened permitting careful

nspection and assessment of extent of disease (Fig 29). The classic D2esection proceeds with dissection of the anterior leaf of the transverseolon and the peritoneal surface of the pancreas at the base of the lesserac. In our opinion, this maneuver adds nothing to the operation in terms

IG 29. Exposure of lesser sac. The short gastric and left gastroepiploic vessels are divided close tohe spleen using the Harmonic Scalpel®. (From Brennan MF. Total gastrectomy for carcinoma. Inaker RJ, Fischer JF, editors. Mastery of Surgery. Philadelphia: Lippincott Williams & Wilkins;001:997-1006. Reproduced with permission.)

f clearance of cancer or potential cure of the patient. This tissue


rai

rsatpsto

FacW

6

epresents a trivial peritoneal surface in terms of the peritoneal surfacerea at risk and does not significantly facilitate lymphadenectomy ofmportant nodal basins.The next maneuver should be the dissection and suture ligation of the

ight and left gastroepiploic arteries and veins. This adds mobility to thepecimen and facilitates duodenal transection and dissection of zone IInd III nodes. The duodenum is dissected circumferentially just distal tohe pylorus in proximal cancers and approximately 3 cm distal to theylorus in antral cancers. We typically divide the duodenum with atapler. The staple line is not routinely inverted. Dissection of the areolarissue and lymph nodes of the porta is commenced from above at the level

IG 30. The left gastric artery is suture ligated and divided at its origin. Exposure is usually bestchieved with cephalad retraction on the divided stomach. (From Brennan MF. Total gastrectomy forarcinoma. In Baker RJ, Fischer JF, editors. Mastery of Surgery. Philadelphia: Lippincott Williams &ilkins; 2001:997-1006. Reproduced with permission.)

f the bifurcation of the hepatic artery, reflecting the tissue toward the


malllcss

Ipe2grdvrdsab

e3acdmdstthp

mRdHc

C

idline. This dissection is thus taken along the hepatic artery to the celiacxis and the origin of the left gastric artery. The left gastric artery is sutureigated at its origin (Fig 30). Exposure may be best achieved from below,ifting the stomach anteriorly and cephalad, or from above, retracting theesser curve caudally and to the patient’s left. At this time, the greaterurve is dissected. The Harmonic Scalpel facilitates safe division of thehort gastric and left gastroepiploic arteries as close as possible to theplenic hilum (Fig 29).For reasons reviewed above, splenectomy is avoided if at all possible.

f subtotal gastrectomy is planned, 1 or 2 short gastric vessels should bereserved. The dissection on the lesser curve should be within 2 cm of thesophagogastric junction and include the nodal tissue of zone Ia (see Fig6). The stomach can be divided with a heavy wire 90-mm stapler. If totalastrectomy is planned, the greater curve dissection should includeemoval of all tissue to the level of diaphragm. Similarly, the lesser curveissection should include division of the hepatic branch of the anterioragal nerve as well as all tissue below the diaphragm to the level of theight crus. Since the vagus nerves tether the tissue cephalad, the proximalissection is facilitated by bilateral truncal vagotomy (Fig 31). Thishould be performed early in the proximal dissection. The vagus nervesre divided at the GE junction and dissected for 3 to 4 cm to divideranches to the distal esophagus and proximal stomach.To achieve 6-cm margins in patients with proximal tumors, we believe

xposure is frequently enhanced by a modified Dragstedt maneuver (Figs2 to 35). The central tendon of the diaphragm is carefully incised withknife. Blunt dissection permits grasping the divided edges with Allis

lamps, followed by further division. The original Dragstedt maneuver,escribed to facilitate exposure of the distal esophagus during vagoto-ies, involved a short transverse incision. A vertical incision of the

iaphragm to the hiatus is routinely added. The inferior phrenic vein isuture ligated. With this maneuver, the hiatus, inferior mediastinum, andhe distal 10 cm of the esophagus is exposed widely. After completion ofhe anastomosis, the diaphragmatic incision is closed with interruptedorizontal mattress sutures. In some cases, it may also be appropriate tolace tacking sutures between the Roux limb and the diaphragm.Lessons learned performing Roux-en-Y gastric bypass procedures inorbidly obese patients have facilitated the safety of construction of theoux limb. Standard texts describing Roux limb construction illustrateivision of the jejunum 8 to 12 cm distal to the ligament of Treitz.owever, the jejunal mesentery is short and the mesenteric vasculature is

omplex close to the ligament of Treitz. In virtually all patients, the


mmjstjj

FjtMp

6

esentery lengthens and the mesenteric vasculature simplifies approxi-ately 25 cm distal to the ligament of Treitz. We routinely divide the

ejunum at this point with a stapler. A single arcade vessel is divided anduture ligated and the Roux limb will then reach the mediastinum in aension-free fashion in all patients. A retrocolic Roux-en-Y esophago-ejunostomy is then performed. The length of the Roux limb to the

IG 31. The phreno-esophageal bundles and lymphatic tissue surrounding the esophagogastricunction are dissected caudally before division of the esophagus. Bilateral truncal vagotomy facilitateshis dissection. (From Brennan MF. Total gastrectomy for carcinoma. In Baker RJ, Fischer JF, editors.

astery of Surgery. Philadelphia: Lippincott Williams & Wilkins; 2001:997-1006. Reproduced withermission.)

ejuno-jejunostomy should be 45 to 50 cm to prevent bile reflux.


cchptgasrslRa

FraSA

C

There are many methods of reconstruction or restoration of intestinalontinuity, none of which have been proven superior. Randomized andohort studies have concluded that the safety and function of stapled andand-sewn jejuno-esophageal anastomoses are equivalent.163-166 Ourreference is to perform a hand-sewn anastomosis after subtotal gastrec-omy and a stapled Roux-en-Y esophageal anastomosis after totalastrectomy. An additional unresolved issue is the value of incorporatingjejunal pouch into the Roux-en-Y reconstruction. Small randomized

tudies have reported greater meal size and less weight loss in patientseconstructed with Hunt-Lawrence pouches compared with those recon-tructed with standard Roux-en-Y limbs.167-170 In these series, weightoss at 1 year was approximately 20% of preoperative weight in theoux-en-Y groups and approximately 12% in the Hunt-Lawrence groups,

IG 32. The central tendon of the diaphragm is exposed through an upper-midline incision withoutine excision of the xiphoid. The length of the transverse incision in the diaphragm (arrow)verages 10 cm. In most cases, the incision is “T’d” through the hiatus. (From Thirlby RC, KraemerJM, Hill LD. Transdiaphragmatic approach to the posterior mediastinum and thoracic esophagus.rch Surg 1993;128:897. Reproduced with permission.)

difference that reached statistical significance. However, the long-term


bw

pauPfp

esapawF

Fps

6

enefits of the pouch procedures are likely not clinically significant ande continue to perform a standard Roux-en-Y reconstruction.Subtotal Gastrectomy. As mentioned above, subtotal gastrectomy isossible in many patients with antral cancers. Bilateral truncal vagotomylso is routinely performed because a Roux-en-Y reconstruction islcerogenic. We prefer a hand-sewn anastomosis, using a double-armedrolene suture for the seromuscular layer. As mentioned below, we stillrequently place nasogastric tube during the procedure, which is left inlace for 1 to 3 days.Total Gastrectomy. Our preferred anastomotic technique is a stapled

nd-esophagus to side-Roux limb anastomosis using a 25-mm EEA™

tapler (USSC, Norwalk, CT). Alternatively, a single layer runningnastomosis using monofilament suture (polydioxanone or polypro-ylene) is acceptable. However, with the proximal progression of cancersnd resultant increased esophageal resections necessary in our practice,e feel more comfortable with a double-staple technique as illustrated in

IG 33. Intraoperative photograph shows incision in diaphragm (upper arrow, “Defect in Dia-hragm”) and esophageal hiatus (lower arrow, “Hiatus”). The bridge of diaphragm between thesetructures can be divided to improve exposure.

igs 36 to 39.171,172 In this technique, a heavy Prolene suture is attached


ttpcpiasmapdfioj

FeT1

C

o the anvil of the stapler before passing the anvil into the midesophagushrough a small gastrotomy. The esophagus is then stapled at least 6 cmroximal to palpable tumor with a 30-mm stapler. The esophagus isarefully divided taking care not to divide the Prolene tag sutures. Afterlacement of lateral stay sutures (needles left in place), the Prolene sutures then used to pull the anvil through the staple line. A standard EEAnastomosis is then constructed. The anastomosis is reinforced with the 2tay sutures. Using this technique, together with the modified Dragstedtaneuver described previously, we have been able consistently to

ccomplish total gastrectomies with clear margins in patients withroximal gastric cancers. To our knowledge, there are no well-controlledata showing lower leak rates of high risk anastomoses reinforced withbrin glue products. Regardless, we have increasingly been reinforcingur esophageal anastomoses with fibrin glue. We perform a stapled

IG 34. Using blunt dissection, the pericardium and heart are retracted cephalad, and the lowersophagus and posterior mediastinum are exposed. (From Thirlby RC, Kraemer SJM, Hill LD.ransdiaphragmatic approach to the posterior mediastinum and thoracic esophagus. Arch Surg993;128:89. Reproduced with permission.)

ejuno-jejunostomy with a 50-cm Roux limb.


Fam

6

IG 35. Anterior view of exposure of posterior mediastinum achieved via a transdiaphragmaticpproach. (From Thirlby RC, Kraemer SJM, Hill LD. Transdiaphragmatic approach to the posterior
ediastinum and thoracic esophagus. Arch Surg 1993;128:897. Reproduced with permission.)

F

aserK

FvDt

C

rozen SectionsWhat is the role of frozen section in operations for gastric cancer? There

re 2 issues. First, is an anastomosis with microscopic tumor in the wallafe? The answer, based on multiple studies is “yes.” Second, what is theffect of positive microscopic margins on overall survival? Based on aeview of 47 patients with positive margins in a series of 572 patients,

IG 36. Anvil, with spike and heavy polypropylene suture attached, are passed to the mid-esophagusia a proximal gastrotomy. (From Cebrian ET, Gimenez TR, Fernandez LF, Herroros AT, Sanchez EJ.ouble-stapling technique for mechanical circular oesophageojejunal anastomosis after total gastrec-

omy. Br J Surg 1994;81:408. Reproduced with permission.)

im and colleagues concluded that the significance of a positive micro-


smm5ocsai

Fst1

6

copic margin is dependent on the extent of disease.94 In patients withore than 5 positive lymph nodes, there was no relationship betweenargin status and survival. On the other hand, in patients with fewer thanpositive lymph nodes, survival was negatively affected by the presence

f a positive microscopic margin. The obvious practical problem with thisonclusion is that the operating team does not know the definitive nodaltatus at the time of resection. Others have also found that residual diseasefter surgery is an important negative factor for survival.173 Regardless,

IG 37. Esophagus is stapled with a 30 mm stapler taking care to place the suture centrally in thetaple line. (From Cebrian ET, Gimenez TR, Fernandez LF, Herroros AT, Sanchez EJ. Double-staplingechnique for mechanical circular oesophageojejunal anastomosis after total gastrectomy. Br J Surg994;81:408. Reproduced with permission.)

n patients in whom curative resections are being performed, we believe


feme

E

p

FGcw

C

rozen sections of margins should be obtained. Consistent with thexperience of others, we have found that “clearing” the distal (duodenal)argin is a more frequent and difficult problem than clearing the

sophageal margin.156

xtended Resections for T4 DiseaseAggressive surgery with multiorgan resections is frequently indicated in

IG 38. The esophagus is divided, leaving the polypropylene suture intact. (From Cebrian ET,imenez TR, Fernandez LF, Herroros AT, Sanchez EJ. Double-stapling technique for mechanical

ircular oesophageojejunal anastomosis after total gastrectomy. Br J Surg 1994;81:408. Reproducedith permission)

atients with T4 gastric cancers. Several studies have reported long-term


FdDt

6

IG 39. Stay sutures are placed laterally. The anvil with spike is pulled through the staple line andocked to the stapler. (From Cebrian ET, Gimenez TR, Fernandez LF, Herroros AT, Sanchez EJ.ouble-stapling technique for mechanical circular oesophageojejunal anastomosis after total gastrec-

omy. Br J Surg 1994;81:408. Reproduced with permission.)


spsssJTlaougItCoplR

N

HrepIwidst

F

Caapem

C

urvival in this subset of patients that is equivalent to that in T3atients.174-176 In patients with clear margins (RO resections), 5-yearurvival rates of 37% have been reported.175,176 However, recent studiesuggest that 5-year survival rates may be as low as 16% with medianurvival times of only approximately 1 year.177 In this recent series fromapan, 5-year survival rates in patients who had noncurative resections of4 tumors were only 10% and median survival time was only 8 months,

eading the authors to conclude that noncurative resections should bevoided in patients with T4 gastric cancers. The assessment of adjacentrgan invasion by preoperative CT or intraoperative assessment isnreliable. In 1 series of 21 patients undergoing multiorgan resections forastric cancers, only 8 (38%) had pathologically confirmed T4 disease.178

n other words, preoperative staging and intraoperative assessment tendso suggest adjacent organ invasion when it does not exist. PreoperativeT is inaccurate in assessing T4 lesions, with a positive predictive valuef only 50%. Regardless, aggressive multiorgan resections can beerformed with little increased morbidity with the expectation thatong-term survival is possible in approximately one third of patients withO resections.

aso-Jejunal TubesPlacement of a naso-jejunal tube after total gastrectomy is routine.owever, there are few if any data to support this practice.179 In fact, a

ecently published randomized trial suggests that this practice is unnec-ssary, with equivalent leak rates in patients with or without tubes.180 Therotocol used by the surgeons in this trial included NPO status for 7 days.n the few patients who developed leaks in the “no tube” group, tubesere placed with fluoroscopic guidance. Virtually all patients with leaks

n both groups were managed conservatively with bowel rest andrainage. Only 1 patient actually required operation. On the basis of thistudy, we do not believe that routine naso-jejunal tube placement afterotal gastrectomy is necessary.

eeding JejunostomyThe role of enteral feeding after total gastrectomy is controversial.onflicting studies have concluded that routine enteric feedings (throughfeeding jejunostomy placed in the operating room) are and are not

ssociated with better outcomes. Ferlay and colleagues1 randomized 195atients undergoing major upper gastrointestinal cancer operations tonteral feeding via jejunostomy tubes or control. Complications and
edian length of hospital stay were not significantly different between the

2emcbtnwtipdeosgj

upwrIrIt

C

gtselltlgc

r

6

groups. Another similar randomized study of patients undergoingsophagectomy or pancreatoduodenectomy reported impaired respiratoryechanics and decreased mobility in the enteral feeding group and

oncluded that routine immediate postoperative tube feeding should note used in a routine fashion.181 On the other hand, several studies supporthe safety and efficacy of routine immediate postoperative enteralutrition after major upper gastrointestinal surgery for cancer. Protocolsith slow progression of volume have been shown to be safe and well

olerated.182 Randomized studies suggest that the hospital length of stays shorter in those managed with enteral nutrition.183 Furthermore,rospective randomized studies suggest that complications and cost areecreased.184 Finally, a meta-analysis of randomized controlled trials ofnteral nutrition in patients undergoing upper gastrointestinal cancerperations demonstrated a lower risk of infectious complications and ahorter overall hospital length of stay in treatment arms.185 NCCNuidelines concluded that the surgeon should “consider placing a feedingejunostomy tube.”Our practice has been to place feeding catheters in most patientsndergoing total gastrectomy and begin feeding at a slow rate on the firstostoperative day. The motility of the Roux limb is poor for severaleeks, and we believe that hospital stay is shortened and short-term

ecovery is enhanced in a majority of patients treated with this protocol.n addition, the majority of patients are now receiving adjuvant chemo-adiotherapy that further impairs functional status for weeks after surgery.n some of these patients, nutritional and functional status during adjuvantreatment can be better maintained with supplemental tube feedings.

holecystectomyAt least 30% of patients who undergo total gastrectomy will developallstones within 1 to 2 years.186 Gallbladder contraction is impaired dueo both decreased vagal tone and to decreased cholecystokinin (CCK)ecretion (CCK-stimulated gallbladder contraction is triggered by nutri-nts in the duodenum). Weight loss also is associated with increasedithogenicity of bile. Total gastrectomy (vs. subtotal) and hepatoduodenalymph node dissection are independent predictors of gallbladder forma-ion. Presumably, excision of the lymphatics of the hepatoduodenaligament results in disruption of essential neural pathways related toallbladder function. Therefore, there may be a role for prophylacticholecystectomy as part of most operations for gastric cancer.Is there a downside to performing cholecystectomy? First, although the

isk of cholelithiasis is high, the risk of symptoms may be low, at less than


1peprdettts

D

dadigbd

P

phfomp

aipa4tn

t

C

% in 1 series. Cholecystectomy has also been linked to increased risk forostgastrectomy syndromes in patients undergoing gastric resections,specially bile reflux and diarrhea. Since virtually all gastric canceratients are reconstructed with Roux-en-Y anatomy, the risk for bileeflux is nil. However, cholecystectomy could increase the risk ofiarrhea and aggravate the symptoms of dumping syndrome. In ourxperience, significant dumping syndrome is unusual after total gastrec-omy for cancer. In summary, a strong case for prophylactic cholecys-ectomy during gastrectomy for cancer cannot be made. However, weend to perform cholecystectomy in young patients and in those with earlytage tumors in whom prolonged survival is anticipated.

rainsProphylactic drain placement during total gastrectomy (near the duo-enal stump and/or the esophageal anastomosis) is common. We are notware of any studies justifying this practice and do not routinely placerains during operations for gastric cancer. A recently published random-zed study found no difference in outcomes in drained and “no drain”roups and concluded that prophylactic drain placement does not add anyenefit in patients undergoing gastrectomy with extended lymph nodeissection.187

ostoperative ManagementThere is little good evidence regarding the optimal postoperative care ofatients undergoing gastric resection. Traditionally, naso-jejunal tubesave been used for 3 to 7 days and oral alimentation has been postponedor 5 to 7 days. Increasingly, perhaps based on successful “fast-tracking”f other patient groups undergoing major gastrointestinal operations,ore aggressive progression of diet is being incorporated safely into

ostoperative care. Our program is outlined below.Postoperative Analgesia. We routinely use patient-controlled epidural

nalgesia for 48 to 72 hours. This practice is associated with shorterntensive care unit (ICU) stay, fewer complications (eg, DVT), decreasedostoperative ileus, and probably shortened length of hospital stay. Inddition, we believe routine use of ketorolac (unless contraindicated) for8 to 72 hours followed by scheduled oral ibuprofen for the duration ofhe hospital stay improves postoperative pain management, decreasesarcotic requirements, and improves patient satisfaction.Diagnostic Studies. In total gastrectomy patients, our practice continues

o include a diagnostic radiographic study to rule out anastomotic leak on


tc

iriopirdp3aodt

P

ocO3ci(soam

Krflis

pur

6

he third postoperative day. If this study is normal, oral intake isommenced immediately.Alimentation. In patients in whom jejunal feeding catheters were placed

ntraoperatively, we begin infusion of full-strength tube feedings at a slowate (eg, 30 mL/hr) on the first postoperative day. Infusion rates are notncreased aggressively, with the intent to achieve “goal” rates by the thirdr fourth postoperative day. Oral intake is commenced on the thirdostoperative day with frequent low volume liquids. We use a standard-zed protocol of 30 mL every 10 to 15 minutes. At discharge, volumes areestricted to 4 ounces at a time and liquids are maintained for 10 to 14ays. Our goal is hospital discharge in 5 to 7 days. To achieve this, manyatients require supplemental (nocturnal) tube feedings at home for 2 toweeks. The diet is progressed to a soft or pureed diet at 10 to 14 days

nd then advanced as tolerated to regular food over the next month. In ourpinion, the feeding catheter should be left in place until the patientemonstrates adequate alimentation through the initial stages of adjuvantreatment.

ostoperative Complications and OutcomesA large review of surgical series published in 1989 reported an averageperative mortality rate of 22% in patients undergoing gastrectomy forancer.188 Similarly, the Assessment of Stomach and Esophageal Cancerutcomes from Treatment (ASCOT) database, representing patients from2 hospitals in England and Wales, demonstrated a postoperative surgicalomplication rate of 18.3% and medical complication rate of 32.4%. Then-hospital mortality rate was 10.3% (61 patients). Anastomotic leaks3.2%) or intra-abdominal abscesses (3.1%) were the most commonurgical complications, with 10.2% of these patients requiring a secondperation.189 However, advancements in anesthesia, surgical technique,nd perioperative care have decreased the overall 30-day morbidity andortality rates of surgery for gastric cancer.In a recent retrospective case series at Seoul National University inorea, the overall morbidity and mortality rates were 17% and 0.6%,

espectively.190 The most common complications were intra-abdominaluid collections (4.5%) and wound infections (3.7%). Morbidity was

ncreased in older patients who underwent multiorgan resections (eg,plenectomy; pancreatectomy and splenectomy).190

Another large series of 700 gastric cancer patients reported thatostoperative deaths occurred in 5.7%40 of patients.191 For patients whonderwent operations for recurrent gastric cancer or cancer in the gastric
emnant, reoperation rates were 30%. Complications were also common

arurwTajt

pmRrjochnmrpadf

dasctim

hooreap

C

fter palliative procedures. Surgical reintervention for complications wasequired in 20% of palliative total gastrectomies and 16.7% of thosendergoing palliative subtotal gastrectomies.191 The leading cause forelaparotomy was anastomotic leak. The most common site of leakageas the esophago-jejunostomy. The National Cancer Center Hospital inokyo and the Dutch Gastric Cancer Trial have reported leak rates of 7%nd 8%, respectively. A major risk factor for leakage of an esophago-ejunostomy is an intrathoracic anastomosis. More recent reports suggesthat leak rates should be as low as 1%.192

Most anastomotic leaks manifest early (eg, third postoperative day) aseritonitis or with abnormal drain output. On the other hand, many leaksanifest later (eg, 7 to 9 days) with intra-abdominal abscesses.191

eoperation or percutaneous drainage can be used to control leaks. Largeeviews suggest that outcomes in patients with leaks at the esophago-ejunostomy are better if they are managed with conservative percutane-us drainage (vs. surgical intervention). However, these data do notontrol for the severity of disease and no randomized controlled studiesave examined this issue.193 Regardless, wide drainage, either percuta-eous or surgical, is the cornerstone of treatment. Many leaks can beanaged with percutaneous techniques, avoiding reoperation. Operative

epair of an esophago-jejunostomy is a challenge, with poor tissuesreventing effective suture placement at the anastomosis. In the setting ofn intrathoracic anastomosis, cervical esophagostomy in addition to widerainage permits diversion of oropharyngeal secretions and preventsurther contamination of the pleural space.Successful management of anastomotic leakage with percutaneousrains requires expertise in the percutaneous techniques usually onlyvailable to interventional radiologists. Sequential exchange or “up-izing” of the drainage tubes should be guided by drain output and fluidollections determined by serial CT. Additional percutaneous drainageubes should be considered if drainage is not adequate. “Tube checks,” thenjection of contrast into the drainage tube, is an inexpensive method ofonitoring and characterizing abscesses and adjusting drain position.192

Novel stenting techniques for managing esophago-jejunostomy leaksave been reported in recent years.194,195 Self-expanding covered plasticr metal stents can be placed endoscopically to seal a leak that is less thanne third of the anastomosis circumference. Langer and colleagueseported successful stenting of 89% of patients who presented withsophageal anastomotic leakage.194 Unfortunately, stenting techniquesre particularly challenging with a Roux-en-Y anastomosis, requiring
lacement of the guide wire at least 15 cm past the leak. In addition, this

icope

utetw

N

P

sobpstcuTg

piemdo

twphWjp

6

nvasive technique can also result in further injury and complete dehis-ence of the anastomosis. In the Langer series, enlargement of the leakccurred in 8%2 of patients. Reintervention is also common with stentingrocedures. Most commonly, the stent is dislodged or migrates, requiringndoscopic removal or adjustment.Endoscopic and interventional techniques continue to evolve and willndoubtedly have a role in the management of postoperative complica-ions of gastric cancer. Although no current randomized controlled trialsxist to show a significant outcome improvement with stenting, thisechnique is very appealing and is being adopted in hospitals world-ide.194

utritional Complications

athophysiologyVirtually all patients who undergo operation for gastric cancer have

ignificant gastrointestinal side effects. It is imperative that surgeons notnly understand the pathophysiology of the sequelae of gastric surgery,ut also take active measures in directing the postoperative care of theiratients. Although many patients do not have major postgastrectomyymptoms, all patients have nutritional sequelae and most have symptomshat affect their quality of life. All too frequently, the physicians assumingare of these patients (eg, medical oncologists, internists) have littlenderstanding of the many important complications of gastrectomy.herefore, it is imperative that surgeons understand these outcomes anduide the nutritional education and care of their patients.The side effects of gastric surgery can be divided into 2 categories:ostcibal symptoms and nutritional deficiencies. Postcibal symptomsnclude anorexia or decreased hunger in the fasted state, early satiety, andarly and/or late dumping syndrome. Nutritional deficiencies includealdigestion of polymeric foods with malabsorption of calories, iron

eficiency, and osteomalacia. This review will focus on the pathophysi-logy of the postgastrectomy state and provide insight into its treatment.Why do patients lose weight after gastrectomy and how much weight do

hey lose? Clearly, restriction of meal size is the key factor in determiningeight loss after gastrectomy. Meal size is probably less restricted inatients with a gastric remnant. Hence, weight loss is less in patients whoave subtotal gastrectomy than in those undergoing total gastrectomy.eight loss may be less in total gastrectomy patients reconstructed with

ejunal pouches. In addition, caloric consumption is decreased in many
atients because of postcibal symptoms related to the dumping syndrome

acf

aapitmtgtutttdp

ppsdrrarlmibp

MATisrt

C

nd malabsorption. Dumping syndrome results in avoidance of refinedarbohydrates. Some patients avoid fatty foods because malabsorption ofats causes postprandial gas, bloating, and diarrhea.Total gastrectomy also affects hunger. The pathophysiology of hunger

nd satiety is very complex. Scores of gastrointestinal and neural peptidesffecting satiety have been linked to the control of body weight and/or theathophysiology of human fatness.196,197 More recently, peptides affect-ng hunger have been identified. For example, ghrelin is a gastric peptidehat significantly affects hunger and initiation of meals.198 Empirically,

ost gastrectomy patients (and most gastric bypass patients) claim thathey rarely get hungry. It is very likely that most, if not all, totalastrectomy patients have a physiologic impairment of the signals thatrigger hunger and/or initiation of meals. In our opinion, this factor is annderappreciated side effect of gastrectomy. It should be reviewed duringhe nutritional counseling of all patients. Patients should understand thathey will not experience normal hunger and that they should avoid theendency to skip meals. In summary, the net effect of these factors isecreased calorie consumption and weight loss in most total gastrectomyatients in the range of approximately 10% over the first year.Several studies have reported that weight loss is less in total gastrectomyatients reconstructed with jejunal pouches.199 Nozoe and colleagues com-ared nutritional outcomes in 16 gastric cancer patients reconstructed withimple Roux-en-Y to 14 patients with jejunal pouches.169 Body weightecreased 20% and 12% at 1 year in the simple and pouch patients,espectively. Another small randomized study (n � 10 in each group)eported that body weights 2 years after operation were approximately 85%nd 90% of preoperative weights in simple and pouch Roux-en-Y patients,espectively. However, most reports from North America suggest that weightoss at 1 year in gastric cancer patients after curative resections is approxi-ately 10% of preoperative weight and actually results in an end weight that

s near ideal body weight. Others have reported insignificant differences inody composition among different operative types.200 We continue toerform simple Roux-en-Y reconstructions in virtually all patients.Steatorrhea follows all gastric operations for gastric cancer.201-203

any patients also demonstrate abnormal absorption of carbohydrates.bsorption of nitrogen is within normal ranges in virtually all patients.202

he cause of malabsorption is complex but is largely due to derangementsn “digestive balance.”202 This refers to the ratios between nutritionalubstrates and digestive enzymes. Pancreatic enzyme secretion occurs inesponse to cephalic vagal stimulation and reflexes triggered by food in
he gastric antrum and the duodenum. Not surprisingly, there is marked

iF“jwWta

rcgijc

athplmscllsgpHaAgu

T

mnP

6

mpairment of pancreatic enzyme secretion after total gastrectomy.201

urthermore, the mixing of substrates and enzymes is disturbed by theasynchrony” of the food bolus and pancreatic enzymes entering theejunum. Finally, many of the digestive enzymes can only attackater-insoluble, polymeric foods when they have been broken down.henever there is defective gastric sieving, digestion is impaired. That is,

he lack of gastric grinding or trituration of solid foods probably impairsbsorption.202

Intrinsic factor secretion from the parietal cells is eliminated byesection of the proximal stomach. Vitamin B12 deficiency with perni-ious anemia thus follows total gastrectomy in 2 to 7 years after totalastrectomy if the vitamin is not administered parenterally. Folate andron are absorbed most effectively from the duodenum and proximalejunum. Hence, iron and folate deficiency is also common in gastricancer patients.Bone disease with loss of bone mineral content and osteomalcia occurs

fter total gastrectomy and becomes clinically significant withime.202,204-207 Postgastrectomy patients studied years postoperativelyave abnormal bone biopsies, elevated serum alkaline phosphatase andarathyroid hormone levels, and decreased serum 25-hydroxy vitamin Devels.208 Pathologic fractures have been reported to occur in approxi-

ately 10% of patients with long-term follow-up after peptic ulcerurgery.202 The severity of decreased bone density has been reported toorrelate with weight loss but not serum alkaline phosphatase or calciumevels.204 Bone density has been correlated with vitamin 1,23-(OH)2–Devels, but several studies have reported that there are no highly sensitiveerum markers for the development of osteomalacia after gastric sur-ery.202 The assumption is that decreased bone density is related to thereviously discussed malabsorption of fats and fat-soluble vitamins.owever, there is no consistent relationship between the presence or

bsence of bone disease and steatorrhea in postgastrectomy patients.202

bsorption of calcium has been shown to be normal in most patients withastric resections. In summary, the cause of postoperative osteomalacia isnknown.202

reatmentWeight Loss. In our experience, weight loss is not a major problem inost patients. Nutritional counseling and encouragement counteracts the

egative effects of early satiety, depressed hunger, and food avoidances.
atients are advised to eat multiple small meals regardless of hunger and

tc

Bsf1

aaitonpStnfsvtwspip

S

G

mbgtrdpn

C

o modify dietary composition to minimize symptoms of dumping orarbohydrate, lactose, or fat malabsorption.Iron, Folate, and Vitamin B12. Deficiencies of iron, folate, and vitamin

12 are preventable with proper supplementation. Iron replacementhould probably be administered as solutions or chewable formulations oferrous salts, not large tablets. Vitamin B12 supplementation should be000 micrograms monthly administered by intramuscular injection.202

Osteomalacia and Malabsorption of Polymeric Foods. Treatmentnd/or prevention of osteomalacia and malabsorption of polymeric foodsfter gastrectomy are problematic. We believe the standard of carencludes supplemental calcium and vitamin D in postgastrectomy pa-ients.204 Tablets of calcium carbonate should be pulverized by chewingr be administered as solution. However, we would emphasize that we areot aware of any studies that have demonstrated convincingly that thisrogram will decrease the likelihood of developing bone disease.202,206

imilarly, malabsorption of polymeric foods is multifactorial and noreatment has been proven to be effective. For example, there is little oro evidence that supplemental exogenous pancreatic enzymes affect fecalat excretion or symptoms of fat malabsorption after gastrectomy.202 Aingle study reported that the bisphosphonate alendronate improvesitamin D-resistant osteopenia in postgastrectomy gastric cancer pa-ients.209 Thirteen patients with progressive osteopenia despite treatmentith vitamin D were studied after initiation of alendronate. Statistically

ignificant improvements in parameters such as bone mineral density andarathyroid hormone levels were reported. If these findings are confirmedn larger studies, alendronate may become routine in postgastrectomyatients.

pecial Considerations

astric Stump CancerGastric stump cancer is defined as a gastric carcinoma occurring 5 orore years after gastric surgery for benign disease.210 The association

etween surgery for peptic ulcer and the subsequent development ofastric cancer has been noted for decades. Original reports suggested thathe incidence was highest after partial gastrectomy with Billroth IIeconstruction.211 However, more recent studies suggest that the inci-ence is similar in patients undergoing Billroth I reconstruction oryloroplasty. Cases of gastric cancer after proximal gastric vagotomy areow being reported.210

A causal relationship between the surgical procedure and the eventual


ccoccbscpttg

hsadfta

otCiaBflrhgil0pd

d“r

6

ancer was supported by well-controlled animal experiments that con-luded that the combination of pancreaticobiliary reflux produced byperations for peptic ulcer and decreased gastric acid secretion wasarcinogenic.210,212 N-Nitroso compounds are recognized as importantarcinogens and the relationship between bile reflux and gastric cancerecomes more relevant in this patient population. The hypochlorhydrictomach with high pH promotes bacterial overgrowth, which thenonverts dietary nitrates and nitrites to carcinogenic N-nitroso com-ounds. Furthermore, bile acids degrade gastric mucous, facilitatingransmucosal flow of large intraluminal molecules and causing atrophy ofhe mucosal cells. Bacterial deconjugation of refluxed bile acids may alsoenerate cocarcinogens.Several human cohort studies, comparing populations of patients whoad undergone surgery for peptic ulcer to a population of age- andex-matched persons who had not undergone operations for peptic ulcer,lso suggest a causal relationship between operations and the subsequentevelopment of gastric cancer.211,213,214 Risk factors for cancer includedemale gender, Billroth II reconstruction, and age at time of opera-ions.210,211,214 In most studies, the risk becomes statistically significantfter 15 to 20 years and increases with longer follow-up.211

Is the risk for gastric cancer increased in patients who have hadperations for peptic ulcer? Several series from Europe have concludedhat the answer is “yes.”211,213-215 For example, data from the Swedishancer Registry show that the average adjusted risk for gastric cancer

ncreased 28% for each successive 5-year interval after operation.211 Thedjusted risk was greater in women and in those who had undergoneillroth II operations for gastric ulcer. The relative risk in those followed

or more than 30 years was approximately 3-fold. On the other hand, 2arge cohort studies have concluded that there is not an increasedisk.178,216 A study of 338 residents of Olmsted County, Minnesota, whoad operation for peptic ulcer between 1935 and 1959 found only 2astric cancers: a relative risk of 0.8 (95% CI, 0.1-2.7).217 Thesenvestigators concluded that there was not an association. Similarly, aarger cohort study from North Carolina calculated a relative risk of.7.178 Regardless, we believe the bulk of the literature supports theositive association between surgery for peptic ulcer and the subsequentevelopment of gastric cancer.Is there a causal relationship between operations for peptic ulcer and theevelopment of cancer? We believe the answer to this question isprobably not.” The flaw in all human cohort studies suggesting a causal
elationship is that the control groups did not have peptic ulcer disease. In

tohscftIsgaspybd

sutOracddcmrrsiw(mtsgdm“

C

hese studies, patients with peptic ulcers severe enough to warrantperation were compared with a population of individuals who did notave operations for peptic ulcer.218 These studies antedated the under-tanding of the relationship between H. pylori, peptic ulcer, and gastricancer. Most studies now suggest that the relationship between surgeryor peptic ulcer and cancer is probably due to the presence of H. pylori inhe stomach of the operated cohort.219 For example, data from thenpatient Registry of the Swedish National Board of Health and Welfareuggest that there is an increased risk for stomach cancer in patients withastric ulcers and that there are likely etiologic factors in common (eg,trophic gastritis induced by H. pylori).219 In conclusion, recent studiesuggest that although the risk of gastric cancer is likely increased inatients who have had operations for peptic ulcer more than 15 to 20ears ago, there is probably not a clinically significant causal relationshipetween the physiologic changes produced by the operation and theevelopment of gastric cancer.What is the clinical significance of gastric stump cancer? The role of

creening for gastric cancer in patients who have had operations for pepticlcer in the remote past is controversial.220,221 There is good evidencehat there is a “dysplasia-cancer” sequence in these patients.222,223

fferhaus and colleagues from the University of Leiden, Netherlands,eported long-term follow-up of 504 asymptomatic patients 15 to 46 yearsfter partial gastrectomy.224 At first endoscopy, there were 7 malignan-ies identified, mild dysplasia was found in 58 patients, and severeysplasia was identified in none. Follow-up biopsies identified severeysplasia in 6 patients, 3 of whom eventually were diagnosed withancers. Of 34 patients with severe atrophy on random stomal biopsies, 2anifested early stump cancer during follow-up.224 Similarly, another

eport that reviewed the results of a screening program in 354 gastricemnant patients concluded that patients with moderate or severe dyspla-ia required close follow-up.225 These investigators identified 22 patientsn their screening program with moderate dysplasia; 3 were diagnosedith stump cancers at 2, 2, and 6 years after the first endoscopy. Seven

41%) of 17 patients with severe dysplasia had stump cancers within aedian time of 2 years. These authors recommended close surveillance in

hese patients.225 In the United States, Greene and colleagues reportedimilar results in a screening program in 163 patients who had previousastric resections for peptic ulcer.221 Of the 15 patients with severeysplasia, 9 (60%) had associated microscopic cancers. Four additionalacroscopic cancers were identified. All 13 patients were reportedly

asymptomatic.” Greene has concluded that “patients who are at least 20


yaisrtpcmabnspscrWeo

ccsccVaimp3odgptraid

6

ears postpartial gastrectomy for benign disease should be considered fornnual endoscopic surveillance.”226 However, well-conducted hypothet-cal cohort studies in the United States have appropriately concluded thatcreening in American patients is probably not justified.227 Given theelatively low risk of gastric cancer in postpartial gastrectomy patients inhe United States, any benefit of endoscopic screening becomes nil if theostoperative 5-year survival rate of patients treated for gastric stumpancers falls below 80%.227 Since the majority of cancers detected inost “screening” programs are at the index procedure and are frequently

dvanced, this 80% survival cutoff seems unlikely to be achieved. Weelieve, therefore, that wholesale screening of asymptomatic patients isot justified. On the other hand, endoscopy with random biopsies of thetomach (and especially peristomal gastric mucosa) is indicated in anyatient with a history of surgery for peptic ulcer who has a change inymptoms related to his/her upper gastrointestinal tract. An interestingoncept, which has not, to our knowledge, been addressed adequately,elates to the concept of H. Pylori eradication in this patient population.

e would propose evaluation of H. Pylori cytologies and H. Pyloriradication in all H. Pylori-positive patients with a remote history of anperation for peptic ulcer.What are the surgical implications in patients with gastric stump

ancers? Stage for stage, patients with the diagnosis of gastric stumpancers should be evaluated and undergo surgical resection using theame principles as those used for patients with primary gastric can-ers.227-230 However, for reasons elucidated below, diagnostic laparos-opy may not be warranted. The largest surgical series was reported byiste and colleagues from the University of Bergen, Oslo, Norway.231 Inseries of 819 patients, the median age was 69 years and the median

nterval from index operation to cancer diagnosis was 29 years. Theajority of patients had a short duration of symptoms. Twenty-one

ercent of patients had localized disease, 25% had regional disease, and9% had metastatic disease; resectability rate was only 41% and theverall 5-year survival rate was only 10%. In patients with localizedisease, the 5-year survival rate was approximately 40%. These investi-ators concluded that the apparent poor prognosis relative to patients withrimary gastric cancers was due to differences in patient characteris-ics.231 On the other hand, a large series from Japan suggests that theesectability rate in gastric stump cancer patients is approximately 90%,nd that 5-year survival rates in all patients approaches 40%. Annteresting study from Japan also suggests that there are clinicopathologic
ifferences between gastric stump cancers and primary gastric cancers.232

Wctdg0ow

ed

E

(dmaScG

bcu1NUoahpEtd

nEhFm

C

hereas the 5-year survival rates were similar (52% in gastric stumpancers and 62% in primary cancers), there was a distinct difference inerms of patterns of recurrence. The gastric stump cancer patients did notevelop peritoneal metastases. The percentages of peritoneal and hemato-enic (eg, liver) metastases were 41% and 31% in primary cancers and% and 83% in stump cancers, respectively.232 The practical implicationf this finding is that diagnostic laparoscopy would seem not to bearranted in this patient group.Finally, as operations for peptic ulcer become uncommon, the clinical

ntity of gastric stump cancer likely will become rare over the next 2ecades.209

arly Gastric CancerIn 1962, the Japanese Endoscopy Society described early gastric cancer

EGC) as gastric cancer limited to the mucosa and submucosa indepen-ent of lymph node metastasis.71,233 Early gastric cancer has several grossanifestations and EGC historically has been managed differently than

dvanced gastric cancer. In the early 1970s, the Japanese Endoscopicociety outlined a macroscopic classification system for EGC. Thislassification system was adopted by the Japanese Research Society forastric Cancer71 (Fig 3).Like other forms of gastric cancer, the incidence and presentation variesetween countries. In Japan, EGC comprises 40% to 50% of gastricancers at time of presentation. In the United States and Europe, EGC isncommon. Only 28 (18%) of 213 gastric cancers resected from 1970 to979 at Columbia-Presbyterian Hospital in New York were EGC.234 TheCDB data suggest that only approximately 10% of gastric cancers in thenited States are EGC. In a French study over 25 years, 102 (15%) casesf EGC were identified (mean age of 60).235 Early gastric cancer isssociated with peptic ulcer disease.234 Twenty-five percent of patientsave been diagnosed with peptic ulcer disease, Barrett’s esophagus, orernicious anemia before being diagnosed with EGC.236 The majority ofGC manifests as epigastric pain, less frequently as dyspepsia, and more

han 50% of patients have seen a physician within 2 months of theiriagnosis.EGC is typically located at the gastric antrum along the lesser curveear the angularis.14 In Japan, lymph nodes are positive in 10% ofGC. Large series have suggested that lymph node metastasis does notave significant impact on survival of patients with EGC.234 In arench study, lymph node metastases were more frequent (18%) but
ore than one half of the tumors were 2 to 5 cm in size.235 The depth

odi

cccHU6

mbt(ottsT

S

lpbpnstpsrpl

fwicn

6

f invasion also correlates with lymph node metastasis. More recentata suggest that size, depth, and lymph node metastasis directlympact survival.236

In Japan, the 5-year survival rate for patients with EGC is 85%.237 Aohort of EGC patients at Memorial Sloan-Kettering Cancer Centeronfirmed these excellent outcomes in the United States.236 A Germanohort of 130 patients had an overall 10-year survival rate of 91%.238

owever, most other reports have found worse outcomes. In a Columbianiversity study, the 5-year survival rate for patients with EGC was only8%, with 29% having positive lymph nodes.234

EGC can be managed with minimally invasive techniques. Endoscopicucosal resection (EMR) is used widely in Japan. This approach is

ecoming more common in the United States as surgeons and gastroen-erologists become more familiar with the technique. EMR is indicated in1) mucosal tumors; (2) type I, IIa, and IIc EGC without evidence of ulcerr scar; (3) well or moderately differentiated EGC; and (4) tumors smallerhan 2 cm.239 EMR is contraindicated in large, poorly differentiatedumors that invade the submucosa. In our opinion, other treatment optionsuch as local injection with 5-fluorouracil and endoscopic neodymium-AG laser ablation are not appropriate.240,241

entinel Lymph Node BiopsyAlthough several case series and reports describe the use of sentinel

ymph node biopsy in gastric cancer, its role is still being defined. Mostublished reports demonstrate the feasibility of sentinel lymph nodeiopsy in gastric cancer. Japanese studies suggest that the majority ofatients have predictable metastasis with easy detection of sentinel lymphodes. The frequency of false-negative sentinel lymph node evaluation, orkip metastasis, is controversial. A large study from Japan reported thathe sentinel lymph node is not in the first level nodes in 5% of theatients.242 With this potential skip in lymphatic metastasis, negativeentinel lymph nodes and a failure to complete a lymphadenectomy mayesult in undertreatment. On the other hand, a German case series of 135atients demonstrated no “skip nodes” in their application of sentinelymph node biopsy.With preliminary data suggesting sentinel lymph node biopsy is

easible, how can it be applied? Ideally, it should be applied to patientsith T1N0M0 (stage 1) tumors who plan to undergo minimally

nvasive procedures. No randomized controlled trials have beenonducted. An observational study with short-term follow-up showed
o adverse outcomes with local gastric resection and sentinel lymph

nfottg

M

dpTodlddsa

carrgsdfathtgm

P

cwsN

C

ode biopsy for EGC.243 In this study, indocyamine green was used toacilitate sentinel lymph node biopsy. We look forward to the resultsf randomized trials to help us understand the role of this novelechnique. For now, sentinel lymph node biopsy should be limited torials and management of gastric cancers should follow the standarduidelines outlined previously.

inimally Invasive TechniquesA Japanese surgeon, Kitano, reported the first laparoscopic-assistedistal gastrectomy (LADG) in 1991.244 Between 1991 and 2001, 4552atients underwent laparoscopic surgery for stomach cancer in Japan.244

he use of laparoscopy in gastric cancer is more common in Japan andther Asian countries compared with Western countries. The proceduresescribed include the following: laparoscopic local resection withoutymph node dissection, laparoscopic gastrectomy with lymph nodeissection, and laparoscopic gastrectomy with extensive lymph nodeissection.244 The role of minimally invasive approaches to early and latetage gastric cancer is not well established despite numerous case reportsnd case-control studies.Patients with EGC who are not eligible for EMR are likely the best

andidates for laparoscopic local resection. Laparoscopic wedge resectionnd intragastric mucosal resection are the 2 techniques described toemove early gastric cancers. It has been estimated that 1428 local wedgeesections were completed between 1991 and 2001.244 Laparoscopicastrectomy has been accomplished using totally laparoscopic, laparo-copic-assisted, or hand-assisted techniques.244 Laparoscopic-assistedistal gastrectomy is the most common procedure. Short-term outcomesrom randomized controlled trials examining open versus laparoscopic-ssisted gastrectomy suggest similar complication rates and operativeimes.244 The reported benefits of laparoscopic techniques are shorterospital stay, fewer complications, and fewer days off work. From 1992o 1996, a case series of 59 patients randomized to laparoscopic distalastric resections or open techniques showed similar morbidity andortality rates.245 Long-term outcomes have not been reported.

alliative SurgeryFew indications exist for palliative surgery in patients with gastric

ancer. The intent of palliative surgery is to relieve pain and sufferingithout increasing a patient’s morbidity or mortality. Palliative

urgery should relieve pain, obstructive symptoms, or hemorrhage.246

umerous palliative procedures have been reported and include


gtGnrehlc

srpuuupbnwnr

tmhpost

tmlnw

cpsa

6

astroenterostomy (enteric bypass), partial gastrectomy, total gastrec-omy, esophagogastrectomy, gastrostomy, jejunostomy, and stenting.astric resection, endoscopic techniques (laser argon ablation, epi-ephrine injection) and arterial embolization can be used to treat acuteefractory hemorrhage. No controlled trials have investigated the mostffective approach to palliate gastric cancer. Selection bias andeterogeneity of the patient population makes interpretation of pub-ished studies difficult. What is clear is that palliative gastric surgeryarries high morbidity and mortality rates.247

Is there a role for palliative resection? Several studies suggest a smallurvival benefit with noncurative resections.248,249 In a retrospectiveeview of gastric cancer patients from 1941 to 1987 at MD Anderson,alliative total gastrectomy was performed in 45 of 219 patients sched-led to undergo total gastrectomy.250 Another 21 of the 219 patientsnderwent only exploratory laparotomy or bypass procedure. Patientsndergoing palliative total gastrectomies had improved survival com-ared with the group undergoing exploratory laparotomy with or withoutypass (10.4 months vs. 3.4 months). Clearly, these groups of patients areot matched with respect to extent of disease. The degree of palliationas examined in this study on a scale of good, fair, or poor. In this group,o patients experienced “good” palliation, but 86% of the palliativeesections had “fair” palliation.Observational data representing 503 patients who underwent palliative

reatment in the Norwegian Stomach Cancer Trial suggest a doubling ofean survival time with palliative resections.248 Thirty-day mortality,

owever, was 11% to 13% for patients who underwent resection. Inatients who did not undergo an operation, the 30-day mortality rate wasnly 2%. An Italian case series demonstrated similar improved meanurvival with resection (3 to 8 months) but high operative mortality (10%o 15%).251

There probably is a role for palliative total gastrectomy. In a retrospec-ive chart review of palliative total gastrectomy at the Mayo Clinic, theajority of patients (59%) felt this procedure improved their quality of

ife based on the ability to maintain adequate oral intake, ability to doormal daily activities, absence of dysphagia, and ability to maintaineight.249 However, the in-hospital mortality rate was 8%.What is the role of palliative bypass procedures in patients with gastric

ancer? In our opinion, palliation is infrequently provided by bypassrocedures and the perioperative mortality is high. In a Mayo Cliniceries, only 19% of patients who underwent a bypass gastroenterostomy
ctually felt they benefited from the operation.246

rptaschtwmpbd

paompa(s

btdi3pmctosriw

tc

C

Gastrostomy and jejunostomy have traditionally been felt to have littleole in patients with gastric cancer. A gastrostomy tube may benefit theatient requiring frequent nasogastric suction for gastric outlet obstruc-ion. A jejunostomy can be used for nutritional supplementation, therebyvoiding total parental nutrition and hydration. Feeding jejunostomyhould be limited to patients who are to undergo adjuvant or neoadjuvanthemotherapy and in patients with slowly progressive tumors to facilitateospice care, thereby avoiding prolonged hospitalization.246 Feedingubes are not without complications, however. More than 20% of patientsill require general anesthesia for feeding tube placement. Approxi-ately one third will need replacement due to malfunction. Thirteen

ercent of patients will have a major complication such as aspiration,leeding, infection, or peritonitis. On the other hand, procedure-relatedeath is rare (less than 1%).252

With the emergence of self-expanding metal stents (SEMS), endoscopicalliative techniques are replacing surgical intervention.253 Placement ofSEMS is an effective alternative to surgical bypass in gastric outlet

bstruction. Many different stent configurations are available to accom-odate varying anatomic situations.253 Perforation and bleeding are

otentially lethal but occur in less than 1.2% of procedures. Obstructionfter stent placement, due to progression of disease or technical failureinsufficient stensosis cover, stent fracture, stent migration, or collapsedtent), can occur in approximately 18% of cases.253

More recent series suggest that noncurative gastric resections shoulde avoided if possible. Between 1993 and 2002, 165 patients werereated at Memorial Sloan-Kettering Cancer Center with metastaticisease identified at laparoscopy.254 There were no upfront resectionsn this cohort of patients. Eventually, interventions were necessary in3% of patients for obstruction, 8% for bleeding, and only 1% forerforation during chemotherapy. The median survival time was 10onths; virtually all patients received chemotherapy and many re-

eived radiation. Obstructions were usually treated with stents, gas-rostomy, and/or jejunostomy. No patient had a gastric resection forbstruction, although 12% of patients did have laparotomy (eg, formall bowel obstruction, jejunostomy tubes). Consistent with previouseports, the authors found that less than one half of the patients withntestinal obstruction due to peritoneal carcinomatosis were improvedith operation.Several recent reports suggest a potential role for laparoscopic surgical

echniques in palliative surgery. Laparoscopic gastroenterostomy and
holecysto-jejunostomy are possible palliative options.147 However, these

rn

NT

fmdUmaaanmtgam

S

aimpsdegtdTct1

C

o

6

eports are only small case series without comparison with open tech-iques.

eoadjuvant and Adjuvant ChemoradiationherapyGastric cancer displays a strong propensity for systemic involvement

rom the time of initial presentation (or even before). As a result,aximum therapeutic success for all stages of gastric cancer ultimately is

etermined by the effectiveness of drug therapies applied to this disorder.nfortunately, advances in the drug therapy of gastric cancer have beenuch slower than desired. A variety of reasons are possible, including (1)relatively low incidence of gastric cancer in countries most able to

dvance clinical chemotherapeutic research, (2) the frequent presence ofdvanced disease at clinical presentation, (3) the importance of coordi-ated multidisciplinary participation (often lacking) in the optimumanagement of gastric cancer, (4) patient comorbidity, and (5) therapeu-

ic nihilism. Fortunately, the tempo of progress in the drug therapy ofastric cancer has accelerated in recent years, both in terms of breadth ofgents and options for their integrated usage with other therapeuticodalities.

ingle-Agent Drug TherapyBeginning with 5-fluorouracil (5-FU), a variety of chemotherapeutic

gents have been found to display at least a 10% objective response raten advanced gastric cancer. Key agents used initially included 5-FU,itomycin-C, doxorubicin, epirubicin, methotrexate, etoposide, and cis-

latin. More recently, a variety of contemporary agents have also showningle-agent activity in gastric cancer, especially oxaliplatin, paclitaxel,ocetaxel, and irinotecan. This latter group of agents in particular havexpanded the range of possible drug combinations for the treatment ofastric cancer. Single-agent response rates in advanced gastric areypically between 15% and 25%. These agents are shown with theirosage as applied in gastric cancer, along with common side effects inable 4. Results for the use of systemic therapy in advanced gastricancer can be compared against outcomes from best supportive care— 3-o 5-month median life expectancy, with 1-year survival rates lower than0%, and no survivors at 2 years from diagnosis.

ombination Drug TherapyGiven the limited response rates of single-agent therapies, combinations
f chemotherapeutic agents were an obvious strategy for advanced gastric

cc(idr5u

grFrbcic

T

5

MD

E

ME

C

OP

D

I

C

C

ancer to improve patient response rates and overall survival. The firstombination chemotherapy which received broad attention was FAM5-FU, doxorubicin, and mitomycin-C), first reported in 1980.255 In thenitial report, 26 of 62 patients (42%) achieved a response. The survivaluration for the entire patient population was 9 months, althoughesponders lived significantly longer than nonresponders (12.5 months vs..5 months). This regimen thus became a mainstay of treatment, partic-larly in the United States in the 1980s and into the 1990s.The FAM regimen, like other chemotherapeutic regimens in advancedastric cancer, had progressively disparate results after the initial expe-ience, however. In a review of more than 650 U.S. patients receivingAM, the overall response rate using FAM was 30% (2% completeesponses); the overall survival of treated patients typically variedetween 5 and 10 months.256 As with other regimens, the response toombination chemotherapy in advanced gastric cancer appeared superiorn the hands of Japanese investigators. Using the similar regimen of 5-FU,

ABLE 4. Chemotherapeutic agents in gastric cancer

Agent Dose Major toxicities

-Fluorouracil Wide variety of dosesand schedulesused

mucositis, diarrhea, hand-foot syndrome

itomycin C 10 mg/m2 myelosuppression, renal toxicityoxorubicin 30–50 mg/m2 myelosuppression, nausea/vomiting,

cardiac toxicitypirubicin 50 mg/m2 myelosuppression, nausea/vomiting,

cardiac toxicityethotrexate 1,500 mg/m2 mucositis, hepatic/renal toxicitytoposide 100–120 mg/m2 myelosuppression, peripheral

neuropathyisplatin 60–100 mg/m2 neutropenia, nausea/vomiting, renal

toxicityxaliplatin 85–130 mg/m2 neutropenia, peripheral neuropathyaclitaxel 175 mg/m2 neutropenia, musculoskeletal pain,

peripheral neuropathyocetaxel 75–100 mg/m2 mucositis, neutropenia, musculoskeletal

painrinotecan 75–100 mg/m2 myelosuppression, nausea/vomiting,

diarrheaapecitabine 1500–2500 mg/m2

orally divideddosage over 2weeks

mucositis, hand-foot syndrome

ytarabine, and mitomycin-C, Ogawa reported an overall response rate of


3t

hcavphscg

eFamcTF(a2g

tecdramar

wcr7mt

6

6%, and median survival times of 16 to 20 months in a review of morehan 350 patients.257

The initial modest promise of combination regimens was dampened,owever, by results from 2 randomized trials. In 1982, Cocconi andolleagues reported no difference between 5-FU and 5-FU, cytarabine,nd mitomycin-C in response rate, response duration, and overall sur-ival.258 In 1985, the North Central Cancer Treatment Group com-ared 5-FU to FAM in 100 patients.259 Although response rates wereigher in the combination treatment arm (27% vs. 17%), overallurvival was identical in both arms (7 months). These 2 combinationsast significant doubt as to the value of drug combinations in advancedastric cancer.Subsequently, chemotherapy for advanced gastric cancer began to

volve in 2 different directions. The first was to attempt to improve theAM regimen by adding additional drugs. Foremost among thesettempts was experience with FAMTX, which substituted high-doseethotrexate for mitomycin-C in the regimen.260 FAMTX was formally

ompared with FAM by the European Organization for the Research andreatment of Cancer (EORTC).261 Response rates were much higher withAMTX versus FAM (41% vs. 9%, P � 0.0001) as were median survival42 weeks vs. 29 weeks, P � 0.004) and 1- and 2-year survival rates (41%nd 9% vs. 22% and 0%, respectively). Serious toxicity was similar in thearms. FAMTX thus became a new standard for treatment for advanced

astric cancer in the early 1990s.The second major therapeutic direction was to employ cisplatin for the

reatment of advanced gastric cancer. Beginning with the cisplatin/toposide combination (EP), a variety of drug combinations containingisplatin were employed in advanced gastric cancer, including cisplatin,oxorubicin, and cisplatin (EAP).262 The EAP regimen produced highesponse rates: typically 50% to 70% with complete response ratesnywhere from 5% to 20%.263 The overall survival was typically 8 to 10onths for the treatment population. The EAP regimen was also associ-

ted with significant toxicity, particularly in elderly patients; treatment-elated mortality was reported at 10% or more.Owing to the toxicity of EAP, Wilke and colleagues created a regimenith etoposide added to 5-FU and leucovorin (ELF), a regimen specifi-

ally designed for patients older than 65.264 In 51 patients, the responseate was 53%, including 12% complete responses. Response rates were0% and 49%, respectively, in patients with locally advanced versusetastatic disease; the overall survival was 9.5 months. Significant

oxicity was largely limited to myelosuppression.


ocEap(mc

bFrsipr

Ebrvpcw

cDtct

T

C

Given the synergistic cytotoxicity of cisplatin and 5-FU in a varietyf in vitro tumor models and clinical studies, cisplatin was alsoombined with 5-FU in patients with advanced gastric cancer. TheORTC subsequently tested this regimen (CF) against the FAMTXnd ELF regimens described previously.265 In this study of 274atients, no significant difference was found in toxicity, response rateswhich ranged from 20% to 27%), and median survival (7 to 8onths). The identity of the “best regimen” for advanced gastric

ancer remained uncertain.Cisplatin was also tested as a substitute for mitomycin-C (remem-ering the high degree of myelosuppression of the latter drug) in theAM regimen to create FAP. This regimen produced a 34% responseate, with 5% complete responses.256 Cunningham and colleagues thenubstituted epirubicin, an anthracycline analog of doxorubicin popularn Europe, for doxorubicin to create the ECF regimen. In a trial of 52atients, a 37% response rate was achieved, with 17% completeesponses.266

A subsequent randomized clinical trial solidified the importance of theCF regimen. The first, conducted by the MRC, randomized 256 patientsetween FAMTX and ECF, with ECF clearly proving to be the superioregimen.267 Response rate (46% vs. 21%), median survival (8.7 monthss. 6.1 months), and 2-year survival rates (14% vs. 5%) all clearly favoredatients receiving ECF. Based on this trial, ECF became the standard ofare for advanced gastric cancer entering the twenty-first century, at leastith respect to tumor response.Since 2000, clinical research has centered on the use of the newer

hemotherapeutic agents proven active in advanced gastric cancer.ocetaxel is foremost among these agents at this time. Exemplary is

he phase III trial reported by Moiseyenko and colleagues thatompared docetaxel, cisplatin, and 5-FU (DCF) with CF only.268 In

ABLE 5. Major chemotherapeutic regimens in gastric cancer

Regimen Drugs

FAM 5-FU, adriamycin, mitomycin CFAMTX 5-FU, adriamycin, mitomycin C, methotrexateEAP Etoposide, adriamycin, cisplatinELF Etoposide, 5-FU, leucovorinCF Cisplatin, 5-FUECF Epirubicin, cisplatin, 5-FUDCF Docetaxel, cisplatin, 5-FU

his large study involving 457 patients, DCF produced a superior


rm96Db

tapteprc5strcc5a(

F

epSTdctig

ocbc

6

esponse rate (37% vs. 25%, P � 0.01), time to progression (5.6onths vs. 3.7 months, P � 0.01), and 2-year survival rate (18% vs.

%). However, the benefit of DCF was less clear in patients older than5 years, particularly with a 4% to 8% toxic death rate estimated forCF. Overall grade III-IV toxicity rates for these regimens wereetween 75% and 80%.Significant combination chemotherapy regimens employed during

he historical evolution of drug treatment for advanced gastric cancerre listed in Table 5. At present, the DCF and ECF regimens haveroduced the highest tumor response rates, but they are also the mostoxic. As such, no single “best treatment ” for advanced gastric cancerxists, and the choice of therapy ideally is individualized to particularatient circumstances. Present benchmark statistics for chemotherapyegimens in advanced gastric cancer are response rates of 30% to 40%,omplete response rates of 10% to 20%, time to tumor progression ofto 6 months, overall survival time of 8 to 10 months, 1-year overall

urvival rates of 40% to 50%, and 2-year overall survival rate of 15%o 20%. Therapeutic toxicity remains a significant issue. The mostecent meta-analysis on this subject concludes the following: (1)hemotherapy significantly improves survival over best supportiveare, (2) combination chemotherapy improves survival to single-agent-FU, although the effect size is smaller, and (3) the best results arechieved with regimens containing 5-FU, anthracyclines, and cisplatineg, ECF).269

uture Directions in Drug TherapyFuture research in this area is evolving along 3 separate lines. The first

xamines the role of other, newer, chemotherapeutics (particularly oxali-latin, irinotecan, and oral 5-FU “prodrugs” such as capecitabine and-1), that have proven valuable in other gastrointestinal malignancies.he second examines the role of so-called targeted therapies, drugsesigned to inhibit the function of a particular molecular target critical toancer cell growth. Major examples of therapies presently under inves-igation at present include cetuximab, an epidermal growth factor inhib-tor, and bevacizumab, a vascular epidermal growth factor inhibitor, bothiven in conjunction with chemotherapy.Finally, there is growing emphasis on clinical and molecular predictorsf chemotherapeutic responsiveness in advanced gastric cancer. Suchonsiderations are particularly important given the relatively modestenefit/toxicity ratios of present chemotherapy programs for gastric
ancer, as well as the expense of the agents themselves. Examples of the

fent(acrao

R

gslap

staprogtwt

papcticmea

C

ormer might include such features as patient performance status, pres-nce or absence of pain, extent of visceral involvement (eg, liver), andature of prior therapy. For example, low tissue levels of expression ofhymidine synthetase (critical to intracellular 5-FU metabolism), p53related to chemotherapeutic resistance), and BCL2 (important to cellularpoptosis) have been found to correlate with superior survival in gastricancer.270 More sophisticated techniques for prediction of therapeuticesponse (eg, molecular profiling of individual tumors) are also an activerea of research throughout oncology, including gastrointestinal oncol-gy.

adiation Therapy for Locoregional DiseaseIn the American population, 80% to 90% of patients with locoregionalastric cancer are at risk for recurrence following surgery. The risk isignificant for all but patients with T1-2N0M0 disease. Recurrence risk isocal, systemic, or both. Thus, the use of radiotherapy and chemotherapys (neo)adjuvant treatment for resected gastric cancer finds obviousotential application.With respect to radiation therapy, the tissues near the stomach (liver,

mall intestine, kidney, and spinal cord) limit the amount of radiationhat can be delivered as an adjuvant treatment. The stomach itself islso radiosensitive, with bleeding and ulceration an important com-lication at radiation doses greater than 5000 cGy. Consequently,adiation therapy for gastric cancer is typically administered at a dosef 4500 cGy using 180 cGy/day fractions. Radiation therapy is notenerally used without chemotherapy (see following discussion) andhe exact optimum integration of radiation therapy and chemotherapyith respect to radiation and chemotherapeutic dose, schedule, and

iming are not known.Radiation fields used to treat gastric cancer must consider typicalatterns of cancer spread. For cancers originating in the gastricntrum, it is not necessary to radiate the entire cardia, but radiation oferiduodenal lymph nodes is mandatory. For cancers originating in theardia, coverage of the cardia and distal esophagus is important owingo the potential for local spread, but periduodenal lymph noderradiation is not necessary. In all cases, posterior penetration andancer extension to the pancreas or other retroperitoneal structuresust be considered; appropriate field coverage of these areas is

ssential. Radiation fields are typically constructed anteroposterior,
lthough both lateral and oblique fields are useful for the final dose

bd

gpmcotmb

mSoil5

P

barps0co

oisO3at�aFS

6

oost. When oblique fields are used, care must be taken to limit theose to the liver to 2500 cGy or less.The delivery of adjuvant chemoradiation to patients with resectedastric cancer requires complex and dedicated supportive care. Keyotential complications of such therapy typically include weight loss,ucositis, dehydration, nausea and vomiting, and diarrhea. These

omplications are potentially serious enough to produce interruptionf therapy, hospitalization, or even death. The wise clinician considershese complications in advance of chemoradiation and takes steps toitigate their severity, throughout and even before chemoradiation

egins.Virtually no studies have evaluated radiation therapy as a sole adjuvantodality to surgery in the adjuvant treatment of resected gastric cancer.uch an approach would be expected to have an impact on diseaseutcome; however, given the high propensity for occult metastatic diseasen resected gastric cancer. Experience with radiation therapy thus isargely confined to its concomitant use with chemotherapy, typically-FU.

ostoperative ChemotherapyDiscouragingly, adjuvant chemotherapy alone (usually 5-FU or 5-FUased) failed to show with confidence a survival advantage to surgerylone when applied to resected gastric cancer for many years. An initialeport by the Gastrointestinal Study Group (GITSG) randomizing 142atients to chemotherapy using 5-FU plus methyl CCNU produced atatistically significant survival advantage at 5 years (50% vs. 31%, P �.03).271 However, additional studies employing the identical drugombination failed to produce statistically significant differences inverall survival in similar patient groups.272

Several additional studies comparing postoperative chemotherapy tobservation likewise failed to demonstrate a role for chemotherapy alonen the adjuvant treatment of gastric cancer. Exemplary of this point is atudy reported by Lise and colleagues of behalf of the Europeanrganization for Research and Treatment of Cancer (EORTC) in which14 patients were randomized between an intensified version of 5-FU,driamycin, and mitomycin C (FAM2) versus surgery only.273 Althoughhe time to disease progression was improved in the chemotherapy arm (P

0.02), median survival was not statistically different between the 2rms (42 vs. 36 months, P � 0.30). Similar results were obtained whenAM was applied as an adjuvant treatment to gastric cancer by the
outhwest Oncology Group (SWOG).274

wJNctotr

tfttac(sccc

P

arrisrrtCttwdicmT

C

Japanese investigators, however, came to quite different conclusionshen analyzing their data on adjuvant chemotherapy for gastric cancer in

apan. Collected experiences analyzed by Imanaga and Nakazato275 andakjima and colleagues276 using mitomycin C, either individually or in

ombination with other agents, displayed (1) higher overall survival rateshan seen in the Western experiences, and (2) a statistically superiorutcome to surgery alone when chemotherapy was used. These data formhe basis for the routine use of systemic chemotherapy followingesection of gastric cancer in Japan today.A meta-analysis performed by Hermans and colleagues in 1993 at-

empted to answer the question of the role of adjuvant chemotherapyollowing curative surgery for gastric cancer.277 Using 11 randomizedrials with complete clinical data encompassing more than 2000 patients,he odds ratio for recurrence following surgery and adjuvant chemother-py was 0.88 versus surgery alone, a trend that favored adjuvanthemotherapy, but not to a point that achieved statistical significance95% CI, 0.78-1.08). A second meta-analysis performed in 1998 on thisubject produced similar results (odds ratio recurrence with adjuvanthemotherapy, 0.81; 95% CI, 0.67-0.98).278 Thus, postoperative adjuvanthemotherapy had not been shown to improve survival in resected gastricancer (at least in Western patients) before 2000.

ostoperative Combined Modality TherapyAnother line of research emanating from the United States for the

djuvant therapy of gastric cancer involved the combined use ofadiation therapy with fluorinated pyrimidines (usually 5-FU) asadiation sensitizers. Although postoperative radiation therapy bytself seems to have a modest favorable benefit on local control, nourvival benefit has been detected in randomized trials. Integration ofadiation therapy with 5-FU, however, had shown survival benefit inandomized trials, although the patient numbers were small. Notewor-hy in this regard is the study from Moertel and colleagues at the Mayolinic.279 In this study involving 62 patients, treatment with radiation

herapy (3750 cGy in 24 fractions over 4 to 5 weeks), plus chemo-herapy (concomitant bolus 5-FU 15 mg/kg/day � 3) was comparedith surgery only. Although both radiation therapy and chemotherapyosing would be regarded as inferior to today’s methodologies,mprovement for the treatment group was seen with locoregionalontrol (61% vs. 46%), disease-free survival (17 months vs. 9onths), and overall survival (20 months v s. 12 months, P � 0.05).
he use of combined modality radiation and chemotherapy with 5-FU

wdr

5tvrepaR(oggt

im0mdi1

F5

6

as also of benefit in esophageal cancer, resulting in prolongedisease-free survival for this disease without the need for surgicalesection.280

Since the demonstrated benefit of integrated radiation therapy and-FU in patients with known residual gastric and esophageal cancer,he United States Intergroup study was initiated in 1991 to test thealue of the 5-FU/leucovorin chemotherapy regimen coupled withadiation therapy in patients with resected gastric cancer. This studynrolled 603 patients and was published in 2001.281 Eighty-fiveercent of patients were node positive. Sixty-four percent of patientsssigned to the chemoradiation arm were able to complete all therapy.easons for failure to complete therapy included therapeutic toxicity

17%), patient choice (8%), disease progression or death (6%), andther reasons (4%). Seventy-three percent of patients experiencedrade III or higher toxicity by common toxicity criteria (CTC) (42%rade III, 31% grade IV). There were 3 toxic deaths (1%) in thereatment arm.Both disease-free and overall survival rates were significantly improved

n the combined modality study arm. The median time to relapse was 30onths in the treatment arm versus 19 months in the control arm (P �

.001). Overall survival was 36 months in the treatment arm versus 27onths in the control arm (odds ratio 0.65, P � 0.005). The 3-year

isease-free survival rate was 48% in the chemoradiation arm versus 31%n the surgery arm. Local relapse rates were 29% in the surgery arm and

IG 40. The United States Intergroup Trial. Randomization of adjuvant chemoradiation with-flurouracil and leucovorin versus docetaxel, cisplatin, and 5-FU. Study is ongoing.

9% in the control arm. This landmark study demonstrated for the first


ttforpo

T

tcwbirnC2e(sttrrTtct

F

cacmstpm

C

ime (1) the ability to carry out large-scale clinical trials for the adjuvantherapy of gastric cancer in the United States, and (2) a survival advantageor the adjuvant therapy of gastric cancer in Western patients. As a resultf this trial, a follow-up Intergroup Trial was initiated in the United Statesandomizing the above regimen to the more contemporary pre- andost-chemotherapy regimen of DCF (Fig 40). This trial is presentlyngoing.

he MAGIC TrialWhile the aforementioned Intergroup Trial was being conducted in

he United States, efforts to use some of the newer, more activehemotherapy regimens for the adjuvant therapy of gastric cancerere being employed in Europe. In particular, these regimens wereeing employed from a neoadjuvant standpoint, in an attempt tomprove patient tolerance of adjuvant therapy, to improve resectabilityates (downstage) in patients, and to improve patient survival. Mostotable among such trials is the MRC Adjuvant Gastric Infusionalhemotherapy (MAGIC) trial reported recently.282 Between 1994 and002, 503 patients (74% of whom had gastric cancer, the remaindersophageal cancer) were randomized to 6 cycles of ECF chemotherapy3 administered preoperatively, 3 administered postoperatively) versusurgery only. Sixty-four percent of patients completed all 6 plannedherapy cycles. Preoperative chemotherapy improved curative resec-ion rates. With more than 3 years of follow-up, the 5-year survivalates for the 2 study arms were 36% (ECF) versus 23% (surgery only),epresenting a 25% reduction in hazard for recurrence (P � 0.009).his large-scale trial further establishes the importance of systemic

herapy in addition to surgery for the curative treatment of gastricancer, and emphasizes the potential for neoadjuvant approaches inhis setting.

uture Directions for Neoadjuvant TherapyMultiple directions for future clinical research in locoregional gastric

ancer now present themselves. The success of the MAGIC trial encour-ges new approaches to neoadjuvant therapy for gastric cancer, as well asomparison with conventional postoperative combined modality treat-ent. As exemplified by the current United States Intergroup Trial,

uperior chemotherapy regimens must be integrated into (neoadjuvant)herapy programs as they prove successful in more advanced disease,erhaps even without the use of radiation therapy. Novel chemoradiation
ethods beyond the simple use of 5-FU require immediate consideration.

Fsas

6

inally, revisitation of intraperitoneal chemotherapy (not convincinglyhown beneficial to date in Western trials), or integration of immunother-py with adjuvant therapy techniques may eventually find fruition in thisetting.

REFERENCES1. Ferlay J, Bray F, Pisani P, Parkin DM. GLOBOCAN 2002: Cancer Incidence,

Mortality and Prevalence Worldwide. Lyon: IARC Press; 2004.2. Parkin DM, Whelan SL, Ferlay J, Storm H. Cancer Incidence in Five Continents,

Vol. I to VIII. Lyon: IARC Press; 2005.3. Corella D, Guillen M. Dietary habits and epidemiology of gastric carcinoma.

Hepatogastroenterology 2001;48:1537-43.4. Ries L, Eisner M, Kosary C, Hankey B, Miller B, Clegg L, Mariotto A, Feuer E,

Edwards B. SEER Cancer Statistics Review, 1975-2002.5. Tsugane S, de Souza JM, Costa ML Jr, Mirra AP, Gotlieb SL, Laurenti R, et al.

Cancer incidence rates among Japanese immigrants in the city of Sao Paulo, Brazil,1969-78. Cancer Causes Control 1990;1:189-93.

6. Stemmermann GN. Gastric cancer in the Hawaii Japanese Gann 1977;68:525-35.7. Coggon D, Barker DJ, Cole RB, Nelson M. Stomach cancer and food storage.

J Natl Cancer Inst 1989;81:1178-82.8. Boeing H, Frentzel-Beyme R, Berger M, Berndt V, Gores W, et al. Case-control

study on stomach cancer in Germany. Int J Cancer 1991;47:858-64.9. Munoz N, Plummer M, Vivas J, Moreno V, De SS, Lopez G, et al. A case-control

study of gastric cancer in Venezuela. Int J Cancer 2001;93:417-23.10. Jedrychowski W, Boeing H, Popiela T, Wahrendorf J, Tobiasz-Adamczyk B, Kulig

J. Dietary practices in households as risk factors for stomach cancer: a familialstudy in Poland. Eur J Cancer Prev 1992;1:297-304.

11. van den Brandt PA, Botterweck AA, Goldbohm RA. Salt intake, cured meatconsumption, refrigerator use and stomach cancer incidence: a prospective cohortstudy (Netherlands). Cancer Causes Control 2003;14:427-38.

12. Devesa SS, Blot WJ, Fraumeni JF Jr. Changing patterns in the incidence ofesophageal and gastric carcinoma in the United States. Cancer 1998;83:2049-53.

13. Locke GR III, Talley NJ, Carpenter HA, Harmsen WS, Zinsmeister AR, Melton LJIII. Changes in the site- and histology-specific incidence of gastric cancer during a50-year period. Gastroenterology 1995;109:1750-6.

14. Shang J, Pena AS. Multidisciplinary approach to understand the pathogenesis ofgastric cancer. World J Gastroenterol 2005;11:4131-9.

15. Kubo A, Corley DA. Marked multi-ethnic variation of esophageal and gastriccardia carcinomas within the United States. Am J Gastroenterol 2004;99:582-8.

16. Blot WJ, Devesa SS, Kneller RW, Fraumeni JF Jr. Rising incidence of adenocar-cinoma of the esophagus and gastric cardia. JAMA 1991;265:1287-9.

17. Wang WH, Huang JQ, Zheng GF, Lam SK, Karlberg J, Wong BC. Non-steroidalanti-inflammatory drug use and the risk of gastric cancer: a systematic review andmeta-analysis. J Natl Cancer Inst 2003;95:1784-91.

18. Correa P, Piazuelo MB, Camargo MC. The future of gastric cancer prevention.
Gastric Cancer 2004;7:9-16.

C

19. Watson P, Lynch HT. Extracolonic cancer in hereditary nonpolyposis colorectalcancer. Cancer 1993;71:677-85.

20. Aarnio M, Salovaara R, Aaltonen LA, Mecklin JP, Jarvinen HJ. Features of gastriccancer in hereditary non-polyposis colorectal cancer syndrome. Int J Cancer1997;74:551-5.

21. Theuer CP, Campbell BS, Peel DJ, Lin F, Carpenter P, Ziogas A, et al.Microsatellite instability in Japanese vs European American patients with gastriccancer. Arch Surg 2002;137:960-5.

22. Caldas C, Carneiro F, Lynch HT, Yokota J, Wiesner GL, Powell SM, et al. Familialgastric cancer: overview and guidelines for management. J Med Genet1999;36:873-80.

23. Guilford P, Hopkins J, Harraway J, McLeod M, McLeod N, Harawira P, et al. E-cadheringermline mutations in familial gastric cancer. Nature 1998;392(6674):402-5.

24. Becker KF, Atkinson MJ, Reich U, Becker I, Nekarda H, Siewert JR, et al.E-cadherin gene mutations provide clues to diffuse type gastric carcinomas. CancerRes 1994;54:3845-52.

25. Tahara E. Mechanisms of carcinogenesis: contributions of molecular epidemiology.In: Buffler PA, editor. Mechanisms of Carcinogenesis: Contributions of MolecularEpidemiology. Lyon: International Agency for Research on Cancer; 2004;327-49.

26. World Health Organization. Diet, Nutrition, and the Prevention of ChronicDiseases: Report of a Joint WHO/FAO Expert Consultation. Geneva: World HealthOrganization; 2003.

27. Tsugane S. Salt, salted food intake, and risk of gastric cancer: epidemiologicevidence. Cancer Sci 2005;96:1-6.

28. Sugimura T, Fujimura S. Tumour production in glandular stomach of rat byN-methyl-N=-nitro-N-nitrosoguanidine. Nature 1967;216(118):943-4.

29. Yamaguchi N, Kakizoe T. Synergistic interaction between Helicobacter pylorigastritis and diet in gastric cancer. Lancet Oncol 2001;2:88-94.

30. Blot WJ, Li JY, Taylor PR, Guo W, Dawsey S, Wang GQ, et al. Nutritionintervention trials in Linxian, China: supplementation with specific vitamin/mineralcombinations, cancer incidence, and disease-specific mortality in the generalpopulation. J Natl Cancer Inst 1993;85:1483-92.

31. Albanes D, Heinonen OP, Taylor PR, Virtamo J, Edwards BK, Rautalahti M, et al.Alpha-tocopherol and beta-carotene supplements and lung cancer incidence in thealpha-tocopherol, beta-carotene cancer prevention study: effects of base-linecharacteristics and study compliance. J Natl Cancer Inst 1996;88:1560-70.

32. Virtamo J, Pietinen P, Huttunen JK, Korhonen P, Malila N, Virtanen MJ, et al.Incidence of cancer and mortality following alpha-tocopherol and beta-carotenesupplementation: a postintervention follow-up. JAMA 2003;290:476-85.

33. Tredaniel J, Boffetta P, Buiatti E, Saracci R, Hirsch A. Tobacco smoking andgastric cancer: review and meta-analysis. Int J Cancer 1997;72:565-73.

34. Gammon MD, Schoenberg JB, Ahsan H, Risch HA, Vaughan TL, Chow WH, et al.Tobacco, alcohol, and socioeconomic status and adenocarcinomas of the esophagusand gastric cardia. J Natl Cancer Inst 1997;89:1277-84.

35. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans,International Agency for Research on Cancer, National Cancer Institute (U.S.).Alcohol Drinking. Lyon, France: World Health Organization, International Agency
for Research on Cancer; 1988.

6

36. World Cancer RF, American Institute for Cancer Research. Food, Nutrition, and thePrevention of Cancer: A Global Perspective. Washington, DC: The Institute; 1997.

37. Warren J. Unidentified curved bacilli on gastric epithelium in active chronicgastritis. Lancet 1983;1:1273-5.

38. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans.Schistosomes, liver flukes and Helicobacter pylori. Lyon, 7-14 June 1994. IARCMonogr Eval Carcinog Risks Hum 1994;61:1-241.

39. Huang JQ, Sridhar S, Chen Y, Hunt RH. Meta-analysis of the relationship betweenHelicobacter pylori seropositivity and gastric cancer. Gastroenterology 1998;114:1169-79.

40. Holcombe C. Helicobacter pylori: the African enigma. Gut 1992;33:429-31.41. Marshall BJ, Windsor HM. The relation of Helicobacter pylori to gastric adeno-

carcinoma and lymphoma: pathophysiology, epidemiology, screening, clinicalpresentation, treatment, and prevention. Med Clin North Am 2005;89:313-44, viii.

42. Malaty HM, Graham DY. Importance of childhood socioeconomic status on thecurrent prevalence of Helicobacter pylori infection. Gut 1994;35:742-5.

43. Staat MA, Kruszon-Moran D, McQuillan GM, Kaslow RA. A population-basedserologic survey of Helicobacter pylori infection in children and adolescents in theUnited States. J Infect Dis 1996;174:1120-3.

44. El-Omar EM, Carrington M, Chow WH, McColl KE, Bream JH, Young HA, et al.Interleukin-1 polymorphisms associated with increased risk of gastric cancer.Nature 2000;404(6776):398-402.

45. Zagari RM, Bazzoli F. Gastric cancer: who is at risk? Dig Dis 2004;22:302-5.46. Sugiyama A, Maruta F, Ikeno T, Ishida K, Kawasaki S, Katsuyama T, et al.

Helicobacter pylori infection enhances N-methyl-N-nitrosourea-induced stomachcarcinogenesis in the Mongolian gerbil. Cancer Res 1998;58:2067-9.

47. Nomura A, Stemmermann GN, Chyou PH, Kato I, Perez-Perez GI, Blaser MJ.Helicobacter pylori infection and gastric carcinoma among Japanese Americans inHawaii. N Engl J Med 1991;325:1132-6.

48. Parsonnet J, Friedman GD, Vandersteen DP, Chang Y, Vogelman JH, OrentreichN, et al. Helicobacter pylori infection and the risk of gastric carcinoma. N EnglJ Med 1991;325:1127-31.

49. The EUROGAST Study Group. An international association between Helicobacterpylori infection and gastric cancer. Lancet 1993;341:1359-62.

50. Uemura N, Mukai T, Okamoto S, Yamaguchi S, Mashiba H, Taniyama K, et al.Effect of Helicobacter pylori eradication on subsequent development of cancer afterendoscopic resection of early gastric cancer. Cancer Epidemiol Biomarkers Prev1997;6:639-42.

51. Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, Yamakido M,et al. Helicobacter pylori infection and the development of gastric cancer. N EnglJ Med 2001;345:784-9.

52. Ebert MP, Leodolter A, Malfertheiner P. Novel strategies in the prevention ofgastric cancer. Hepatogastroenterology 2001;48(42):1569-71.

53. Wong BC, Lam SK, Wong WM, Chen JS, Zheng TT, Feng RE, et al. Helicobacterpylori eradication to prevent gastric cancer in a high-risk region of China: arandomized controlled trial. JAMA 2004;291:187-94.

54. Malfertheiner P, Sipponen P, Naumann M, Moayyedi P, Megraud F, Xiao SD, etal. Helicobacter pylori eradication has the potential to prevent gastric cancer: a
state-of-the-art critique. Am J Gastroenterol 2005;100:2100-15.

C

55. Aranha GV, Georgen R. Gastric linitis plastica is not a surgical disease. Surgery1989;106:758-62.

56. Gertsch P, Yip SK, Chow LW, Lauder IJ. Free perforation of gastric carcinoma.Results of surgical treatment. Arch Surg 1995;130:177-81.

57. Allum WH, Brearley S, Wheatley KE, Dykes PW, Keighley MR. Acute haemor-rhage from gastric malignancy. Br J Surg 1990;77:19-20.

58. Inoue M, Tsugane S. Epidemiology of gastric cancer in Japan. Postgrad Med J2005;81(957):419-24.

59. Maruyama M, Barreto-Zuniga R, Kimura K. Misconceptions on early gastriccancer in Japan. Hepatogastroenterology 2001;48(42):1560-4.

60. Stael von HC, Eriksson S, Huldt B, Hammar E. Endoscopic screening during 17years for gastric stump carcinoma. A prospective clinical trial Scand J Gastroen-terol 1991;26:1020-6.

61. Everett SM, Axon AT. Early gastric cancer: disease or pseudo-disease? Lancet1998;351:1350-2.

62. Wobbes T, Thomas CM, Segers MF, Nagengast FM. Evaluation of seven tumormarkers (CA 50, CA 19-9, CA 19-9 TruQuant, CA 72-4, CA 195, carcinoembry-onic antigen, and tissue polypeptide antigen) in the pretreatment sera of patientswith gastric carcinoma. Cancer 1992;69:2036-41.

63. Chan AO, Chu KM, Lam SK, Cheung KL, Law S, Kwok KF, et al. Early predictionof tumor recurrence after curative resection of gastric carcinoma by measuringsoluble E-cadherin. Cancer 2005;104:740-6.

64. Karayiannakis AJ, Syrigos KN, Polychronidis A, Zbar A, Kouraklis G, SimopoulosC, et al. Circulating VEGF levels in the serum of gastric cancer patients: correlationwith pathological variables, patient survival, and tumor surgery. Ann Surg2002;236:37-42.

65. Chen J, Rocken C, Malfertheiner P, Ebert MP. Recent advances in moleculardiagnosis and therapy of gastric cancer. Dig Dis 2004;22:380-5.

66. Tay ST, Leong SH, Yu K, Aggarwal A, Tan SY, Lee CH, et al. A combinedcomparative genomic hybridization and expression microarray analysis of gastriccancer reveals novel molecular subtypes. Cancer Res 2003;63:3309-16.

67. Yasui W, Oue N, Ito R, Kuraoka K, Nakayama H. Search for new biomarkers ofgastric cancer through serial analysis of gene expression and its clinical implica-tions. Cancer Sci 2004;95:385-92.

68. Tomlinson AJ, Hincapie M, Morris GE, Chicz RM. Global proteome analysis of ahuman gastric carcinoma. Electrophoresis 2002;23:3233-40.

69. Halvorsen RA Jr, Yee J, McCormick VD. Diagnosis and staging of gastric cancer.Semin Oncol 1996;23:325-35.

70. Low VH, Levine MS, Rubesin SE, Laufer I, Herlinger H. Diagnosis of gastriccarcinoma: sensitivity of double-contrast barium studies. AJR Am J Roentgenol1994;162:329-34.

71. Japanese Research Society for Gastric Cancer. The general rules for the gastriccancer study in surgery. Jpn J Surg 1973;3:61-71.

72. Fuchs CS, Mayer RJ. Gastric carcinoma. N Engl J Med 1995;333:32-41.73. Gore RM, Levine MS. Textbook of gastrointestinal surgery. 2nd ed. Philadelphia:

WB Saunders; 2000.74. Levine MS, Creteur V, Kressel HY, Laufer I, Herlinger H. Benign gastric ulcers: diagnosis

and follow-up with double-contrast radiography. Radiology 1987;164:9-13.


6

75. Thompson G, Somers S, Stevenson GW. Benign gastric ulcer: a reliable radiologicdiagnosis? AJR Am J Roentgenol 1983;141:331-3.

76. Shindoh N, Nakagawa T, Ozaki Y, Kyogoku S, Sumi Y, Katayama H. Overlookedgastric carcinoma: pitfalls in upper gastrointestinal radiology. Radiology2000;217:409-14.

77. Japanese classification of gastric carcinoma. 2nd English edition. Responseassessment of chemotherapy and radiotherapy for gastric carcinoma: clinicalcriteria. Gastric Cancer 2001;4:1-8.

78. Ming SC. Gastric carcinoma. A pathobiological classification. Cancer1977;39:2475-85.

79. Lauren P. The two histological main types of gastric carcinoma: diffuse andso-called intestinal-type carcinoma. an attempt at a histo-clinical classification.Acta Pathol Microbiol Scand 1965;64:31-49.

80. Cunningham SC, Kamangar F, Kim MP, Hammoud S, Haque R, Maitra A, et al.Survival after gastric adenocarcinoma resection: eighteen-year experience at asingle institution. J Gastrointest Surg 2005;9:718-25.

81. Wu MS, Shun CT, Wang HP, Sheu JC, Lee WJ, Wang TH, et al. Genetic alterationsin gastric cancer: relation to histological subtypes, tumor stage, and Helicobacterpylori infection. Gastroenterology 1997;112:1457-65.

82. Kokkola A, Sipponen P. Gastric carcinoma in young adults. Hepatogastroenterol-ogy 2001;48:1552-5.

83. Hansson LE, Sparen P, Nyren O. Survival in stomach cancer is improving: resultsof a nationwide population-based Swedish study. Ann Surg 1999;230:162-9.

84. Buzzoni R, Bajetta E, Di BM, Miceli R, Beretta E, Ferrario E, et al. Pathologicalfeatures as predictors of recurrence after radical resection of gastric cancer. Br JSurg 2005;93:205-9.

85. Roder JD, Bottcher K, Busch R, Wittekind C, Hermanek P, Siewert JR. Classifi-cation of regional lymph node metastasis from gastric carcinoma. German GastricCancer Study Group. Cancer 1998;82:621-31.

86. Siewert JR, Bottcher K, Stein HJ, Roder JD. Relevant prognostic factors in gastriccancer: ten-year results of the German Gastric Cancer Study. Ann Surg1998;228:449-61.

87. Schott A, Vogel I, Krueger U, Kalthoff H, Schreiber HW, Schmiegel W, et al.Isolated tumor cells are frequently detectable in the peritoneal cavity of gastric andcolorectal cancer patients and serve as a new prognostic marker. Ann Surg1998;227:372-9.

88. Kodera Y, Nakanishi H, Ito S, Mochizuki Y, Ohashi N, Yamamura Y, et al.Prognostic significance of intraperitoneal cancer cells in gastric carcinoma: analysisof real time reverse transcriptase-polymerase chain reaction after 5 years offollowup. J Am Coll Surg 2006;202:231-6.

89. Jonas S, Weinrich M, Tullius SG, Al-Abadi H, Steinbrich R, Radke C, et al.Microscopic tumor cell dissemination in gastric cancer. Surg Today 2004;34:101-6.

90. Yasuda K, Adachi Y, Shiraishi N, Inomata M, Takeuchi H, Kitano S. Prognosticeffect of lymph node micrometastasis in patients with histologically node-negativegastric cancer. Ann Surg Oncol 2002;9:771-4.

91. Siewert JR, Feith M, Werner M, Stein HJ. Adenocarcinoma of the esophagogastricjunction: results of surgical therapy based on anatomical/topographic classification
in 1,002 consecutive patients. Ann Surg 2000;232:353-61.

1

1

1

1

1

1

1

1

C

92. Hundahl SA, Macdonald JS, Benedetti J, Fitzsimmons T. Surgical treatmentvariation in a prospective, randomized trial of chemoradiotherapy in gastric cancer:the effect of undertreatment. Ann Surg Oncol 2002;9:278-86.

93. Marrelli D, Roviello F, De SA, Fotia G, Giliberto C, Garosi L, Pinto E. Risk factorsfor liver metastases after curative surgical procedures for gastric cancer: aprospective study of 208 patients treated with surgical resection. J Am Coll Surg2004;198:51-8.

94. Kim SH, Karpeh MS, Klimstra DS, Leung D, Brennan MF. Effect of microscopicresection line disease on gastric cancer survival. J Gastrointest Surg 1999;3:24-33.

95. Novotny AR, Schuhmacher C, Busch R, Kattan MW, Brennan MF, Siewert JR.Predicting individual survival after gastric cancer resection: validation of aU.S.-derived nomogram at a single high-volume center in Europe. Ann Surg2006;243:74-81.

96. Dicken BJ, Graham K, Hamilton SM, Andrews S, Lai R, Listgarten J, et al.Lymphovascular invasion is associated with poor survival in gastric cancer: anapplication of gene-expression and tissue array techniques. Ann Surg2006;243:64-73.

97. Marrelli D, DeStefano A, deManzoni G, Morgagni P, DiLeo A, Roviello F.Prediction of recurrence after radical surgery for gastric cancer: a scoring systemobtained from a prospective multicenter study. Ann Surg 2005;241:247-55.

98. Roesch T. Endoscopic ultrasonography: equipment and technique. GastrointestEndosc Clin N Am 2005;15:13-31, vii.

99. Paramo JC, Gomez G. Dynamic CT in the preoperative evaluation of patients withgastric cancer: correlation with surgical findings and pathology. Ann Surg Oncol1999;6:379-84.

00. Davies J, Chalmers AG, Sue-Ling HM, May J, Miller GV, Martin IG, et al. Spiralcomputed tomography and operative staging of gastric carcinoma: a comparisonwith histopathological staging. Gut 1997;41:314-9.

01. Willis S, Truong S, Gribnitz S, Fass J, Schumpelick V. Endoscopic ultrasonographyin the preoperative staging of gastric cancer: accuracy and impact on surgicaltherapy. Surg Endosc 2000;14:951-4.

02. Kelly S, Harris KM, Berry E, Hutton J, Roderick P, Cullingworth J, et al. Asystematic review of the staging performance of endoscopic ultrasound in gastro-oesophageal carcinoma. Gut 2001;49:534-9.

03. Bhandari S, Shim CS, Kim JH, Jung IS, Cho JY, Lee JS, et al. Usefulness ofthree-dimensional, multidetector row CT (virtual gastroscopy and multiplanarreconstruction) in the evaluation of gastric cancer: a comparison with conventionalendoscopy, EUS, and histopathology. Gastrointest Endosc 2004;59:619-26.

04. Aithal GP, Anagnostopoulos GK, Kaye P. EUS-guided Trucut mural biopsies in theinvestigation of unexplained thickening of the esophagogastric wall. GastrointestEndosc 2005;62:624-9.

05. Nguyen PT, Chang KJ. EUS in the detection of ascites and EUS-guided paracen-tesis. Gastrointest Endosc 2001;54:336-9.

06. Prasad P, Schmulewitz N, Patel A, Varadarajulu S, Wildi SM, Roberts S, et al.Detection of occult liver metastases during EUS for staging of malignancies.Gastrointest Endosc 2004;59:49-53.

07. Raju GS, Waxman I. High-frequency US probe sonography-assisted endoscopic
mucosal resection. Gastrointest Endosc 2000;52(6 Suppl):S39-49.

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

6

08. Buskens CJ, Westerterp M, Lagarde SM, Bergman JJ, ten Kate FJ, van Lanschot JJ.Prediction of appropriateness of local endoscopic treatment for high-grade dyspla-sia and early adenocarcinoma by EUS and histopathologic features. GastrointestEndosc 2004;60:703-10.

09. Marks WM, Callen PW, Moss AA. Gastroesophageal region: source of confusionon CT. AJR Am J Roentgenol 1981;136:359-62.

10. Botet JF, Lightdale CJ, Zauber AG, Gerdes H, Winawer SJ, Urmacher C, et al.Preoperative staging of gastric cancer: comparison of endoscopic US and dynamicCT. Radiology 1991;181:426-32.

11. Habermann CR, Weiss F, Riecken R, Honarpisheh H, Bohnacker S, Staedtler C, etal. Preoperative staging of gastric adenocarcinoma: comparison of helical CT andendoscopic US. Radiology 2004;230:465-71.

12. Dux M, Richter GM, Hansmann J, Kuntz C, Kauffmann GW. Helical hydro-CT fordiagnosis and staging of gastric carcinoma. J Comput Assist Tomogr1999;23:913-22.

13. Fukuya T, Honda H, Kaneko K, Kuroiwa T, Yoshimitsu K, Irie H, et al. Efficacyof helical CT in T-staging of gastric cancer. J Comput Assist Tomogr1997;21:73-81.

14. Kumano S, Murakami T, Kim T, Hori M, Iannaccone R, Nakata S, et al. T stagingof gastric cancer: role of multi-detector row CT. Radiology 2005;237:961-6.

15. Lee JH, Jeong YK, Kim DH, Go BK, Woo YJ, Ham SY, Yang SO. Two-phasehelical CT for detection of early gastric carcinoma: importance of the mucosalphase for analysis of the abnormal mucosal layer. J Comput Assist Tomogr2000;24:777-82.

16. Shimizu K, Ito K, Matsunaga N, Shimizu A, Kawakami Y. Diagnosis of gastriccancer with mdct using the water-filling method and multiplanar reconstruction:CT-histologic correlation. AJR Am J Roentgenol 2005;185:1152-8.

17. Takao M, Fukuda T, Iwanaga S, Hayashi K, Kusano H, Okudaira S. Gastric cancer:evaluation of triphasic spiral CT and radiologic-pathologic correlation. J ComputAssist Tomogr 1998;22:288-94.

18. Minami M, Kawauchi N, Itai Y, Niki T, Sasaki Y. Gastric tumors: radiologic-pathologic correlation and accuracy of T staging with dynamic CT. Radiology1992;185:173-8.

19. Tsuda K, Hori S, Murakami T, Nakamura H, Tomoda K, Nakanishi K, et al.Intramural invasion of gastric cancer: evaluation by CT with water-filling method.J Comput Assist Tomogr 1995;19:941-7.

20. Fukuya T, Honda H, Hayashi T, Kaneko K, Tateshi Y, Ro T, et al. Lymph-nodemetastases: efficacy for detection with helical CT in patients with gastric cancer.Radiology 1995;197:705-11.

21. Kim AY, Han JK, Seong CK, Kim TK, Choi BI. MRI in staging advanced gastriccancer: is it useful compared with spiral CT? J Comput Assist Tomogr2000;24:389-94.

22. Sohn KM, Lee JM, Lee SY, Ahn BY, Park SM, Kim KM. Comparing MR imagingand CT in the staging of gastric carcinoma. AJR Am J Roentgenol2000;174:1551-7.

23. Antoch G, Saoudi N, Kuehl H, Dahmen G, Mueller SP, Beyer T, et al. Accuracy
of whole-body dual-modality fluorine-18-2-fluoro-2-deoxy-D-glucose positron

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

C

emission tomography and computed tomography (FDG-PET/CT) for tumor stagingin solid tumors: comparison with CT and PET. J Clin Oncol 2004 1;22:4357-68.

24. Chen J, Cheong JH, Yun MJ, Kim J, Lim JS, Hyung WJ, et al. Improvement inpreoperative staging of gastric adenocarcinoma with positron emission tomogra-phy. Cancer 2005;103:2383-90.

25. Kim SK, Kang KW, Lee JS, Kim HK, Chang HJ, Choi JY, et al. Assessment oflymph node metastases using (18)F-FDG PET in patients with advanced gastriccancer. Eur J Nucl Med Mol Imaging 2005;33:148-55.

26. Stahl A, Ott K, Weber WA, Becker K, Link T, Siewert JR, et al. FDG PET imagingof locally advanced gastric carcinomas: correlation with endoscopic and his-topathological findings. Eur J Nucl Med Mol Imaging 2003;30:288-95.

27. Mochiki E, Kuwano H, Katoh H, Asao T, Oriuchi N, Endo K. Evaluation of18F-2-deoxy-2-fluoro-D-glucose positron emission tomography for gastric cancer.World J Surg 2004;28:247-53.

28. Yoshioka T, Yamaguchi K, Kubota K, Saginoya T, Yamazaki T, Ido T, et al.Evaluation of 18F-FDG PET in patients with a metastatic, or recurrent, gastriccancer. J Nucl Med 2003;44:690-9.

29. Yun M, Lim JS, Noh SH, Hyung WJ, Cheong JH, Bong JK, et al. Lymph nodestaging of gastric cancer using (18)F-FDG PET: a comparison study with CT.J Nucl Med 2005;46:1582-8.

30. De Potter T, Flamen P, Van CE, Penninckx F, Filez L, Bormans G, et al.Whole-body PET with FDG for the diagnosis of recurrent gastric cancer. Eur J NuclMed Mol Imaging 2002;29:525-9.

31. Ott K, Fink U, Becker K, Stahl A, Dittler HJ, Busch R, et al. Prediction of responseto preoperative chemotherapy in gastric carcinoma by metabolic imaging: results ofa prospective trial. J Clin Oncol 2003;21:4604-10.

32. Shandall A, Johnson C. Laparoscopy or scanning in oesophageal and gastriccarcinoma? Br J Surg 1985;72:449-51.

33. Gross E, Bancewicz J, Ingram G. Assessment of gastric cancer by laparoscopy. BrMed J (Clin Res Ed) 1984;288:1577 (letter)

34. Watt I, Stewart I, Anderson D, Bell G, Anderson JR. Laparoscopy, ultrasound andcomputed tomography in cancer of the oesophagus and gastric cardia: a prospectivecomparison for detecting intra-abdominal metastases. Br J Surg 1989;76:1036-9.

35. Tschmelitsch J, Weiser MR, Karpeh MS. Modern staging in gastric cancer. SurgOncol 2000;9:23-30.

36. Molloy RG, McCourtney JS, Anderson JR. Laparoscopy in the management ofpatients with cancer of the gastric cardia and oesophagus. Br J Surg 1995;82:352-4.

37. Kriplani AK, Kapur BM. Laparoscopy for pre-operative staging and assessment ofoperability in gastric carcinoma. Gastrointest Endosc 1991;37:441-3.

38. Burke EC, Karpeh MS, Conlon KC, Brennan MF. Laparoscopy in the managementof gastric adenocarcinoma. Ann Surg 1997;225:262-7.

39. Finch MD, John TG, Garden OJ, Allan PL, Paterson-Brown S. Laparoscopicultrasonography for staging gastroesophageal cancer. Surgery 1997;121:10-7.

40. Jaffer A, Bekaii-Saab T, Javie M, Minsky B. Gastric Cancer Clinical PracticeGuidelines in Oncology. http://www.nccn.org/professionals/physician_gls/PDF/gastric.pdf, 2006, v.1.2006, accessed 8/22/2006

41. D’Ugo DM, Pende V, Persiani R, Rausei S, Picciocchi A. Laparoscopic staging of
gastric cancer: an overview. J Am Coll Surg 2003;196:965-74.



1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

6

42. Inada T, Ogata Y, Kubota T, Ishihara M, Tomikawa M, Ando J, et al. D2-lymphadenectomy improves the survival of patients with peritoneal cytology-positive gastric cancer. Anticancer Res 2002;22:291-4.

43. Scartozzi M, Galizia E, Graziano F, Catalano V, Berardi R, Baldelli AM, et al.Over-DI dissection may question the value of radiotherapy as a part of an adjuvantprogramme in high-risk radically resected gastric cancer patients. Br J Cancer 200528;92:1051-4.

44. Harrison LE, Karpeh MS, Brennan MF. Extended lymphadenectomy is associatedwith a survival benefit for node-negative gastric cancer. J Gastrointest Surg1998;2:126-31.

45. Cuschieri A, Weeden S, Fielding J, Bancewicz J, Craven J, Joypaul V, et al. Patientsurvival after D1 and D2 resections for gastric cancer: long-term results of theMRC randomized surgical trial. Surgical Co-operative Group. Br J Cancer1999;79(9-10):1522-30.

46. Bonenkamp JJ, Hermans J, Sasako M, van de Velde CJ, Welvaart K, Songun I, etal. Extended lymph-node dissection for gastric cancer. N Engl J Med1999;340:908-14.

47. Fatouros M, Roukos DH, Lorenz M, Arampatzis I, Hottentrott C, Encke A, et al.Impact of spleen preservation in patients with gastric cancer. Anticancer Res2005;25:3023-30.

48. Brady MS, Rogatko A, Dent LL, Shiu MH. Effect of splenectomy on morbidity andsurvival following curative gastrectomy for carcinoma. Arch Surg 1991;126:359-64.

49. Griffith JP, Sue-Ling HM, Martin I, Dixon MF, McMahon MJ, Axon AT, et al.Preservation of the spleen improves survival after radical surgery for gastric cancer.Gut 1995;36:684-90.

50. Smith JW, Shiu MH, Kelsey L, Brennan MF. Morbidity of radical lymphadenec-tomy in the curative resection of gastric carcinoma. Arch Surg 1991;126:1469-73.

51. Edwards P, Blackshaw GR, Lewis WG, Barry JD, Allison MC, Jones DR.Prospective comparison of D1 vs modified D2 gastrectomy for carcinoma. Br JCancer 2004;90:1888-92.

52. McCulloch P, Nita ME, Kazi H, Gama-Rodrigues J. Extended versus limited lymphnodes dissection technique for adenocarcinoma of the stomach. Cochrane DatabaseSyst Rev 2004;(4):CD001964.

53. Jansen EP, Boot H, Verheij M, van de Velde CJ. Optimal locoregional treatment ingastric cancer. J Clin Oncol 2005;23:4509-17.

54. McCulloch P, Niita ME, Kazi H, Gama-Rodrigues JJ. Gastrectomy with extendedlymphadenectomy for primary treatment of gastric cancer. Br J Surg 2005;92:5-13.

55. Karpeh MS, Leon L, Klimstra D, Brennan MF. Lymph node staging in gastriccancer: is location more important than number? An analysis of 1,038 patients. AnnSurg 2000;232:362-71.

56. Bozzetti F, Bonfanti G, Bufalino R, Menotti V, Persano S, Andreola S, et al.Adequacy of margins of resection in gastrectomy for cancer. Ann Surg1982;196:685-90.

57. Harrison LE, Karpeh MS, Brennan MF. Proximal gastric cancers resected via atransabdominal-only approach. Results and comparisons to distal adenocarcinomaof the stomach. Ann Surg 1997;225:678-83.

58. Zinninger MM. Extension of gastric cancer in the intramural lymphatics and its
relation to gastrectomy. Am Surg 1954;20:920-7.

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

C

59. Gouzi JL, Huguier M, Fagniez PL, Launois B, Flamant Y, Lacaine F, et al. Totalversus subtotal gastrectomy for adenocarcinoma of the gastric antrum. A Frenchprospective controlled study. Ann Surg 1989;209:162-6.

60. Robertson CS, Chung SC, Woods SD, Griffin SM, Raimes SA, Lau JT, et al. Aprospective randomized trial comparing R1 subtotal gastrectomy with R3 totalgastrectomy for antral cancer. Ann Surg 1994;220:176-82.

61. Bozzetti F, Marubini E, Bonfanti G, Miceli R, Piano C, Crose N, et al. Total versussubtotal gastrectomy: surgical morbidity and mortality rates in a multicenter Italianrandomized trial. The Italian Gastrointestinal Tumor Study Group. Ann Surg1997;226:613-20.

62. Bozzetti F, Marubini E, Bonfanti G, Miceli R, Piano C, Gennari L. Subtotal versustotal gastrectomy for gastric cancer: five-year survival rates in a multicenterrandomized Italian trial. Italian Gastrointestinal Tumor Study Group. Ann Surg1999;230:170-8.

63. Walther BS, Oscarson JE, Graffner HO, Vallgren S, Evander A. Esophagojejunos-tomy with the EEA stapler. Surgery 1986;99:598-603.

64. Wong J, Cheung H, Lui R, Fan YW, Smith A, Siu KF. Esophagogastricanastomosis performed with a stapler: the occurrence of leakage and stricture.Surgery 1987;101:408-15.

65. Seufert RM, Schmidt-Matthiesen A, Beyer A. Total gastrectomy and oesophagoje-junostomy—a prospective randomized trial of hand-sutured versus mechanicallystapled anastomoses. Br J Surg 1990;77:50-2.

66. Walther B, Lowenhielm P, Strand SE, Stahlberg F, Uvelius B, Oscarson J, et al.Healing of esophagojejunal anastomoses after experimental total gastrectomy. Acomparative study using manually sutured or stapled anastomoses. Ann Surg1986;203:439-46.

67. Herfarth C, Schlag P, Buhl K. Surgical procedures for gastric substitution. WorldJ Surg 1987;11:689-98.

68. Nakane Y, Okumura S, Akehira K, Okamura S, Boku T, Okusa T, et al. Jejunalpouch reconstruction after total gastrectomy for cancer. A randomized controlledtrial. Ann Surg 1995;222:27-35.

69. Nozoe T, Anai H, Sugimachi K. Usefulness of reconstruction with jejunal pouch intotal gastrectomy for gastric cancer in early improvement of nutritional condition.Am J Surg 2001;181:274-8.

70. Thiede A, Fuchs KH, Hamelman H. Pouch and Roux-en-Y reconstruction aftergastrectomy. Arch Surg 1987;122:837-42.

71. Legaspi A, Irani H. Stapled transabdominal lower esophageal anastomosis withoutpurse-string suture. Surg Gynecol Obstet 1990;170:156-8.

72. Tejero CE, Ratia GT, Fernandez FL, Tieso HA, Jorge SE. Double-staplingtechnique for mechanical circular oesophagojejunal anastomosis after total gastrec-tomy. Br J Surg 1994;81:408-9.

73. Rohde H, Gebbensleben B, Bauer P, Stutzer H, Zieschang J. Has there been anyimprovement in the staging of gastric cancer? Findings from the German GastricCancer TNM Study Group. Cancer 1989;64:2465-81.

74. Kobayashi A, Nakagohri T, Konishi M, Inoue K, Takahashi S, Itou M, et al.Aggressive surgical treatment for T4 gastric cancer. J Gastrointest Surg2004;8:464-70.

75. Martin RC, Jaques DP, Brennan MF, Karpeh M. Extended local resection for


1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

6

advanced gastric cancer: increased survival versus increased morbidity. Ann Surg2002;236:159-65.

76. Shchepotin IB, Chorny VA, Nauta RJ, Shabahang M, Buras RR, Evans SR.Extended surgical resection in T4 gastric cancer. Am J Surg 1998;175:123-6.

77. Kunisaki C, Akiyama H, Nomura M, Matsuda G, Otsuka Y, Ono HA, et al. Surgicaloutcomes in patients with t4 gastric carcinoma. J Am Coll Surg 2006;202:223-30.

78. Sandler RS, Johnson MD, Holland KL. Risk of stomach cancer after gastric surgeryfor benign conditions. A case-control study. Dig Dis Sci 1984;29:703-8.

79. Nelson R, Edwards S, Tse B. Prophylactic nasogastric decompression afterabdominal surgery. Cochrane Database Syst Rev 2005;(1):CD004929.

80. Doglietto GB, Papa V, Tortorelli AP, Bossola M, Covino M, Pacelli F. Nasojejunaltube placement after total gastrectomy: a multicenter prospective randomized trial.Arch Surg 2004;139:1309-13.

81. Watters JM, Kirkpatrick SM, Norris SB, Shamji FM, Wells GA. Immediatepostoperative enteral feeding results in impaired respiratory mechanics and de-creased mobility. Ann Surg 1997;226:369-77.

82. McCarter MD, Gomez ME, Daly JM. Early postoperative enteral feeding followingmajor upper gastrointestinal surgery. J Gastrointest Surg 1997;1:278-85.

83. Gianotti L, Braga M, Vignali A, Balzano G, Zerbi A, Bisagni P, et al. Effect of route ofdelivery and formulation of postoperative nutritional support in patients undergoing majoroperations for malignant neoplasms. Arch Surg 1997;132:1222-9.

84. Senkal M, Zumtobel V, Bauer KH, Marpe B, Wolfram G, Frei A, et al. Outcomeand cost-effectiveness of perioperative enteral immunonutrition in patients under-going elective upper gastrointestinal tract surgery: a prospective randomized study.Arch Surg 1999;134:1309-16.

85. Heys SD, Walker LG, Smith I, Eremin O. Enteral nutritional supplementation withkey nutrients in patients with critical illness and cancer: a meta-analysis ofrandomized controlled clinical trials. Ann Surg 1999;229:467-77.

86. Kobayashi T, Hisanaga M, Kanehiro H, Yamada Y, Ko S, Nakajima Y. Analysisof risk factors for the development of gallstones after gastrectomy. Br J Surg2005;92:1399-403.

87. Kim J, Lee J, Hyung WJ, Cheong JH, Chen J, Choi SH, et al. Gastric cancer surgerywithout drains: a prospective randomized trial. J Gastrointest Surg 2004;8:727-32.

88. Allum WH, Powell DJ, McConkey CC, Fielding JW. Gastric cancer: a 25-yearreview. Br J Surg 1989;76:535-40.

89. McCulloch P, Ward J, Tekkis PP. Mortality and morbidity in gastro-oesophagealcancer surgery: initial results of ASCOT multicentre prospective cohort study. BMJ2003 22;327:1192-7.

90. Park DJ, Lee HJ, Kim HH, Yang HK, Lee KU, Choe KJ. Predictors of operativemorbidity and mortality in gastric cancer surgery. Br J Surg 2005;92:1099-102.

91. Shchepotin IB, Evans SR, Chorny VA, Shabahang M, Buras RR, Nauta RJ.Postoperative complications requiring relaparotomies after 700 gastrectomiesperformed for gastric cancer. Am J Surg 1996;171:270-3.

92. Sasako M, Katai H, Sano T, Maruyama K. Management of complications aftergastrectomy with extended lymphadenectomy. Surg Oncol 2000;9:31-4.

93. Lang H, Piso P, Stukenborg C, Raab R, Jahne J. Management and results ofproximal anastomotic leaks in a series of 1114 total gastrectomies for gastric
carcinoma. Eur J Surg Oncol 2000;26:168-71.

1

1

1

1

1

1

2

2

2

2

2

2

2

2

2

2

2

2

C

94. Langer FB, Wenzl E, Prager G, Salat A, Miholic J, Mang T, et al. Management ofpostoperative esophageal leaks with the Polyflex self-expanding covered plasticstent. Ann Thorac Surg 2005;79:398-403.

95. Kwak HS, Lee JM, Jin GY, Han YM, Yang DH. Treatment of gastrojejunalanastomotic leak with a covered metallic stent. Hepatogastroenterology2003;50:62-4.

96. Woods SC, Seeley RJ. Understanding the physiology of obesity: review of recentdevelopments in obesity research. Int J Obes Relat Metab Disord 2002;26(Suppl4):S8-10.

97. Chagnon YC, Perusse L, Weisnagel SJ, Rankinen T, Bouchard C. The humanobesity gene map: the 1999 update. Obes Res 2000;8:89-117.

98. Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Dellinger EP, et al.Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery.N Engl J Med 2002;346:1623-30.

99. Miholic J, Meyer HJ, Kotzerke J, Balks J, Aebert H, Jahne J, et al. Emptying of thegastric substitute after total gastrectomy. Jejunal interposition versus Roux-yesophagojejunostomy. Ann Surg 1989;210:165-72.

00. Kiyama T, Mizutani T, Okuda T, Fujita I, Tokunaga A, Tajiri T, et al. Postoperativechanges in body composition after gastrectomy. J Gastrointest Surg 2005;9:313-9.

01. Friess H, Bohm J, Muller MW, Glasbrenner B, Riepl RL, Malfertheiner P, et al.Maldigestion after total gastrectomy is associated with pancreatic insufficiency.Am J Gastroenterol 1996;91:341-7.

02. Meyer JH. Nutritional outcomes of gastric operations. In: Thirlby RC, editor.Gastroenterology Clinics of North America. Philadelphia: WB Saunders;1994:227-60.

03. Stael von Holstein C, Walther B, Ibrahimbegovic E, Akesson B. Nutritional statusafter total and partial gastrectomy with Roux-en-Y reconstruction. Br J Surg1991;78:1084-7.

04. Bisballe S, Eriksen EF, Melsen F, Mosekilde L, Sorensen OH, Hessov I.Osteopenia and osteomalacia after gastrectomy: interrelations between biochemicalmarkers of bone remodelling, vitamin D metabolites, and bone histomorphometry.Gut 1991;32:1303-7.

05. Inoue K, Shiomi K, Higashide S, Kan N, Nio Y, Tobe T, et al. Metabolic bonedisease following gastrectomy: assessment by dual energy X-ray absorptiometry.Br J Surg 1992;79:321-4.

06. Tovey FI, Hall ML, Ell PJ, Hobsley M. Postgastrectomy osteoporosis. Br J Surg1991;78:1335-7.

07. Wetscher G, Redmond E, Watfah C, Perdikis G, Gadenstatter M, Pointner R. Bonedisorders following total gastrectomy. Dig Dis Sci 1994;39:2511-5.

08. Kozawa K, Imawari M, Shimazu H, Kobori O, Osuga T, Morioka Y. Vitamin Dstatus after total gastrectomy. Dig Dis Sci 1984;29:411-6.

09. Suzuki Y, Ishibashi Y, Omura N, Kawasaki N, Kashiwagi H, Yanaga K, et al.Alendronate improves vitamin D-resistant osteopenia triggered by gastrectomy inpatients with gastric cancer followed long term. J Gastrointest Surg 2005;9:955-60.

10. Northfield TC, Hall CN. Carcinoma of the gastric stump: risks and pathogenesis.Gut 1990;31:1217-9.

11. Lundegardh G, Adami HO, Helmick C, Zack M. Risk of cancer following partial
gastrectomy for benign ulcer disease. Br J Surg 1994;81:1164-7.

2

2

2

2

2

2

2

2

2

2

2

2

2

2

2

2

2

2

2

6

12. Mason GR. Perspectives a century later on the “Ansa en Y” of Cesar Roux. Am JSurg 1991;161:262-5.

13. Toftgaard C. Gastric cancer after peptic ulcer surgery. A historic prospective cohortinvestigation. Ann Surg 1989;210:159-64.

14. Offerhaus GJ, Tersmette AC, Huibregtse K, van de Stadt J, Tersmette KW, StijnenT, et al. Mortality caused by stomach cancer after remote partial gastrectomy forbenign conditions: 40 years of follow up of an Amsterdam cohort of 2633postgastrectomy patients. Gut 1988;29:1588-90.

15. Stael von Holstein CC, Anderson H, Eriksson SB, Huldt B. Mortality after remotesurgery for benign gastroduodenal disease. Gut 1995;37:617-22.

16. Lundegardh G, Ekbom A, McLaughlin JK, Nyren O. Gastric cancer risk aftervagotomy. Gut 1994;35:946-9.

17. Schafer LW, Larson DE, Melton LJ III, Higgins JA, Ilstrup DM. The risk of gastriccarcinoma after surgical treatment for benign ulcer disease. A population-basedstudy in Olmsted County, Minnesota. N Engl J Med 1983;309:1210-3.

18. Schnapka G, Hofstaedter F, Schwamberger K, Reissigl H. Gastric stump carcinomafollowing Billroth II resection for peptic ulcer disease. Comparison with cancer innon-operated stomach. Endoscopy 1984;16:171-4.

19. Hansson LE, Nyren O, Hsing AW, Bergstrom R, Josefsson S, Chow WH, et al. Therisk of stomach cancer in patients with gastric or duodenal ulcer disease. N EnglJ Med 1996;335:242-9.

20. Pointner R, Schwab G, Konigsrainer A, Bodner E, Schmid KW. Early cancer of thegastric remnant. Gut 1988;29:298-301.

21. Greene FL. Early detection of gastric remnant carcinoma. The role of gastroscopicscreening. Arch Surg 1987;122:300-3.

22. Geboes K, Rutgeerts P, Broeckaert L, Vantrappen G, Desmet V. Histologicappearances of endoscopic gastric mucosal biopsies 10-20 years after partialgastrectomy. Ann Surg 1980;192:179-82.

23. Marrero JM, de Caestecker JS, Corbishley CM, McCormick C, Northfield TC.Gastric DNA content in postgastrectomy patients. Relationship to mucosal dyspla-sia. Cancer 1996;77:19-24.

24. Offerhaus GJ, van de Stadt J, Huibregtse K, Tersmette AC, Tytgat GN. The mucosaof the gastric remnant harboring malignancy. Histologic findings in the biopsyspecimens of 504 asymptomatic patients 15 to 46 years after partial gastrectomywith emphasis on nonmalignant lesions. Cancer 1989;64:698-703.

25. Stael von Holstein C, Hammar E, Eriksson S, Huldt B. Clinical significance ofdysplasia in gastric remnant biopsy specimens. Cancer 1993;72:1532-5.

26. Greene FL. Management of gastric remnant carcinoma based on the results of a15-year endoscopic screening program. Ann Surg 1996;223:701-6.

27. Sonnenberg A. Endoscopic screening for gastric stump cancer—would it bebeneficial? A hypothetical cohort study. Gastroenterology 1984;87:489-95.

28. Sasako M, Maruyama K, Kinoshita T, Okabayashi K. Surgical treatment ofcarcinoma of the gastric stump. Br J Surg 1991;78:822-4.

29. Kodera Y, Yamamura Y, Torii A, Uesaka K, Hirai T, Yasui K, et al. Gastricremnant carcinoma after partial gastrectomy for benign and malignant gastriclesions. J Am Coll Surg 1996;182:1-6.

30. Furukawa H, Iwanaga T, Hiratsuka M, Imaoka S, Ishikawa O, Kabuto T, et al.
Gastric remnant cancer as a metachronous multiple lesion. Br J Surg 1993;80:54-6.

2

2

2

2

2

2

2

2

2

2

2

2

2

2

2

2

2

2

2

C

31. Viste A, Eide GE, Glattre E, Soreide O. Cancer of the gastric stump: analyses of819 patients and comparison with other stomach cancer patients. World J Surg1986;10:454-61.

32. Ikeguchi M, Kondou A, Shibata S, Yamashiro H, Tsujitani S, Maeta M, et al.Clinicopathologic differences between carcinoma in the gastric remnant stump afterdistal partial gastrectomy for benign gastroduodenal lesions and primary carcinomain the upper third of the stomach. Cancer 1994;73:15-21.

33. Eckardt VF, Giessler W, Kanzler G, Remmele W, Bernhard G. Clinical andmorphological characteristics of early gastric cancer. A case-control study. Gas-troenterology 1990;98:708-14.

34. Green PH, O’Toole KM, Weinberg LM, Goldfarb JP. Early gastric cancer.Gastroenterology 1981;81:247-56.

35. Moreaux J, Bougaran J. Early gastric cancer. A 25-year surgical experience. AnnSurg 1993;217:347-55.

36. Lawrence M, Shiu MH. Early gastric cancer. Twenty-eight-year experience. AnnSurg 1991;213:327-34.

37. Okuda H, Suzuki S, Suzuki H, Kurokawa K, Kitamura Y, Mitsunaga A, et al.Diagnosis and prognosis of early gastric cancer: the experience in Japan. TropGastroenterol 1988;9:7-13.

38. Gebhardt C, Husemann B, Hermanek P, Gentsch HH. Clinical aspects and therapyof early gastric cancer. World J Surg 1981;5:721-4.

39. Sano T, Katai H, Sasako M, Maruyama K. The management of early gastric cancer.Surg Oncol 2000;9:17-22.

40. Kuwayama H, Eastwood GL, Kohashi E, Honda T. Endoscopic local injection ofearly gastric carcinoma with 5-fluorouracil. Dig Dis Sci 1984;29:498-501.

41. Sakita T, Koyama S, Ishii M, Togo J, Miyamoto J, Nakahara A, et al. Early cancerof the stomach treated successfully with an endoscopic neodymium-YAG laser:report of a case. Am J Gastroenterol 1981;76:441-5.

42. Kitagawa Y, Fujii H, Mukai M, Kubota T, Otani Y, Kitajima M. Radio-guidedsentinel node detection for gastric cancer. Br J Surg 2002;89:604-8.

43. Seto Y, Yamaguchi H, Shimoyama S, Shimizu N, Aoki F, Kaminishi M. Results oflocal resection with regional lymphadenectomy for early gastric cancer. Am J Surg2001;182:498-501.

44. Kitano S, Shiraishi N. Minimally invasive surgery for gastric tumors. Surg ClinNorth Am 2005;85:151-64, xi.

45. Huscher CG, Mingoli A, Sgarzini G, Sansonetti A, Di Paola M, Recher A, et al.Laparoscopic versus open subtotal gastrectomy for distal gastric cancer: five-yearresults of a randomized prospective trial. Ann Surg 2005;241:232-7.

46. ReMine WH. Palliative operations for incurable gastric cancer. World J Surg1979;3:721-9.

47. Miner TJ, Jaques DP, Karpeh MS, Brennan MF. Defining palliative surgery inpatients receiving noncurative resections for gastric cancer. J Am Coll Surg2004;198:1013-21.

48. Haugstvedt T, Viste A, Eide GE, Soreide O. The survival benefit of resection inpatients with advanced stomach cancer: the Norwegian multicenter experience.Norwegian Stomach Cancer Trial. World J Surg 1989;13:617-21.

49. Monson JR, Donohue JH, McIlrath DC, Farnell MB, Ilstrup DM. Total gastrectomy
for advanced cancer. A worthwhile palliative procedure. Cancer 1991;68:1863-8.

2

2

2

2

2

2

2

2

2

2

2

2

2

2

2

2

6

50. Boddie AW Jr, McMurtrey MJ, Giacco GG, McBride CM. Palliative totalgastrectomy and esophagogastrectomy. A reevaluation. Cancer 1983;51:1195-200.

51. Bozzetti F, Bonfanti G, Audisio RA, Doci R, Dossena G, Gennari L, et al.Prognosis of patients after palliative surgical procedures for carcinoma of thestomach. Surg Gynecol Obstet 1987;164:151-4.

52. Cosentini EP, Sautner T, Gnant M, Winkelbauer F, Teleky B, Jakesz R. Outcomesof surgical, percutaneous endoscopic, and percutaneous radiologic gastrostomies.Arch Surg 1998;133:1076-83.

53. Dormann AJ. Endoscopic palliation and nutritional support in advanced gastriccancer. Dig Dis 2004;22:351-9.

54. Sarela AI, Miner TJ, Karpeh MS, Coit DG, Jaques DP, Brennan MF. Clinicaloutcomes with laparoscopic stage M1, unresected gastric adenocarcinoma. AnnSurg 2006;243:189-95.

55. Macdonald JS, Schein PS, Woolley PV, Smythe T, Ueno W, Hoth D, et al.5-Fluorouracil, doxorubicin, and mitomycin (FAM) combination chemotherapy foradvanced gastric cancer. Ann Intern Med 1980;93:533-6.

56. Preusser P, Achterrath W, Wilke H, Lenaz L, Fink U, Heinicke A, et al.Chemotherapy of gastric cancer. Cancer Treat Rev 1988;15:257-77.

57. Ogawa M. A recent overview of chemotherapy for advanced stomach cancer inJapan. Antibiot Chemother 1978;24:149-59.

58. Cocconi G, DeLisi V, Di BB. Randomized comparison of 5-FU alone or combinedwith mitomycin and cytarabine (MFC) in the treatment of advanced gastric cancer.Cancer Treat Rep 1982;66:1263-6.

59. Cullinan SA, Moertel CG, Fleming TR, Rubin JR, Krook JE, Everson LK, et al. Acomparison of three chemotherapeutic regimens in the treatment of advancedpancreatic and gastric carcinoma. Fluorouracil vs fluorouracil and doxorubicin vsfluorouracil, doxorubicin, and mitomycin. JAMA 1985;253:2061-7.

60. Klein HO. Long-term results with FAMTX (5-fluorouracil, adriamycin, methotrex-ate) in advanced gastric cancer. Anticancer Res 1989;9:1025-6.

61. Wils JA, Klein HO, Wagener DJ, Bleiberg H, Reis H, Korsten F, et al. Sequentialhigh-dose methotrexate and fluorouracil combined with doxorubicin–a step aheadin the treatment of advanced gastric cancer: a trial of the European Organization forResearch and Treatment of Cancer Gastrointestinal Tract Cooperative Group. J ClinOncol 1991;9:827-31.

62. Kelsen DP, Buckner J, Einzig A, Magill G, Heelan R, Vinciguerra V. Phase II trialof cisplatin and etoposide in adenocarcinomas of the upper gastrointestinal tract.Cancer Treat Rep 1987;71:329-30.

63. Preusser P, Wilke H, Achterrath W, Fink U, Lenaz L, Heinicke A, et al. Phase IIstudy with the combination etoposide, doxorubicin, and cisplatin in advancedmeasurable gastric cancer. J Clin Oncol 1989;7:1310-7.

64. Wilke H, Preusser P, Fink U, Achterrath W, Meyer HJ, Stahl M, et al. Newdevelopments in the treatment of gastric carcinoma. Semin Oncol 1990;17(1 Suppl2):61-70.

65. Vanhoefer U, Rougier P, Wilke H, Ducreux MP, Lacave AJ, Van CE, et al. Finalresults of a randomized phase III trial of sequential high-dose methotrexate,fluorouracil, and doxorubicin versus etoposide, leucovorin, and fluorouracil versus
infusional fluorouracil and cisplatin in advanced gastric cancer: A trial of the

2

2

2

2

2

2

2

2

2

2

2

2

2

2

2

C

European Organization for Research and Treatment of Cancer GastrointestinalTract Cancer Cooperative Group. J Clin Oncol 2000;18:2648-57.

66. Cunningham D, Cahn A, Menzies-Gow N. Cisplatin, epirubicin and 5-fluorouracil(CEF) has significant activity in advance gastric cancer. Proc ASCO 1990;9:123.

67. Waters JS, Norman A, Cunningham D, Scarffe JH, Webb A, Harper P, et al.Long-term survival after epirubicin, cisplatin and fluorouracil for gastric cancer:results of a randomized trial. Br J Cancer 1999;80(1-2):269-72.

68. Moiseyenko VM, Ajani JA, Tjulandin A, Majlis M, Consela C, Boni A. Finalresults of a randomized controlled phase III trial (TAX 325) comparing docetaxel(T) combined with cisplatin (C) and 5-flurouracil (F) to CF in patients withmetastatic gastric adenocarcinoma. Proc ASCO 2005;43:308.

69. Wagner AD, Grothe W, Behl S, Kleber G, Grothey A, Haerting J, et al.Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev 2005;(2):CD004064.

70. Boku N, Chin K, Hosokawa K, Ohtsu A, Tajiri H, Yoshida S, et al. Biologicalmarkers as a predictor for response and prognosis of unresectable gastric cancerpatients treated with 5-fluorouracil and cis-platinum. Clin Cancer Res1998;4:1469-74.

71. The concept of locally advanced gastric cancer. Effect of treatment on outcome.The Gastrointestinal Tumor Study Group. Cancer 1990;66:2324-30.

72. Higgins GA, Amadeo JH, Smith DE, Humphrey EW, Keehn RJ. Efficacy ofprolonged intermittent therapy with combined 5-FU and methyl-CCNU followingresection for gastric carcinoma. A Veterans Administration Surgical Oncology,Group report. Cancer 1983;52:1105-12.

73. Lise M, Nitti D, Marchet A, Sahmoud T, Buyse M, Duez N, et al. Final results ofa phase III clinical trial of adjuvant chemotherapy with the modified fluorouracil,doxorubicin, and mitomycin regimen in resectable gastric cancer. J Clin Oncol1995;13:2757-63.

74. Macdonald JS, Fleming TR, Peterson RF, Berenberg JL, McClure S, Chapman RA,et al. Adjuvant chemotherapy with 5-FU, adriamycin, and mitomycin-C (FAM)versus surgery alone for patients with locally advanced gastric adenocarcinoma: ASouthwest Oncology Group study. Ann Surg Oncol 1995;2:488-94.

75. Imanaga H, Nakazato H. Results of surgery for gastric cancer and effect of adjuvantmitomycin C on cancer recurrence. World J Surg 1977;2:213-21.

76. Nakajima T, Takahashi T, Takagi K, Kuno K, Kajitani T. Comparison of5-fluorouracil with ftorafur in adjuvant chemotherapies with combined inductiveand maintenance therapies for gastric cancer. J Clin Oncol 1984;2:1366-71.

77. Hermans J, Bonenkamp JJ, Boon MC, Bunt AM, Ohyama S, Sasako M, et al.Adjuvant therapy after curative resection for gastric cancer: meta-analysis ofrandomized trials. J Clin Oncol 1993;11:1441-7.

78. Earle CC, Maroun JA. Adjuvant chemotherapy after curative resection for gastriccancer in non-Asian patients: revisiting a meta-analysis of randomised trials. Eur JCancer 1999;35:1059-64.

79. Moertel CG, Childs DS, O’Fallon JR, Holbrook MA, Schutt AJ, Reitemeier RJ.Combined 5-fluorouracil and radiation therapy as a surgical adjuvant for poorprognosis gastric carcinoma. J Clin Oncol 1984;2:1249-54.

80. Herskovic A, Martz K, al-Sarraf M, Leichman L, Brindle J, Vaitkevicius V, et al.


2

2

6

Combined chemotherapy and radiotherapy compared with radiotherapy alone inpatients with cancer of the esophagus. N Engl J Med 1992;326:1593-8.

81. Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, StemmermannGN, et al. Chemoradiotherapy after surgery compared with surgery alone foradenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med2001;345:725-30.

82. Allum N, Cunningham D, Weeden S. UK NCRI Upper GI Clinical Studies Group:Peri-operative chemotherapy in operable gastric and lower esophageal cancer:randomised controlled trial (the Magic Trial). Proc ASCO 2005;22:249.


08 - 09. gastric cancer

Documents

incidence ofstric cancer

rates of gastric cancer

pathogenesisgastric

common cancer

gastric cancerstric

incidence of cardia

highest incidence rates

lowest incidence rates