UPDATE ARTICLE

Gastric Cancer - An Overview

K M ChU,* FRCS(Ed). FACS. FHKAM(Surgery), FCSHK

Department of SurgeryQueen Mary Hospital

Summary

Gastric cancer remains the second leading cause of cancer-related deaths worldwide. Apart from dietary factors,

Helicobacter pylori is currently considered as one of the most important risk factors. The incidence of gastric cancer

in Hong Kong is not high enough to justify population screening with upper endoscopy. Clinical features, however,

can be quite non-specific. Patients may be asymptomatic, especially during early stage of the disease. Upper

endoscopy should be considered in patients presenting with recent onset of ulcer-like symptoms, weight loss, symptoms

of obstruction, bleeding or anaemia, especially if they are elderly. By the time clinical features of metastases are

apparent, the disease would be beyond cure. In recent years, endoscopic ultrasonography and staging laparoscopy

have greatly enhanced the pre-operative staging accuracy. Such information will be important if neoadjuvantchemotherapy is contemplated for advanced disease. At present, surgery remains the mainstay of potentially curative

treatment. Post-operative adjuvant chemotherapy is not recommended unless on a proper trial basis. Early results

of pre-operative neoadjuvant chemotherapy are encouraging but further studies are required to confirm its efficacy.

For unresectable gastric cancer, various treatment options are available and selection has to be individualised. (HK

Pract 1999;21:357-364)

A A *J

Introduction

Despite a steady decline ini n c i d e n c e in many deve lopedcountries, gastric cancer continues tobe the second leading cause ofcancer-related deaths worldwide.1 In

Hong Kong, it is the fourth leadingcause of cancer-related deaths.2

Complete surgical extirpation of thetumour remains the mains tay ofpotentially curative treatment. Ifdiscovered early, prior to dissemina-tion of disease, gastric cancer is

curable after surgical resection.

Nevertheless, despite advances inmedical knowledge and technology,gastric cancer is rarely diagnosed at

an early stage. In Japan, where theincidence of gastric cancer is highand screening is practised, early

* Address for correspondence: Dr. K M Chu, Associate Professor, Division of Upper Gastrointestinal Surgery, Department of Surgery, University of HongKong Medical Centre, Queen Mary Hospital, Pokfulam Road, Hong Kong.

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gastric cancer confined to the mucosaor submucosa constitutes about 50%of all new cases. 3 In Westerncountries as well as in Hong Kong,however, approximately two thirds ofpatients with gastric cancer presentwith stage III or IV disease.4 Curatives u r g i c a l r e sec t ion i s t h e r e f o r eimpossible in the majority of patients.The prognosis of the disease remainsdismal because of the d e l a y inpresen ta t ion as w e l l as a h i g hrecurrence rate despite an apparentcu ra t i ve resect ion for advanceddisease.

Epidemiology

Gastric cancer has a predilectionf o r m a l e s i n v i r t u a l l y e v e r ypopulation studied. Geographically,there is wide variation in incidence ofgastric cancer in different parts of theworld. Japan has one of the highestincidence in the world; the incidencerate in Japan is about 8.5 times thatobserved in North America. Otherareas with high incidence include, forexample, China, Costa Rica, Korea,Chile, Poland, and the former SovietUnion. Various epidemiologicalstudies have examined a number ofpotential risk factors which mighthelp explain the global variation inincidence. In general, gastric cancerappears to have a m u l t i f a c t o r i a laetiology, and the etiological factorsm a y h a v e d i f f e r e n t r e l a t i v eimportance in different parts of theworld. Traditionally, dietary factorshave been g i v e n the g r e a t e s temphasis, although there is no singledietary item that could account for allthe differences in cancer incidence.Gastric cancer has previously beenreported to be associated with an

increased dietary intake of N-nitrosocompounds, nitrites and salts, and adecreased intake of ascorbate, freshf r u i t s and vegetables . 1 A l l i u mvegetables, like onion and garlic, mayplay a protective role by detoxifyingcarcinogens.5 Other risk factors forgastric cancer include smoking, apast history of partial gastrectomy,f a m i l y h i s t o r y o f the d isease ,p e r n i c i o u s a n a e m i a , a t r o p h i cgastri t is , Menetrier's disease, andadenomatous polyps of the stomach.

Nowadays, Helicobacter pylorihas been considered as one of themost important risk factors for gastriccancer. The International Agency forResearch on Cancer (IARC) of theWorld Hea l th Organ i s a t i on hasrecently classified H. pylori as aGroup I carcinogen, a definite causeof g a s t r i c a d e n o c a r c i n o m a inhumans. 6 More evidence has beenaccumulated to support its role ingastric carcinogenesis.7 It is not yetcertain whether global eradication ofthe bacteria wi l l help in bringingdown the incidence of the disease. Avaccine for the prevention of chronicH. pylori i n f e c t i o n is not yetavailable for clinical use. Screeningfor and eradication of H. pylori inasymptomatic individuals is currentlynot recommended.

Pathology

Macroscopically, gastric cancercould be divided into four typesaccord ing to the Borrmann'sc lass i f i ca t ion (1926): polypoid ,fungating, ulcerative, and infiltrative.Linitis plastica represents a specialtype of g a s t r i c cancer which

infiltrates diffusely below the gastricmucosa . Endoscop ica l ly , thestomach with l in i t i s plastica appearsrigid but there is no macroscopicmucosal lesion.

His to log ica l ly , the Lauren'sclassification (1965) separates gastriccancer into intestinal and diffusetypes. These two types of carcinomadiffer from each other with respect totheir epidemiology, pathogenesis, andbehaviour. In general, the intestinaltype of carcinoma is more distallylocated and is associated with a betterprognosis in comparison wi th thediffuse type.

Gastric cancer disseminates byfour main routes. Locally, gastriccancer may infil trate directly intosurrounding structures like pancreas,transverse colon, mesocolon or liver.Lymphatic spread to the regionall y m p h nodes i s common ands u p r a c l a v i c u l a r l y m p h n o d emetastasis signifies systemic spread.Liver is one of the common organsinvolved by haematogenous spread.When a gastric cancer penetrates theserosa, cancer cells may exfoliateinto the peritoneal cavity resulting inp e r i t o n e a l d i s s e m i n a t i o n , o rtranscoelomic spread. Apart fromperitoneal seedlings and ascites, theo v a r y m a y b e i n v o l v e d b ytranscoelomic spread (also calledKrukenberg tumour).

The staging of gastric cancer isaccording to the TNM evaluation. Tstands for the penetration of thegastric wall by the primary tumour.N stands for the nodal involvementw h i l e M rep resen t s s y s t e m i cmetastasis. There are three staging

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systems in use. The InternationalU n i o n A g a i n s t Cancer ( U I C C )class i f ica t ion is the same as theAmerican Joint Committee on Cancer(AJCC) classification.8 The JapaneseResearch Society for gastric cancer(JRSGC) classification differs fromthe other two classifications mainlyin the N staging criteria. While themost recent edition of UICC/AJCCclassification categorises N accordingto the absolute n u m b e r of lymphnodes being positive for metastases,8

the JRSGC classifies lymph nodesinto different stations according tothe i r loca t ion in re la t ion to theprimary tumour.9 The interestedreader may refer to the r e l e v a n tliteratures for further details.

Clinical features

Clinica l features can be quiten o n - s p e c i f i c . Pa t i en t s may beasymptomat ic , especia l ly d u r i n gearly stage of the disease. On theother hand, patients with advanceddisease may p resen t w i t h non-specific symptoms l ike anorexia,weight loss, and malaise. Symptomssuch as epigastric pain and distendingdiscomfort may mimic benign ulcerdisease. In fact, treatment with ulcerhealing drugs either by the patientsthemselves or by the unwary medicalpractitioner accounts for a significantproportion of delay in diagnosis.Otherwise, the presentation of gastriccancer depends on its locat ion,w h e t h e r i t has p r o d u c e d anycomplication, and whether it hasmetastasised. Obstructing tumours inthe gast r ic ou t le t may producesymptoms like distending discomfortor vomiting. Tumours in the gastric

inlet (or cardioesophageal junction)may give rise to dysphagia. Bleedingfrom gastric cancer could be overt oroccult. Occult bleeding may lead tosymptoms of anaemia ul t imately .Acute presentation with symptomsand signs of upper gastrointestinalbleeding like coffee ground vomitingand melaena is not infrequent. Acutefree perforation of gastric cancer,however , i s u n c o m m o n and thepresentat ion is not different fromperforation of benign peptic ulcer.Patient with advanced disease maypresent wi th an abdomina l massw h i c h could be due to a b u l k yprimary tumour, omental secondary,or ovarian secondary (Krukenbergtumour). Clinical features of patientsw i t h s y s t e m i c m e t a s t a s e s a r ed e p e n d e n t on the l o c a t i o n ofmetastases (Table 1). Acanthosisnigricans is an uncommon phenome-non associated with adenocarcinomaof the g a s t r o i n t e s t i n a l t r a c t ,especially gastric cancer. It appearsas hyperpigmented, velvety plaque

that often affects the neck, axilla,flexor areas, and anogenital region.The cause of this hyperpigmentationis currently unknown.

Investigations

Laboratory investigations areu s u a l l y u n h e l p f u l for diagnosis .Anaemia may be present as a resultof b l e e d i n g . F l ex ib l e uppe rendoscopic examination is the mostuseful and specific investigation. Inthe presence of a gastric ulcer or anysuspicious gastric lesion, mult iplebiopsies should be taken forh i s to log ic examina t ion even if i tappears b e n i g n endoscop ica l ly .Barium meal examination is seldomrequired unless endoscopic facility isnot readily available. Serum tumourmarkers such as carcinoembryonicantigen (CEA) and CA 19-9 are non-specific and cannot be utilised fordiagnostic purposes. On the otherhand, tumour markers may be helpful

Table 1: Clinical features in the presence of metastatic disease

Metastases

Supraclavicular lymph node

Pleura, lung

Peritoneum

Portal lymph node

Liver

Umbilicus

Ovary

Pelvis

Bone

Brain

Clinical features

Enlarged supraclavicular lymph node

Dyspnoea, pleural effusion, haemoptysis

Abdominal distension, ascites, mass, bowel

obstruction

Obstructive jaundice

Hepatomegaly, jaundice (late stage)

Sister Joseph's nodule

Ovarian mass (Krukenberg tumour)

Pelvic nodule, rectal (Blumer's) shelf

Bone pain, pathological fracture

Neurologic deficit, change in conscious state

(Continued on pane 361)

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in patients known to have the diseasewi th raised t i t res for moni tor ingresponse to therapy and detection ofrecurrence.

After histological confirmationof gastric carcinoma, the clinician'stask is to determine whe ther thepatient is suitable for surgery. Thiswill mainly involve the assessment ofthe pa t ient ' s f i t n e s s for genera lanaesthesia as well as screening form e t a s t a t i c d isease . C l i n i c a l l yobvious metastat ic disease shouldhave been i d e n t i f i e d d u r i n g thephysical examination. A plain chestx-ray is recommended for screeningmetas ta t i c disease as we l l as forpre-operative assessment. Ultrasono-graphy or computed tomography(CT) are of value in the identificationof ascites, liver metastases, or para-aortic lymphadenopathy. Ultrasono-g r a p h y , h o w e v e r , i s o p e r a t o rdependent. Specific investigationsmay be a p p l i e d fo r c l i n i c a l l ysuspicious metastatic disease. Fineneedle aspiration for cytology, forexample, wou ld be arranged forenlarged supraclavicular lymph node.

In recent years, endoscopicul t rasonography (EUS) has beenfound to be one of the most accuratemethods for assessment of T and Nstages of gastric cancer. Its accuracyis dependent on the experience of theendoscopist. At present, usage ofEUS is best limited to specialistcentres where an accurate pre-operative staging is important asguidance for inclusion in neoadjuvantchemotherapy tr ials .1 0 Its use isprobably not warranted in centreswhere knowledge of T and N stagingwill not affect the surgical decision.

A d v a n c e d g a s t r i c c a n c e rf r e q u e n t l y spreads t h r o u g h theperitoneal route. Such peritonealseedlings are usua l ly small in sizeini t ia l ly and not visible even on CTs c a n n i n g . Laparoscopy permitsdirect visualisation of the peritonealcavity and is the most sensitive andspecific modality for the detection ofperitoneal metastases. The detectionof per i toneal d i s s emina t i on mayobviate the need for laparotomy inp a t i e n t s who do not require anypa l l i a t ive surgery for bleeding orobstruction.

Management

Infrequently, gastric cancer mayperforate acutely with clinical signsof peritonitis. An emergency gastricresection may be performed if thepatient 's condition is stable enoughto w i t h s t a n d the procedure . As i g n i f i c a n t propor t ion of suchpatients can be saved and offeredgood p a l l i a t i o n by e m e r g e n c ygas t r ec tomy. 1 1 In the e l ec t i vesituation, the management of gastriccancer depends on the fitness of thepat ient and the c l in ica l stage ofdisease on presentation. At present,surgery remains the mainstay ofpotentially curative treatment. If thepatient is medically unfit for surgery,only non-surgical options could beoffered.

In Hong Kong, gastric cancer israrely diagnosed at an early stage. InJapan, where screening is practised,early gastric cancer confined to themucosa or submucosa constitutesabout 50% of all new cases. Radicalgastric resection for such patients

carries a five-year survival rate ofabout 90% in most series. Thedistinctly lower incidence of lymphnode metastasis in early mucosalcancer, coupled with the morbidityassociated wi th standard radicalgastric resection, has led to thei n t r o d u c t i o n of o ther forms oftreatment. Such treatment optionscan be b r o a d l y c l a s s i f i ed i n t oendoscopic, laparoscopic and opensurgical techniques. Of the variousendoscopic techniques, endoscopicmucosal resection (EMR) is probablythe best known. The success of EMRrequires that the lesion is limited tothe mucosa and that there is no lymphnode m e t a s t a s i s . E n d o s c o p i cultrasonography is very helpful is thisrespect . The genera l se l ec t ioncriteria for EMR include mucosall e s i o n , w e l l - d i f f e r e n t i a t e dadenocarcinoma, lesion of not morethan 2 cm in diameter and absence ofulceration. For larger lesion or lesiont h a t i n v a d e s t h e s u b m u c o s a ,laparoscopic wedge resection orp a r t i a l gas t rec tomy have beenp e r f o r m e d in v a r i o u s cen t re s .Modifications to the open surgicaltechnique include wedge resection,pylorus-preserving gast rectomy,vagus-preserving gastrectomy, andDl radical gastric resection. Dlindicates lymph node dissection ofthe first tier of lymph node stations(Nl ) under the Japanese (JRSGC)classification.

The majority of gastric cancerdiagnosed in Hong Kong, as in otherWestern countries, is advanced. Thestandard treatment of such patientsinvolves radical gastric resectionwhenever the disease is deemedresectable. The extent of resection

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depends on the location of tumour.Dis ta l s u b t o t a l ga s t r ec tomy i sindicated for a distal lesion whi letotal gastrectomy is indicated for alesion in the body or p r o x i m a lstomach. Splenectomy or distalpancreatectomy is avoided unlessthere is direct tumour involvement.Splenectomy is associated with am a r k e d i n c r e a s e i n s e p t i ccomplications. The issue of extendedlymph node dissection has not beensettled. The value of D2 lymph nodedissection, removing the second tierof lymph node stations (N2) underthe JRSGC classif icat ion, has notbeen p r o v e n w i t h t w o r e c e n tp r o s p e c t i v e r a n d o m i s e d t r i a l scomparing Dl with D2 dissection.12-13

These s t u d i e s were , h o w e v e r ,criticised for being multi-centre trialsas well as for their high morbidityassociated wi th distal pancreat-ectomy. At present, extended lymphnode dissection is best l imi ted tosurgeons wi th experience in theprocedure. Extended lymph nodedissection by inexperienced hands,albeit out of good will, may do moreharm than good to patients.

The results of surgical resectionvary between different centres.14 Ingeneral, the prognosis worsens withincreasing pathological stages. As arough g u i d e l i n e , t he f i v e - y e a rsurvival rates after resection forstages I, II, III, and IV diseases areabout 85%, 50%, 25%, and 10%,respectively.

The va lue of pos topera t iveadjuvant chemotherapy has beenquestioned. In the hope of reducingrecurrence after surgical resection,v a r i o u s s t u d i e s o n a d j u v a n tchemotherapy have been performed

with contradicting results. A meta-analysis of published randomisedtrials on adjuvant chemotherapy aftercurative resection for gastric cancerdid not reveal any significant survivalb e n e f i t . 1 5 T h i s s t u d y w a ssubsequently criticised for omittingone Japanese randomised trial. Atpresent, adjuvant chemotherapy is notr e c o m m e n d e d a f t e r s u r g i c a lresection. Its use should be restrictedto a proper trial setting.

In view of the d i s appo in t ingresults associated with the use ofpos t -opera t ive a d j u v a n t chemo-therapy and the high recurrence rateafter an apparent curative resection,pre-operative neoadjuvant chemo-t h e r a p y h a s been i n t r o d u c e d .Neoadjuvant chemotherapy may helpreduce locoregional tumour volumeand downstage the disease and thusincrease the chance of completetumour resection. Accurate pre-operative staging, including the useof endoscopic ultrasonography andstaging laparoscopy, is necessary forpatient selection and proper analysis.Early results were encouraging butgenuine survival benefit has yet to beconfirmed by proper randomisedtrials.

In the presence of systemicmetastases , gast r ic resect ion isgenerally not indicated. For patientswith synchronous liver metastases,palliative gastrectomy did not conferany prolongation of survival norimprovement in qual i ty of l i fe .1 6

Palliative surgery may, however, beindicated in patients with obstructionor profound bleeding. A palliativebypass in the form of gastrojejunos-tomy may be performed for outletobs t ruc t ion . A l t e rna t ive ly , for

patients who are unfi t for generala n a e s t h e s i a , a s e l f - e x p a n d i n gmetal l ic stent could be deployedendoscopically across the site ofobs t ruc t ion . Pain control is ani m p o r t a n t f ace t o f p a l l i a t i v emanagement and should not beoverlooked. In the presence of apartially obstructed gastrointestinaltract, transdermal narcotics would bean u s e f u l a l t e r n a t i v e to ora lmedication. Neurolytic blockade ofthe coe l i ac g a n g l i o n by theanaesthetist could provide lastingrelief for selected patients havingt u m o u r i n f i l t r a t i o n of the retro-peritoneum.

Systemic chemotherapy hasbeen considered to be a possibletreatment option for unresectableg a s t r i c c a r c i n o m a . Severa lrandomised trials have confirmedsurviva l benefit for unresectabled i sease t rea ted w i th sys temicchemotherapy in comparison to bestsupportive care alone.17-19 FAMTX (am e t h o t r e x a t e - b a s e d r e g i m e nc o n s i s t i n g of 5 - F l u o r o u r a c i l ,doxorubicin, and methotrexate) hasbeen a gold standard in the early 90s.More recently, ECF (an infusional5 - F l u o r o u r a c i l - b a s e d r e g i m e nconsisting of epirubicin, cisplatin,and 5-Fluorouracil) was found to bea m o r e a c t i v e r e g i m e n t h a nFAMTX.20 Although the results oft h e v a r i o u s n e w s y s t e m i cchemotherapy regimens have beenencouraging, the gain of prolongedsurvival is, not infrequently, offset bysystemic toxicity which may lengthenhospital stay, prolong suffering, anddeprecate the quality of survival.

In the hope of reducing thesystemic toxicity, we have recently

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'.'m m W®P m Jf" ilPjlP<- 'mi^--~jix :'--m'^m-m-'-'AW m : IB^

Figure la: Contrast CT scan abdomen of a patientwith carcinoma of stomach and multiplebilobar liver metastases (arrows) beforechemotherapy

Figure 1b: Reassessment CT scan of the same patientrevealing significant response ofmetastases to regional intra-arterialtherapy. His primary tumour (arrow) also

introduced the use of regional intra-arterial chemotherapy for unresec-table gastric carcinoma (Figures la& 1b). Reg iona l i n t r a - a r t e r i a lchemotherapy maximises the localconcentration of chemotherapeuticagents and minimises levels in thesystemic c i r cu l a t i on . The localeffects may thus be enhanced whilesystemic side effects are obviated asfar as possible. Our results so far areencouraging with a clinical responserate comparable to the best systemicregimens while the systemic toxicityis minimal.

Conclusion

The management of gastr iccancer has evolved over the years,With better understanding of itsepidemiology and etiological factors,preventive measures may hopefullyfurther reduce its incidence in thefuture. The issue of Helicobacterpylori eradication or vaccination as apreventive measure is cu r r en t l yunsettled. Surgery still remains the

most i m p o r t a n t t r e a t m e n t f o rresectable gastric cancer. It is veryimportant for the family physician tobe aware of the n o n - s p e c i f i cpresentations of gastric cancer. Forpatients with suspicious symptoms,immediate investigation, preferablywith upper endoscopy, should bearranged. The only hope for cure isto diagnose the disease at its earlystages. The role of pre-operativeneoadjuvant chemotherapy will befurther clarified with ongoing studies.For unresectable disease, varioust rea tment options are availablenowadays. The quality of life ofthese patients should not be ignoredwhen palliative treatment is beingoffered. •

1, Neugut AI, Hayek M, Howe G. Epidemiologyof gastric cancer, Semin Oncol 1996;23:28l-

291.2, Hospital Authority, Hong Kong cancer registry.

Annual report 1991, 1995. :3, Everett SM. Axon ATR. Early gastric cancer

in Europe. Cut 1997 ;41:142-150,

4. Fuchs CS, Mayer RJ. Gastric carcinoma. N

Engl J Med 1995;333:32-41

5. Steinmetz KA, Potter JD. Vegetables, fruit andcancer. II. Mechanisms. .Cancer Causes

Control 1991;2:427-442.: '6. IARC Working Group on the Evaluation of

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liver flukes and Helicobacter pylori. IARC

Monogr Eval Carcinog Risks Hum 1994:61:

177-241.7 . C h u KM, Branicki FJ, Helicobacter pylori and

gastric. cancer. JAMA SEA 1997;13:5-7.8. : Sobin LH, Wittekind C, eds. International

U n i o n Agains t Cancer (UICC): TNM

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classification of gastric carcinoma — 2nd.

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surgical trial. TLancet 1996;3

14. Maruyama K, Sasako M, Kinoshita T, etSurgical treatment for gastric cancer: t

Gastric Cancer

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Key messages

1. Helicobacter pylori is considered as one of the most important risk factors for gastric cancer. However,screening for and eradication of H. pylori in asymptomatic individual is currently not recommended.

2. Patients with suspicious symptoms should be investigated promptly, preferably with upper endoscopy. Do notwait until the patient develops obvious signs of metastases.

3. Surgery remains the mainstay of potentially curative treatment.

4. Various treatment options are available for unresectable gastric cancer and selection has to be individualised.

Japanese approach. Semin Oncol 1996:23:360-

368.

15. Hermans J, Bonenkamp JJ, Boon MC, et al.

Adjuvant therapy a f te r cu ra t i ve resection for

gastric cancer: me ta -ana lys i s of randomized

trials. J Clin Oncol 1993:11:1441-1447.

16. Chow LW, Lim BH, Leung SY, et al. Gastric

carcinoma with synchronous liver metastases:

palliative gastrectomy or not? Aust N Z J Surg

1995:65:719-723.

17. G l i m e l i u s B. Ekstrom K. Hoffman K, et al.

Randomized comparison between chemotherapyplus best supportive care with best supportivecare in advanced gastric cancer. Ann Oncol

1997:8:163-168.

18. Murad AM. Santiago FF, Pctroianu A, et al.M o d i f i e d t h e r a p y w i t h 5 - f l u o r o u r a c i l .doxorub ic in , and methotrexate in advancedgastric cancer. Cancer 1993:72:37-41.

19. Pyrhonen S, Kui tunen T, Nyandoto P, et al.

Randomised compar ison of f l u o r o u r a c i l .

epidoxorubicin and methotrexate (FEMTX) plus

supportive care wi th support ive care alone in

pa t ien ts w i t h non-resectable gastr ic cancer.

Br J Cancer 1995:71:587-591.

20. Webb A. Cunn ingham D. Scarffe JH. et al.

R a n d o m i z e d t r i a l c o m p a r i n g e p i r u b i c i n .

cisplat in, and fluorouracil versus f luorouracil .

doxorubic in , and methot rexate in advanced

esophagogastric cancer. J Clin Oncol 1997:15:

261-267.

TAKING C H O L E S T E R O L T O N E W L O W S

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