IndianCouncilofMedicalResearch

GuidelinesforManagementof StomachCancer

IndianCouncilofMedicalResearch NewDelhi110029 2010 CancerManagementGuidelines

MembersofExpertSubCommitteeon GuidelinesforManagementof StomachCancer

DrParulShukla,TMH,Mumbai(Chairman) DrB.Ganesh,TMH,Mumbai DrBKMReddy,Bangalore DrBPaulTheliath,Allahabad DrChetanDeshmukh,Pune DrHemanthRaj,Chennai DrJaharMajumdar,Kolkata DrP.M.Parikh,TMH,Mumbai DrRajuTitusChacko,Vellore DrGKRath(Chairman,ICMRTaskForce) DrSudeepGupta,TMH,Mumbai DrPrachiPatil,TMH,Mumbai DrUmeshMahantshetty,TMH,Mumbai DrReenaEngineer,TMH,Mumbai DrRaghavaSKPavoor,TMH,Mumbai DrKishoreChaudhry,ScientistF,ICMR

TheaimoftheICMRGuidelinesistoassistoncologistsinmakingthemajorclinical decisionsencounteredinmanagingtheirpatients,wellrealizingthefactthatsome patientsmayrequiretreatmentstrategiesotherthanthatsuggestedintheseguidelines. Thepurposeoftheseguidelinesistoenhanceclinicaldecisionmakingcapabilitiesof clinicians. Thespecificneedsandmanagementstrategyforanindividualpatienthastobefinalized bythetreatingclinician,basedonseveralimportantindividualrelatedcharacteristics.

GuidelinesforManagementof StomachCancer
1) 2) 3) 4) Index: PageNo. 4 8 14 17 Epidemiology Flowsheets Staging

Treatmentmodalityreview

EpidemiologyofGastricCancer
Gastriccancerwhichiscurrentlythefourthmostcommontypeofcancerworldwidehas remained an important malignant disease with significant geographical, ethnic, and socioeconomicdifferencesindistribution. Itisthesecondmostcommoncauseofdeathfromcancer,witharound700,000deaths annually(10%ofallcancerdeaths).[1] TheagestandardizedincidenceratesinJapanand Chinaareamongthehighestintheworld. Untilthe1980s,gastriccancerwasthemostcommontypeofcancerintheworld.Since then, the rates have fallen in all the highincome countries and overall rates are now about15percentlowerthanin1985.[24]GastriccancerisnowmorecommoninAsiathan in US or Europe. Forty two percent of cases occur in China alone. Highrisk areas are China,Japan,EasternEurope,andCentralandSouthAmerica.LowriskareasareSouth EastAsia,NorthernandEasternAfrica,USA,AustraliaandNewZealand..Gastriccanceris the second most common cause of death due to malignancy (lung cancer being the first.)[6] InIndia,theincidenceofgastriccancerislow,comparedtothehighriskareas.Therates varyfrom13.56per100,000(Chennai)and4.6per100,000(Bangalore)amongfemales; among females, the rates vary from 6.68 (Chennai) to 3.42 (Mumbai). Although, very highratesfromnortheastIndia[(Aizawl,Mizoram),(57.3amongmalesand33.6among females)] are reported, it is premature to comment on this since these are relatively recentregistries.[6] The morbidity and mortality due to gastric cancer indicates a downward trend in most countries worldwide. The worldwide incidence of gastric cancer has declined rapidly overtherecentfewdecades.[710]Thedeclineinitiallybeganincountrieswithlowgastric cancerincidencesuchastheUnitedStates.Declineincountrieswithhighincidencelike Japan was slower. Part of the decline may be due to the recognition of certain risk factorssuchasHelicobacterpyloriandcertaindietaryandenvironmentalriskfactors.

 RiskandProtectiveFactorsforGastricCancer Evidence of a positive association between Helicobacter pylori infection and gastric cancerhasbeenprovidedbymostprospectivestudies.H.pyloriisprobablythestrongest riskfactortoday. A large number of studies have indicated that salted, smoked, pickled, and preserved foods(richinsalt,nitrite,andpreformedNnitrosocompounds),chilli,processedmeat, smoked foods and grilled(broiled) and barbequed (charbroiled) animal foods are probablyassociatedwithanincreasedriskofgastriccancer. Incontrast,strongevidencehasbeenprovidedthathighconsumptionoffreshfruitand raw vegetables and a high intake of antioxidants are associated with a reduced risk of gastriccancer.Thereislimitedevidencesuggestingthatpulses(legumes)includingsoya and soya products and foods containing selenium protect against gastric cancer. Domestic refrigeration and reduced salt consumption are considered to play a role in explaining the decreasing temporal trend and the geographical patterns of gastric cancer.[2,11] Familial factors have been suspected to play a role in gastric cancer susceptibility.TherearefewstudiesfromIndiainthisregard.[1214] Screening UpperGIendoscopyasascreeningprocedureforgastriccancerisnotcommoninhigh risk areas the world over due to cost factors involved in implementation. Japan, which has an efficient screening program for gastric cancer has shown steady reduction in mortalityovertheyears.Atpresenttherearenoscreeningprogramsforgastriccancerin India. Prevention Excessive salt intake has been identified as a possible risk factor for gastric cancer in correlationstudiesandcasecontrolstudies.[15,16]Thedailyintaketablesalt,however,has

decreaseddrasticallyinmostwesterncountriesandinJapan,inpartduetopublichealth campaignstoreducehypertensivediseases.Thismaybeinpartresponsiblefordeclinein gastric cancer rates. There is a strong association between high salt intake and risk of gastriccancer. Epidemiologic evidence suggests that increased intake of fresh fruit and vegetable is associated with decreased gastric cancer rates. [16] This has been borne out by case controlandcohortstudiesofgastriccancer.Dietaryindicesofmicronutrientintakehave beencalculatedandindicatepossibleprotectiveeffectsofbetacaroteneandvitaminC, or foods that contain these compounds. A chemoprevention trial in China reported a statistically significant reduction of gastric cancer mortality rate after supplementation with betacarotene, vitamin E, and selenium.[17] The population studied, however, may have been nutritionally deficient, raising questions of generalizability to other populations. In addition, the experimental design did not permit assessment of the relativeeffectsofbetacarotene,vitaminE,andselenium. Prevention of gastric cancer via eradication of Helicobacter pylori infection is being activelyconsideredinseveralcountries.[1821]Whethersuchstrategywillbefeasibleisnot known. Many questions remain unanswered concerning the natural history of Helicobacterpyloriinfection:themechanismoftransmissionandtheratesofreinfection orrecrudescencefordifferentpopulationsareunknown.[22]Sinceabouthalfoftheworld populationisinfected,antibacterialtreatmentseemsimpractical.Preventionrandomized trials are also underway and might soon indicate whether curing Helicobacter pylori infectionreducescancerratesorstopstheprogressionofprecancerouslesions.Overall, it is evident that several factors (including diet, individual susceptibility and H. pylori infection)canberesponsibleforpredisposinganindividualtogastriccancer. References 1.FerlayJ,BrayF,PisaniPandParkinDM.GLOBOCAN2002.IARCPress,2004. 2.ParkinDM,BrayF,FerlayJetal.GlobalCancerstatistics,2002.CACancerJClin2005; 55,74108. 3.ParkinDM.InternationalVariation.Oncogene2004;23:632940 4. Parkin DM, Whelan SL, Ferlay etal. 2005.Cancer Incidence in Five continents Vol I to VIII.IARCCancerBase.7. 5.StewartB.W.andKleihuesP.(Eds).2003.WorldCancerReport.IARCPress.Lyon.

6.NCRP(NationalCancerRegistryProgramme.2006.ConsolidatedreportofPopulation BasedCancerRegistries20012004.Incidenceanddistributionofcancer.ICMR. 7.Haenszel,W.1958.Variationinincidenceofandmortalityfromstomachcancer,with particularreferencetotheUnitedStates.JNatlCancerInst.21:213. 8. Piper, DW. 1978.Stomach cancer. Geneva. International Union Against Cancer. UICC. TechnicalReportSeries,MunozN,AsvallJ.Timetrendsofintestinalanddiffusetypesof gastriccancerinNorway.IntJCancer1971.8:144.Vol34. 9.HirayamaT.Epidemiologyofcancerofthestomachwithspecialreferencetoitsrecent decreaseinJapan.CancerRes1975Nov;35(11Pt.2):34603. 10.Waterhouse,J,MuirC,Correa,P,etal,eds.1976.Cancerincidenceinfivecontinents. Vol III. IARC Scientific Publication no.15. International Agency for Research on Cancer, Lyon. 11. Key TJ, Allen NE, Spencer EA, et al. 2002. The effect of diet on risk of cancer. Lancet.360:8618 12.Mathew A, Gangadharan P, Varghese C, Nair M K. 2000. Diet and stomach cancer: a casecontrolstudyinSouthIndia.EurJCancerPrev.;9(2):8997. 13. Gajalakchmi C and Shanta V. 1996. Lifestyle and risk of stomach cancer: A hospital basedcasecontrolstudy.InternationalJournalofEpidemiology.25:11461153. 14. Rao DN, Ganesh B, Dinshaw KA and Mohandas KM. 2002. A case control study of stomachcancerinMumbai,India.IntJCancer.Vol99;5:727731. 15.Stomach. In:WorldCancerResearchFund inassociationwithAmerican Institute for Cancer Research: Food, Nutrition and the Prevention of Cancer: a global perspective. Washington,DC:AmericanInstituteforCancerResearch,1997,pp148175. 16.BuiattiE,PalliD,DecarliA,etal.1990.Acasecontrolstudyofgastriccanceranddiet inItaly:II.associationwithnutrients.InternationalJournalofCancer45(5):896901. 17. Blot WJ, Li JY, Taylor PR, et al. 1993. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and diseasespecific mortality in the general population. Journal of the National Cancer Institute85(18):14831492. 18.NomuraA,StemmermannGN,ChyouPH,etal.1991.Helicobacterpyloriinfectionand gastric carcinoma among Japanese Americans in Hawaii. New England Journal of Medicine325(16):11321136. 19. Parsonnet J, Friedman GD, Vandersteen DP, et al. 1991. Helicobacter pylori infection andtheriskofgastriccarcinoma.NewEnglandJournalofMedicine325(16):11271131. 20. Forman D, Newell DG, Fullerton F, et al. 1991. Association between infection with Helicobacterpyloriandriskofgastriccancer:evidencefromaprospectiveinvestigation. BritishMedicalJournal302(6788):13021305. 21. Parsonnet J, Harris RA, Hack HM, et al. 1996. Modelling costeffectiveness of Helicobacter pylori screening to prevent gastric cancer: a mandate for clinical trials. Lancet348(9021):1504. 22. Nyren O. 1998. Is Helicobacter pylori really the cause of gastric cancer? Seminars in CancerBiology8(4):27583.

FLOWSHEETS (Note:InthefollowingtextGastricCancerimpliesGastricAdenocarcinoma) EVALUATION/WORKUPANDSTAGING

MULTIDISCIPLINARY EVALUATION HISTORY AND PHYSICAL EXAMINATION CBC, BIOCHEMISTRY(LFT, RFT, BLOOD GROUPING ABDOMINAL+PELVIC CT SCAN CHEST XRAY OESOPHAGOGASTRODUODENOSCOPY WITH MULTIPLE BIOPSIES PET/CT (OPTIONAL IF AVAILABLE)

GI JOINT CLINIC RESECTABLE UNRESECTABLE METASTATIC

RESECTABLE

MEDICALLY FIT

MEDICALLY UNFIT

NEOADJUVANT CHEMOTHERAPY (ECF) (Except for T1 or less)

CHEMORADIATION (CT+RT) Evaluate Primary and Nodal Disease [45 Gy /25# with concomitant 5 FU based chemotherapy-2# (1st and 4th week of RT)] If patient unable/unlikely to tolerate, consider palliative chemotherapy or Best Supportive Care

RADICAL SURGERY (Preferably by a skilled and trained surgical oncologist)

ADJUVANT CHEMORADIATION (CT+RT)

UNRESECTABLE Good Performance Status (KPS>60 or ECOG performance2) Neoadjuvant chemotherapy (ECF) Evaluate for Surgery CT+RT Bypass Surgery (as needed) 1. Bypass Surgery (sos)(Antecolic Gastrojejunostomy) 2. Palliative Chemotherapy(if patient tolerates) 3. Palliative care (Mentioned in metastatic disease chart) 4. Feeding jejunostomy tube

Poor Performance status (KPS<60 or ECOG performance3)

METASTATIC DISEASE

Good Performance Status (KPS>60 or ECOG performance2)

Poor Performance status (KPS<60 or ECOG performance3)

CT-4-6#, 5FU Based Other options: taxane based regimens, oral fluoropyrimidines

Palliation

Evaluate for surgery

Diversion Procedures Palliative chemotherapy (if performance status improves) Palliative RT Best Supportive Care

Surgery

POST RADICAL SURGERY

Pathological Staging

R0 pT1pN0 (Observe) pT2pN0 pT3/4pN0/N1 1# chemoCT+RT (Mc Donalds regimen-in chemo nave pts). If neodj chemo given, continue the same regimen

R1 Adjuvant CT/RT Mc Donalds regimen with additional 5FU/LV after completion of RT Further CT?

R2 CT+RT followed by CT OR CT alone

Disclaimer: Major morbidities and some mortality is expected with McDonald type regimens;highleveltechnicalexpertiseisneededforplanningRTanditisrecommended thatthisshouldnotbeundertakenininexperiencedcenters.

PALLIATION PostTreatmentFollowupserviceshouldbedoneeverythreemonthsforthefirsttwo years,everysixmonthsforthenextthreeyearsandannuallyfromthenon. Everyfollowupvisitshouldincludeathoroughphysicalexamination. VitaminB12supplementation(1000microgramintramuscularoncepermonthlifelong) CBC,LFT Imaging and Oesophagogastroduodenoscopy is recommended if clinically indicated (howoften?) PalliativeSurgery(AntecolicGastrojejunostomy,Feedingtube,Stenting) PalliativeChemotherapy PalliativeRadiotherapy PalliativeCare

STAGING
UICC/AJCCStagingforGastricAdenocarcinoma(7thed.,2010) Primarytumor(T) Tx Primarytumorcannotbeassessed T0 Noevidenceofprimarytumor Tis T1 T1a T1b T2 Carcinomainsitu:intraepithelialtumorwithoutinvasionofthelaminapropria Tumorinvadeslaminapropria,muscularismucosaeorsubmucosa Tumorinvadeslaminapropriaormuscularismucosae Tumorinvadessubmucosa Tumorinvadesmuscularispropria

T3 Tumor penetrates subserosal connective tissue without invasion (visceral peritoneum)withoutinvasionofvisceralperitoneumoradjacentstructures[b,c] T4 Tumorinvadesserosa(visceralperitoneumoradjacentstructures)

T4aTumorinvadesserosa(visceralperitoneum) T4bTumorinvadesadjacentstructures Regionallymphnodes(N) NXRegionallymphnodescannotbeassessed N0Noregionalnodemetastasis[d] N1Metastasisin1to2regionallymphnodes N2Metastasisin3to6regionallymphnodes N3Metastasisin7ormoreregionallymphnodes N3aMetastasisin715regionallymphnodes N3bMetastasisin16ormoreregionallymphnodes Distantmetastasis(M) M0Nodistantmetastasis M1Distantmetastasis

Atumormaypenetratethemuscularispropriawithextensionintothegastrocolic or gastrohepatic ligaments, or into the greater or lesser omentum, without perforationofthevisceralperitoneumcoveringthesestructures.Inthiscase,the tumorisclassifiedT2.

Ifthereisperforationofthevisceralperitoneumcoveringthegastricligamentsor theomentum,thetumorshouldbeclassifiedT3. Theadjacentstructuresofthestomachincludethespleen,transversecolon,liver, diaphragm,pancreas, abdominal wall, adrenalgland,kidney,smallintestine, and retroperitoneum.

Intramuralextensiontotheduodenumoresophagusisclassifiedbythedepthof thegreatestinvasioninanyofthesesites,includingthestomach. A designation of pN0 should be used if all examined lymph nodes are negative, regardlessofthetotalnumberremovedandexamined.

StageGrouping 0 IA IB TisN0M0 T1N0M0 T1N1M0 T2a/bN0M0 II T1N2M0 T2a/bN1M0 T3N0M0 IIIA T2a/bN2M0 T3N1M0 T4N0M0 IIIB IV T3N2M0 T4N13M0 T13N3M0 AnyT/AnyN/M1

 HistologicalGrade GxGradecannotbeassessed G1Welldifferentiated G2Moderatelydifferentiated G3Poorlydifferentiated G4Undifferentiated HISTOPATHOLOGYREPORTING(RCPath) Surgicalhistopathologicalreportingshouldinclude: GrossDescription Typeofspecimen Typeoftumour Specimendimensions Siteoftumour Maximumtumourdiameter Distanceoftumourtonearestmargin

Histology Typeoftumour Laurenclassification(Intestinal/Diffuse) Differentiationbyworstarea(Well/Moderately/Poorly) LocalInvasion Proximalmargininvolved Distalmargininvolved Circumferentialmarginloweroesophagus Lymphatic/vascularinvasion Lymphnodes(Numberpositive/Numberexamined) DistantMetastases

PathologicalStaging RO/R1/R2 pTpNpM

Historyofneoadjuvanttherapy

TREATMENTMODALITIESREVIEW
(SURGERY,CHEMOTHERAPY,CHEMORADIATIONANDRADIATIONTHERAPY) RADICALSURGERY LaparoscopicStagingisrecommendedwherefeasible. Primary resection (Distal gastrectomy for distal gastric cancer and proximal or totalgastrectomyforproximalgastriccancerisrecommended). A5cmproximalanddistalmarginisrecommended. AnR0resectionshouldbethegoal.Ifadjacentorgansareinvolved,everyattempt mustbemadetoresectthemenbloc. AD0dissectionisunacceptable. AD1dissectionistheminimallyacceptabledissection. NodalDissectionD1,overD1andD2. Aminimumof15lymphnodesshouldbeevaluatedforstaging.Thesurgeonand thepathologistshouldworkasateamtoensurethis. Asplenectomyshouldbeavoidedwhenpossible. An antecolic gastrojejunostomy or a feeding jejunostomy is recommended in patientsfoundinoperableonanexploratorylaparotomy. For distal gastric cancer (body and antrum), subtotal gastretctomy is recommended over total gastrectomy (based on evidence that disease free survival is same for both procedures)(level1bevidence)

Bozzetti F, Marubini E, Bonfanti G, Miceli R, Piano C, Gennari L. Subtotal versus total gastrectomy for gastric cancer: fiveyear survival rates in a multicenter randomized Italiantrial.ItalianGastrointestinalTumorStudyGroup.AnnSurg1999;230:1708. OBJECTIVE:Toevaluatetheimpactofsubtotal(SG)versustotal(TG)gastrectomyonthe oncologic outcome of patients with cancer of the distal stomach from 28 Italian institutions.SUMMARYBACKGROUNDDATA:ThereiscontroversyoverwhetherSGand TG have a different impact on the 5year survival probability of patients with cancer of the distal half of the stomach. METHODS: The present analysis involved 618 patients randomizedduringsurgerytoSG(315)orTG(303),providedtherewasatleast6cmfrom the proximal edge of the tumor to the cardia, there was no intrapertoneal or distant spread, and it was possible to remove the tumor entirely. Both surgical treatments included regional lymphadenectomy. RESULTS: Four patients died after SG and seven afterTG.Medianfollowupwas72monthsafterSG(range2to125)and75monthsafter TG (range 7 to 113). Fiveyear survival probability as computed by the KaplanMeier methodwas65.3%forSGand62.4%forTG.Thetestofequivalenceledtotheconclusion that the two procedures may be considered equivalent in terms of 5year survival probability.TheanalysisofsurvivalusingamultivariateCoxregressionmodelshoweda statistically significantimpactonsurvivaloftumorsite,tumorspreadwithin thegastric wall, extent of resection to the spleen plus or minus neighboring organs or structures, and relative frequency of metastasis in resected lymph nodes. CONCLUSIONS: Both procedures have a similar survival probability. The authors believe that SG, which has beenreportedtobeassociatedwithabetternutritionalstatusandqualityoflife,should be the procedure of choice, provided that the proximal margin of the resection falls in healthytissue. Forproximalgastriccancer,bothtotalandproximalgastrectomyisassociatedwithequal survivalrates,andthemorbidityassociatedintermsofnutritionalproblemsissimilar. D1dissectionincludesremovalofthegreaterandlesseromenta(omentalbursa).

D2 dissection includes the removal of the omental bursa, along with the front leaf of the transverse mesocolon, and the lymph nodes along the common hepatic, left gastric and splenic vessels are cleared completely. A splenectomy (to remove stations 10 and 11, see stations labelled in picture below) is required for a D2 dissection for proximal gastric cancers. An over D1 dissection is a D2 lymphadenectomy without the splenectomy and distal pancreatectomy. RadicalSurgeryshouldincludeanR0resectionwithaD1oranoverD1dissection.Thereis continuing conflict with regards to the role of D2 dissection in the current oncological academia. The Japanese surgeons define any lymph nodal dissection less than a D2 dissection as suboptimal. Surgeons in the western hemisphere are of the opinion that there is no significant survival difference between a D1 and a D2 dissection. The Dutch and the MRC RCTs initiallyconcludedthatthereisnosignificantsurvivaldifferencebetweenaD1andaD2 dissection and that a D2 dissection was associated with increased postoperative morbidity and mortality. An Italian RCT and a German prospective study however subsequentlydemonstratedotherwise. AsubsequentJapaneseRCTdemonstratedequivalentmorbidityandmortalitywithaD2 dissectionandaD2plusparaaorticlymphadenectomy,conveyingthemessagethat the highmorbidityandmortalityassociatedwithD2lymphadenectomyintheDutchandthe MRCtrialswasprobablyduetosurgeoninexperience. An over D1 dissection is a D2 dissection without the splenectomy and distal pancreatectomy.

Asplenectomyshouldbeavoidedwherepossible.Itisrequiredtoadequatelyclearthe splenicbasin.Inaproximalgastrectomy,thisisvital.

BonenkampJJ,HermansJ,SasakoMetal.Extendedlymphnodedissectionforgastric cancer.NEnglJMed.1999Mar25;340(12):90814. BACKGROUND:Curativeresectionisthetreatmentofchoiceforgastriccancer,butitis unclearwhetherthisoperationshouldincludeanextended(D2)lymphnodedissection, as recommended by the Japanese medical community, or a limited (D1) dissection. We conducted a randomized trial in 80 Dutch hospitals in which we compared D1 with D2 lymphnodedissectionforgastriccancerintermsofmorbidity,postoperativemortality, longterm survival, and cumulative risk of relapse after surgery. METHODS: Between August1989andJuly1993,atotalof996patientsenteredthestudy.Ofthesepatients, 711 (380 in the D1 group and 331 in the D2 group) underwent the randomly assigned treatmentwithcurativeintent,and285receivedpalliativetreatment.Theproceduresfor quality control included instruction and supervision in the operating room and monitoring of the pathological results. RESULTS: Patients in the D2 group had a significantlyhigherrateofcomplicationsthandidthoseintheD1group(43percentvs.25 percent,P<0.001),morepostoperativedeaths(10percentvs.4percent,P=0.004),and longer hospital stays (median, 16 vs. 14 days; P<0.001). Fiveyear survival rates were similarinthetwogroups:45percentfortheD1groupand47percentfortheD2group (95 percent confidence interval for the difference, 9.6 percent to +5.6 percent). The patients who had R0 resections (i.e., who had no microscopical evidence of remaining disease), excluding those who died postoperatively, had cumulative risks of relapse at fiveyearsof43percentwithD1dissectionand37percentwithD2dissection(95percent confidenceintervalforthedifference,2.4percentto+14.4percent).CONCLUSIONS:Our resultsinDutchpatientsdonotsupporttheroutineuseofD2lymphnodedissectionin patientswithgastriccancer. Hartgrink HH, van de Velde CJ, Putter H et al. Extended lymph node dissection for gastriccancer: who maybenefit? Finalresultsofthe randomized Dutch gastriccancer grouptrial.JClinOncol.2004Jun1;22(11):206977 PURPOSE: The extent of lymph node dissection appropriate for gastric cancer is still underdebate.Wehaveconductedarandomizedtrialtocomparetheresultsofalimited (D1)andextended(D2)lymphnodedissectionintermsofmorbidity,mortality,longterm

survival and cumulative risk of relapse. We have reviewed the results of our trial after followup of more than 10 years. PATIENTS AND METHODS: Between August 1989 and June 1993, 1,078 patients with gastric adenocarcinoma were randomly assigned to undergo a D1 or D2 lymph node dissection. Data were collected prospectively, and patientswerefollowedformorethan10years.RESULTS:Atotalof711patients(380in theD1groupand331intheD2group)weretreatedwithcurativeintent.Morbidity(25%v 43%; P <.001) and mortality (4% v 10%; P =.004) were significantly higher in the D2 dissection group. After 11 years there is no overall difference in survival (30% v 35%; P =.53). Of all subgroups analyzed, only patients with N2 disease may benefit of a D2 dissection. The relative risk ratio for morbidity and mortality is significantly higher than one for D2 dissections, splenectomy, pancreatectomy, and age older than 70 years. CONCLUSION: Overall, extended lymph node dissection as defined in this study generated no longterm survival benefit. The associated higher postoperative mortality offsetsitslongtermeffectin survival.For patientswithN2diseaseanextended lymph nodedissectionmayoffercure,butitremainsdifficulttoidentifypatientswhohaveN2 disease. Morbidity and mortality are greatly influenced by the extent of lymph node dissection, pancreatectomy, splenectomy and age. Extended lymph node dissections maybeofbenefitifmorbidityandmortalitycanbeavoided. Cuschieri A, Weeden S, Fielding J et al. Patient survival after D1 and D2 resections for gastric cancer: longterm results of the MRC randomized surgical trial. Surgical Co operativeGroup.:BrJCancer.1999Mar;79(910):152230 Controversy still exists on the optimal surgical resection for potentially curable gastric cancer. Much better longterm survival has been reported in retrospective/non randomized studies with D2 resections that involve a radical extended regional lymphadenectomythanwiththestandardD1resections.Inthispaperwereportthelong termsurvivalofpatientsenteredintoarandomizedstudy,withfollowuptodeathor3 yearsin96%ofpatientsandamedianfollowupof6.5years.InthisprospectivetrialD1 resection (removal of regional perigastric nodes) was compared with D2 resection (extended lymphadenectomy to include level 1 and 2 regional nodes). Central randomization followed a staging laparotomy. Out of 737 patients with histologically

proven gastric adenocarcinoma registered, 337 patients were ineligible by staging laparotomybecauseofadvanceddiseaseand400wererandomized.The5yearsurvival rateswere35%forD1resectionand33%forD2resection(difference2%,95%CI=12%8%). Therewasnodifferenceintheoverall5yearsurvivalbetweenthetwoarms(HR=1.10, 95%CI0.871.39,whereHR>1impliesasurvivalbenefittoD1surgery).Survivalbasedon deathfromgastriccancerastheeventwassimilarintheD1andD2groups(HR=1.05,95% CI0.791.39)aswasrecurrencefreesurvival(HR=1.03,95%CI0.821.29).Inamultivariate analysis,clinicalstagesIIandIII,oldage,malesexandremovalofspleenandpancreas were independently associated with poor survival. These findings indicate that the classical Japanese D2 resection offers no survival advantage over D1 surgery. However, the possibility that D2 resection without pancreaticosplenectomy may be better than standardD1resectioncannotbedismissedbytheresultsofthistrial. DegiuliM,SasakoM,PontiA,CalvoF.SurvivalresultsofamulticentrephaseIIstudyto evaluateD2gastrectomyforgastriccancer.BrJCancer.2004May4;90(9):172732. Curativeresectionisthetreatmentofchoiceforpotentiallycurablegastriccancer.Two major Western studies in the 1990s failed to show a benefit from D2 dissection. They showed extremely high postoperative mortality after D2 dissection, and were criticised for the potential inadequacy of the pretrial training in the new technique of D2 dissection,priortothephaseIIIstudiesbeinginitiated.Theinclusionofpancreatectomy andsplenectomyinD2dissectionwasassociatedwithincreasedmorbidityandmortality. Followingtheseresults,westartedaphaseIItrialtoevaluatethesafetyandefficacyof pancreaspreserving D2 dissection. The results of this trial regarding the safety of pancreaspreservingD2dissectionwerepublishedin1998.Inthispaper,wepresentthe survival results of this phase II trial to confirm the rationale of carrying out a phase III study comparing D1 vs D2 dissection for curable gastric cancer. Italian patients with histologicallyprovengastricadenocarcinomawereregisteredintheItalianGastricCancer StudyGroupMulticentertrial.ThestudywascarriedoutbasedontheGeneralRulesof the Japanese Research Society for Gastric Cancer. A strict quality control system was achieved by a supervising surgeon of the reference centre who had stayed at the National Cancer Center Hospital, Tokyo, to learn the standard D2 gastrectomy and the

postoperative management. The standard procedure entailed removal of the first and second tier lymph nodes. During total gastrectomy, the pancreas was preserved according to the Maruyama technique. Complete followup was available to death or 5 years in 100% of patients and the median followup time was 4.38 years. Out of 297 consecutive patients registered, 191 patients were enrolled in the study between May 1994 and December 1996. The overall morbidity rate was 20.9%. The postoperative in hospitalmortalitywas3.1%.Theoverall5yearsurvivalrateamongalleligiblepatientswas 55%. Survival was strictly related to stage, depth of wall invasion, lymph node involvementandtypeofgastrectomy(distalvstotal). Our results suggest a survival benefit for pancreaspreserving D2 dissection in Italian patientswithgastriccancerifperformedinexperiencedcentres.AphaseIIItrialamong exclusivelyexperiencedcentresisurgentlyneeded. SiewertJR,BttcherK,RoderJD,BuschR,HermanekP,MeyerHJ.Prognosticrelevance of systematic lymph node dissection in gastric carcinoma. German Gastric Carcinoma StudyGroup.BrJSurg.1993Aug;80(8):10158 Inaprospectivemulticentrestudyof2394patientswithgastriccarcinomatheprognostic relevance of systematic lymph node dissection was evaluated. Of 1654 patients undergoingresection,558hadastandardlymphnodedissection,definedasfewerthan 26nodesinthespecimen,and1096underwentradicallymphadenectomy,i.e.26ormore nodes in the specimen. Radical dissection significantly improved the survival rate in patients with Union Internacional Contra la Cancrum (UICC) stages II and IIIA tumours. Multivariateanalysisidentifiedradicaldissectionasanindependentprognosticfactorin the subgroups of patients with UICC tumour stages II and IIA. Radical dissection conferrednosurvivaladvantageinpatientswithpN2tumours.Therewasnosignificant difference in morbidity and mortality rates between radical and standard lymph node dissection. Radical lymphadenectomy improves survival in patients with UICC gastric cancerstagesIIandIIIA,andshouldbetherecommendedtreatmentforsuchpatients.

 McCullochP,NitaME,KaziH,GamaRodriguesJ.Extendedversuslimitedlymphnodes dissectiontechniqueforadenocarcinomaofthestomach.CochraneDatabaseSystRev. 2004Oct18;(4):CD001964 BACKGROUND: Surgeons disagree about the merits and risks of radical lymph node clearance during gastrectomy for cancer. OBJECTIVES: To evaluate survival and peri operative mortality after limited or extended lymph node removal during gastrectomy for cancer. SEARCH STRATEGY: We searched MEDLINE, EMBASE, CancerLit, LILACS, CentralMedical JournalJapaneseDatabaseand the Cochraneregister, referencesfrom relevantarticlesandconferenceproceedings.Wecontactedknownworkersinthefield. SELECTION CRITERIA: Studies published after 1970 which reported 5 year survival or postoperativemortalityrates,andclearlydefined thenodedissectionperformed,were considered.Weexcludedstudieswhichovertlyincludedpatientsreceivingperioperative chemotherapy, and comparisons with clear systematic treatment allocation bias. Randomised controlled trials (RCTs), nonrandomised comparisons and observational studieswereconsideredseparately.DATACOLLECTIONANDANALYSIS:Threereviewers selected trials for inclusion. Quality assessment and data extraction were performed independently by two reviewers. Results of trials of similar design were pooled. Meta analysis was performed separately for randomised and nonrandomised comparisons. MAIN RESULTS: Two randomised and two nonrandomised comparisons of limited (D1) versusextended(D2)nodedissectionand11cohortstudiesofeitherD1orD2resection wereanalysed.Metaanalysisofrandomisedtrialsdidnotrevealanysurvivalbenefitfor extended lymph node dissection (Risk ratio = 0.95 (95% CI 0.83 1.09), but showed increased postoperative mortality (RR 2.23, 95% CI 1.45 3.45). Prespecified subgroup analysissuggestedapossiblebenefitinstageT3+tumours(RR=0.68,95%CI0.421.10). Nonrandomised comparisons showed no significant survival benefit for extended dissection (RR 0.92, 95% CI 0.83 1.02), but decreased mortality (RR 0.65, 95% CI 0.45 0.93).SubgroupanalysisshowedapparentbenefitinUICCstageIIandIIIa.Observational studies of D2 resection reported much better mortality and survival than those of D1 surgery, but the settings were strikingly different. REVIEWERS' CONCLUSIONS: D2

dissection carries increased mortality risks associated with spleen and pancreas resection, and probably with inexperience and low case volumes. Randomised studies shownoevidenceofoverallsurvivalbenefit,butpossiblebenefitinT3+tumours.These results may be confounded by surgical learning curves and poor surgeon compliance. NonrandomisedcomparisonssuggestapossiblesurvivalbenefitforD2inintermediate UICCstages.Observationalstudiesshowhigh5yearsurvivalandlowoperativemortality after D2 dissection in experienced units, and poor results after D1 dissection in non specialist units. Further studies, with precautions to eliminate learning curve effects, contaminationandnoncompliance,areneededtoevaluateD2dissectioninintermediate stagegastriccancer. Sano T, Sasako M, Yamamoto S, Nashimoto A, Kurita A, Hiratsuka M, Tsujinaka T, Kinoshita T, Arai K, Yamamura Y, Okajima K. Gastric cancer surgery: morbidity and mortality results from a prospective randomized controlled trial comparing D2 and extended paraaortic lymphadenectomyJapan Clinical Oncology Group study 9501. J ClinOncol.2004Jul15;22(14):276773. PURPOSE: Radical gastrectomy with regional lymphadenectomy is the only curative treatment option for gastric cancer. The extent of lymphadenectomy, however, is controversial.ThetwoEuropeanrandomizedtrialsonlyreportedanincreaseinoperative morbidityandmortality,butfailedtoshowsurvivalbenefit,intheD2lymphadenectomy group. We conducted a randomized controlled trial to compare the Japanese standard D2 and D2 + paraaortic nodal dissection. PATIENTS AND METHODS: Only experienced surgeons in both procedures from 24 Japanese institutions participated in the study. Patients with potentially curable gastric adenocarcinoma (T2subserosa, T3, or T4) who were surgically fit were intraoperatively randomized. Postoperative morbidity and hospital mortality were recorded prospectively in a fixed format and were compared betweenthetwogroupsinthisstudy.RESULTS:Atotalof523patientswererandomized betweenJuly1995andApril2001.Postoperativecomplicationswerereportedin24.5%of allpatients.Althoughthemorbidityfortheextendedsurgerygroup(28.1%)wasslightly higherthanthestandardgroup(20.9%),therewasnodifferenceintheincidenceoffour major complications (anastomotic leak, pancreatic fistula, abdominal abscess,

pneumonia) between the two groups. Hospital mortality was reported at 0.80%: one patientineachgroupdiedofoperativecomplications,whileonefromeachgroupdiedof rapidprogressivecancerwhileinpatient.CONCLUSION:Specializedsurgeonscouldsafely perform gastrectomy with D2 lymphadenectomy in patients with low operative risks. Paraaortic lymphadenectomy could be added without increasing major surgical complicationsinthissetting. 1 Right cardial nodes 2 Left cardial nodes 3 Nodes along the lesser curvature 4sa Nodes along the short gastric vessels 4sb Nodes along the left gastroepiploic vessels 4d Nodes along the right gastroepiploic vessels 5 Suprapyloric nodes 6 Subpyloric nodes 7 Nodes along the left gastric artery 8 Nodes along the common hepatic artery (8a-anterosuperior group; 8p-posterior gr) 9 Nodes around the celiac axis 10 Nodes at the splenic hilum 11 Nodes along the splenic artery 12 Nodes in the D1 lymphadenectomy requires the dissection of N1 (1hepatoduodenal ligament 6) 13 Nodes at the posterior aspect D2 lymphadenectomy requires the dissection of N1 of the pancreas head and N2 (711) D3 lymphadenectomy requires the dissection of N1, N2 and N3 (12-15) D4 lymphadenectomy requires the dissection of N1, N2, N3 and N4 (16)

JAPANESE CLASSIFICATION OF LYMPH NODE STATIONS FOR GASTRC CANCER AND D1/D2LYMPHDENECTOMY ENDOSCOPICMUCOSALRESECTION Advances in endoscopic techniques like endoscopic mucosal resection (EMR) and minimal access surgery (laparoscopic wedge resection), has created an interest in applyingthesemodalitiestoearlygastriccancer(T1,mucosalandsubmucosal). Node negative T1 tumours are associated with a 5year survival of more than 90%. As such, there is an interest for performing more limited resection for these tumours. Proper patient selection is paramount when employing endoscopic or limited gastric resections (wedge). The probability of lymph node metastasis in early gastric cancer is influenced by tumour factors and is increased with increasing tumour size, submucosal invasion,poorlydifferentiatedtumours,andlymphaticandvascularinvasion. TherehavebeennoRCTscomparingEMRwithothersurgicaltechniquesforGIcancers. However, it continues to evolve as a promising technology in the diagnosis and treatmentforearlygastriccancers. EndoscopicUltrasoundisusefulinassessingthedepthoftumourinvasionandmayaidin properpatientselection forEMR. Aslong termfollow upand survivaldata arelacking, theroutineuseofendoscopictechniquesoutsideaclinicaltrialisnotrecommendedand shouldberestrictedtomedicalcentreswithextensiveexperience. CHEMOTHERAPYANDCHEMORADIATION Perioperativechemotherapy AphaseIIIrandomizedcontrolledtrialon503patientswithresectableadenocarcinoma of the stomach, esophagogastric junction, or lower esophagus assigned patients to either perioperative chemotherapy and surgery (250 patients) or surgery alone (253 patients) to assess whether the addition of a perioperative regimen of ECF to surgery improvesoutcomesamongpatientswithpotentiallycurablegastriccancer.1

Chemotherapy consisted of three preoperative and three postoperative cycles of intravenous epirubicin (50 mg /m2 bsa) and cisplatin (60 mg/m2) on day 1, and a continuousintravenousinfusionoffluorouracil(200mg/m2meterperday)for21days. As compared with the surgery group, the perioperativechemotherapy group had a higherlikelihoodofoverallsurvival(hazardratiofordeath,0.75;95percentconfidence interval,0.60to0.93;P=0.009;fiveyearsurvivalrate,36percentvs.23percent)andof progressionfree survival (hazard ratio for progression, 0.66; 95 percent confidence interval,0.53to0.81;P<0.001). Rates of postoperative complications were similar in the perioperativechemotherapy groupandthesurgerygroup(46percentand45percent,respectively),aswasthe30day mortaliyaftersurgery.Theresectedtumorsweresignificantlysmallerandlessadvanced intheperioperativechemotherapygroup. Inpatientswithoperablegastricorloweresophagealadenocarcinomas,aperioperative regimenofECFdecreasestumoursizeandstageandsignificantlyimprovesprogression freeandoverallsurvivalandshouldberecommended. NeoadjuvantChemotherapy Therationaleforconsiderationofneoadjuvant chemotherapyisbasedon thepotential to downstage the disease and favor an R0 resection and also to treat occult micro metastaseswhicharelikelytobepresentatthetimeofdiagnosisandwhosetreatment may be delayed due to the surgery. It is also assumed that patients will have a better tolerancetoneoadjuvantchemotherapyvisvisadjuvantchemotherapywheredelayed recovery from surgery may make it impossible to administer any systemic treatment in time. A small randomized Dutch trial compared preoperative FAMTX vs. surgery alone to evaluate the effect of preoperative chemotherapy on resectability and survival.2 59 patientswithprovenadenocarcinomaofthestomachwererandomizedtoreceivefour courses of chemotherapy using 5Fluorouracil, doxorubicin and methotrexate (FAMTX) prior to surgery or to undergo surgery alone. 29 patients were allocated to the FAMTX

regimen prior to surgery and 30 patients had surgery alone. Resectability rates were equalforbothgroups.Completeorpartialresponsewasregisteredin32%oftheFAMTX group. With a median followup of 83 months the median survival since randomization was 18 months in the FAMTX group vs. 30 months in the surgery alone group (p=0.17). ThistrialdidnotshowabeneficialeffectofpreoperativeFAMTX. Ametaanalysisofchemotherapyingastriccancershowedneoadjuvantchemotherapyto have effects in some patients, but no significant benefit was found in the few randomizedstudiesinthesetting.3

A Cochrane database systematic review evaluating the effect of neoadjuvant chemotherapy versus none for patients with resectable gastric cancer in terms of efficacy and toxicity identified a total of 36 published citations or meeting abstracts of which32wereexcludedandfourremainingstudieswereanalysed. 4 Ofthefourclinical trialsenrolled,therewere250and332casesintotal,with106and126deathsattheend of followupin theneoadjuvantchemotherapyandcontrolgroup, respectively. The OR (odds ratio) was 1.05 (95%CI: 0.731.50), which was not statistically significant. Of the evaluable129patientsreceivingneoadjuvantchemotherapy,28.7%demonstratedeithera completeorapartialresponse.Twostudiesofneoadjuvantchemotherapyinresectable gastriccancerhadresectionratedataavailableforanalysisTheR0resectionrateinthe neoadjuvant chemotherapy group was comparable to that in the control [OR: 0.96 (95%CI:0.511.83)].Themorbidityandmortalityofneoadjuvantchemotherapyvariedwith the regimens used preoperatively. Of the 129 patients included in the analyzed studies, someacceptabletoxicitywasobserved. It concluded that there is no definite evidence of the effectiveness of neoadjuvant chemotherapyinresectablegastriccancer,intermsofimprovementsinpatientsurvival, in the trials we reviewed. Neoadjuvant chemotherapy should not be used routinely in clinical setting until further results from randomized clinical trials are available. Neoadjuvantchemotherapyofgastriccancershouldbeappliedundertheframeworkof clinicaltrials.

Adjuvantchemotherapy Adjuvant chemotherapy in gastric cancer is based on the premise of improving the prognosis by treating residual occult micrometastases. S1 is an oral fluoropyrimidine withsomeeffectinadvancedgastriccancer.ArandomizedstudyfromJapantestedS1 as adjuvant chemotherapy in 1059 patients with stage II or III gastric cancer who underwent gastrectomy with extended (D2) lymphnode dissection.5 Patients were randomly assigned to undergo surgery followed by adjuvant therapy with S1 or to undergosurgeryonly.IntheS1group,administrationofS1wasstartedwithin6weeks aftersurgeryandcontinuedfor1year.Thetreatmentregimenconsistedof6weekcycles in which, in principle, 80 mg of oral S1 per square meter of bodysurface area per day wasgivenfor4weeksandnochemotherapywasgivenforthefollowing2weeks. The trial was stopped on the recommendation of the independent data and safety monitoring committee, because the first interim analysis, performed 1 year after enrollment was completed, showed that the S1 group had a higher rate of overall survivalthanthesurgeryonlygroup(P=0.002).Followupdatashowedthe3yearoverall survivalratetobe80.1%intheS1groupand70.1%inthesurgeryonlygroup.Thehazard ratiofordeathintheS1group,ascomparedwiththesurgeryonlygroup,was0.68(95% confidence interval, 0.52 to 0.87; P=0.003). Adverse events of grade 3 or grade 4 were relatively common in the S1 group and included anorexia (6.0%), nausea (3.7%), and diarrhea(3.1%). S1isaneffectiveadjuvanttreatmentforEastAsianpatientswhohaveundergoneaD2 dissectionforlocallyadvancedgastriccancer.Furthertrialswilltellwhethertheseeffects canbeextrapolatedtootherpopulationsofpatients. AphaseIIIJapanesetrialon292patientscompared5fluorouracil(5FU),adriamycin,and polyadenylicpolyuridylic acid (poly A:U) against 5fluorouracil plus adriamycin (FA) for patientswithoperablegastriccancerwhohadD(23)curativeresection.6Patientswere randomly assigned to receive chemotherapy or chemoimmunotherapy. Chemotherapy consistedof12mg/kg5FUeveryweekfor18monthsand40mg/m(2)adriamycinevery3 weeks for 12 cycles. Chemo immunotherapy consisted of FA plus 100 mg of poly A:U

weekly for six cycles and was followed 6 months later by six weekly 50mg booster injections. Patients were balanced with prognostic variables: age, sex, tumor location, differentiation,degreeoftumorinvasion(T(2)T(4a)),andlymphnodestatus(N(0)N(2)). Duringthe 15yearfollowup,chemoimmunotherapysignificantly prolongedoverall(P= 0.013)andrecurrencefree(P=0.005)survivalscomparedwithchemotherapyalone.The survivalbenefitswereprominentinthesubsetofpatientswithT(3)/T(4a),N(2),orstage III.Treatmentsweregenerallywelltoleratedinbotharms.Thustherecouldbeasurvival advantage of chemoimmunotherapy with a regimen of FA and poly A:U in curatively resectedgastricadenocarcinoma. A metaanalysis of 4 Japanese centrally randomized controlled clinical trials conducted between 1980 and 2005 comparing adjuvant chemotherapy for curatively resected gastriccancerwithsurgeryalonefoundthat,inJapan,adjuvantchemotherapyusingoral fluorinated pyrimidines for longterm maintenance therapy appears to be effective for gastric cancer patients after curative resection with an estimated hazard ratio of 0.73 (95%CI=0.600.89).7 However,datafromwesternliteraturehavebeencontradictory. A recent prospective combined analysis of two randomized clinical trials on adjuvant chemotherapy[combined5fluorouracil+adriamycinorepirubicinandmethotrexatewith leucovorin rescue (FAMTX or FEMTX)] compared with a control arm conducted on 397 patients who underwent radical resection for histologically proven adenocarcinoma of thestomachoresophagogastricjunctionshowednosignificantdifferencesbetweenthe treatment and control arms for either DFS (hazards ratio: 0.98, P=0.87) or OS (hazards ratio:0.98,P=0.86).8The5yearOSwas43%inthetreatmentarmand44%inthecontrol armandthe5yearDFSwas41%and42%,respectively.Thus,neitherFAMTXnorFEMTX can be advocated as adjuvant treatment in patients who undergo resection for gastric cancer. Metaanalysesassessingthesafetyandefficacyofdifferentadjuvantchemotherapeutic regimens in patients with gastric carcinomas who have undergone gastrectomy have found adjuvant chemotherapy to have a small survival benefit.3,
913

However; this

requires confirmation in large randomized controlled trials Adjuvant chemotherapy cannotberecommendedasaroutinebecauseofthelackofconfirmedbeneficialeffects. AdjuvantChemoradiation The effect of postoperative (adjuvant) chemoradiotherapy on the survival of patients with resectable adenocarcinoma of the stomach or gastroesophageal junction was investigated in a randomized controlled trial INT 0116 on 603 patients of which 556 patientsfromstageIb throughIVM0cancerwererandomlyassignedtoeither surgery pluspostoperativechemoradiotherapyorsurgeryalone.14Themedianoverallsurvivalin the surgeryonly group was 27 months, as compared with 36 months in the chemoradiotherapy group; the hazard ratio for death was 1.35 (95 percent confidence interval, 1.09 to 1.66; P=0.005). The hazard ratio for relapse was 1.52 (95 percent confidence interval, 1.23 to 1.86; P<0.001). Three patients (1 percent) died from toxic effects of the chemoradiotherapy; grade 3 toxic effects occurred in 41 percent of the patients in the chemoradiotherapy group, and grade 4 toxic effects occurred in 32 percent. Postoperative chemoradiotherapy should therefore be considered for all patients at high risk for recurrence of adenocarcinoma of the stomach or gastroesophagealjunctionwhohaveundergonecurativeresection. AnupdateofINT0116resultswith>6yearsmedianfollowupwasreportedin2004.DFS and OS were identical to the previous reports. DFS was 30 months median for chemoradiationand19monthsforsurgeryalone,p<.001,hazardratio1.52(1.751.85).OS was 35 months median for chemoradiation and 26 months for surgery alone, p=.006, hazardratio1.31(1.081.61).15 Subset analyses fortreatment interactionsandprognostic factors were performed on 6 variables (sex, Tstage, Nstage, location, Dlevel of dissectionanddiffusevs.intestinalhistopathology).Therewerenosignificanttreatment interactions with sex, Tstage, Nstage, location or Dlevel. Positive treatment effects were seen in all these subsets. Significant prognostic factors included Tstage, Nstage and Dlevel of dissection. A possible treatment interaction was seen with diffuse pathologycasesappearingtodopoorlywiththerapy.Thisresultwassignificant(p=.03) using an unadjusted test of significance but after adjustment for multiple testing, this resultwasnotsignificant.

 ADutchphaseI/IIstudyperformedtodeterminethemaximaltolerateddose(MTD)and toxicity profile of postoperative radiotherapy with concurrent daily cisplatin and capecitabinetreatedpatientswithcapecitabine1000mgm(2)twiceaday(b.i.d.)for2 weeks.16 Subsequently, patients received capecitabine (250650 mg m(2) orally b.i.d, 5 days week(1)) and cisplatin (36 mg m(2) i.v., 5 days week(1)) according to an alternatingdoseescalationschedule.Radiotherapywasgiventoatotaldoseof45Gyin 25fractions. Thirtyone patients completed treatment. During chemoradiotherapy, eight patients developed nine items of grade III and one episode of grade IV (mainly haematological) toxicity.TheMTDwasdeterminedtobecisplatin5mgm(2)i.v.andcapecitabine650mg m(2)b.i.d.orally.ThisphaseI/IIstudydemonstratedthatchemoradiotherapywithdaily cisplatinandcapecitabineisfeasibleinpostoperativegastriccanceratthedefineddose level and is currently being tested in a phase III multicenter study. Gastric cancer outcome could be improved with more effective and intensified postoperative chemoradiotherapy. Palliativechemotherapy A Cochrane database systematic review and a metaanalysis on chemotherapy for advanced gastric cancer showed that chemotherapy significantly improves survival in comparison to best supportive care.17,
18

In addition, combination chemotherapy

improves survival compared to singleagent 5FU, but the effect size is much smaller. Among the combination chemotherapy regimens studied, best survival results are achieved with regimens containing 5FU, anthracyclines and cisplatin of which, ECF (epirubicin,cisplatinandcontinuousinfusion5FU)istoleratedbest.Regimensincluding FU as bolus exhibit a higher rate of toxic deaths than regimens using a continuous infusionofFU,suchasepirubicin,cisplatin,andcontinuousinfusionFU. ASwissrandomizedphaseIItrialevaluatedtwodocetaxelbasedregimenstoseewhich wouldbemostpromisingaccordingtooverallresponserate(ORR)forcomparisonina phase III trial with epirubicincisplatinfluorouracil (ECF) as firstline advanced gastric cancer therapy.19 Chemotherapynave patients with measurable unresectable and/or

metastatic gastric carcinoma, a performance status 1, and adequate hematologic, hepatic, and renal function randomly received eight 3weekly cycles of ECF (epirubicin 50mg/m(2)onday1,cisplatin60mg/m(2)onday1,andfluorouracil[FU]200mg/m(2)/d ondays1to21),TC(docetaxelinitially85mg/m(2)onday1[laterreducedto75mg/m(2) as a result of toxicity] and cisplatin 75 mg/m(2) on day 1), or TCF (TC plus FU 300 mg/m(2)/dondays1to14). ORRwas25.0%(95%CI,13%to41%)forECF,18.5%(95%CI,9%to34%)forTC,and36.6%(95% CI, 23% to 53%) for TCF (n = 119). Median overall survival times were 8.3, 11.0, and 10.4 monthsforECF,TC,andTCF,respectively.Toxicitywasacceptable,withonetoxicdeath (TC arm). Grade 3 or 4 neutropenia occurred in more treatment cycles with docetaxel (TC, 49%;TCF,57%;ECF,34%).Global healthstatus/QOL substantiallyimproved withECF and remained similar to baseline with both docetaxel regimens. Time to response and ORRfavorTCFoverTCforfurtherevaluation,particularlyintheneoadjuvantsetting.A trendtowardsincreasedmyelosuppressionandinfectiouscomplicationswithTCFversus TCorECFwasobserved. IntheV325phaseIIItrial,445patientswithadvancedgastricorgastroesophagealcancer randomly received either docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) each on day 1 plusfluorouracil750mg/m(2)/dcontinuousinfusionondays1to5every3weeks(DCF)or cisplatin100mg/m(2)onday1plusfluorouracil1,000mg/m(2)/dcontinuousinfusionon days1to5every4weeks(CF).PatientsreceivingDCFnotonlyhadstatisticallyimproved overallsurvivalandtimetotumorprogression,buttheyalsohadbetterpreservationof QOLandsignificantlyimprovedclinicalbenefitcomparedwithpatientsreceivingCF.20,21

The REAL2 Study is the largestever phase III study in advanced gastrooesophageal cancerconductedin1002advancedgastrooesophagealcancerpatientsfrom61centres mainlyintheUK.22ItaimedtoestablishthepotentialuseofXeloda(X)andoxaliplatin(O) in previously untreated patients and to show Xeloda to be as effective as 5FU, and oxaliplatin to be as effective as cisplatin. Patients were randomised to one of four regimens: epirubicin, cisplatin and 5FU (ECF), epirubicin, oxaliplatin and 5FU (EOF), epirubicin,cisplatinandXeloda(ECX)orepirubicin,oxaliplatinandXeloda(EOX).

 For the capecitabinefluorouracil comparison, the hazard ratio for death in the capecitabine group was 0.86 (95% confidence interval [CI], 0.80 to 0.99); for the oxaliplatincisplatincomparison,thehazardratiofortheoxaliplatingroupwas0.92(95% CI, 0.80 to 1.10). Median survival times in the ECF, ECX, EOF, and EOX groups were 9.9 months, 9.9 months, 9.3 months, and 11.2 months, respectively; survival rates at 1 year were 37.7%, 40.8%, 40.4%, and 46.8%, respectively. In the secondary analysis, overall survivalwaslongerwithEOXthanwithECF,withahazardratiofordeathof0.80inthe EOXgroup(95%CI,0.66to0.97;P=0.02).Progressionfreesurvivalandresponseratesdid notdiffersignificantlyamongtheregimens. Toxic effects of capecitabine and fluorouracil were similar. As compared with cisplatin, oxaliplatin was associated with lower incidences of grade 3 or 4 neutropenia, alopecia, renaltoxicity,andthromboembolismbutwithslightlyhigherincidencesofgrade3or4 diarrhea and neuropathy. Thus, Capecitabine and oxaliplatin are as effective as fluorouracil and cisplatin, respectively, in patients with previously untreated esophagogastric cancer and can be used to replace these drugs in chemotherapy regimens. Anotherlargerandomised,openlabel,internationalphaseIIIstudyinadvancedstomach cancerwasconductedin316patientsenrolledin46centresacross13countriesinAsia, SouthAmericaandEurope.23ItcomparedtheefficacyandsafetyofXelodaandcisplatin with intravenous (i.v.) 5FU and cisplatin . Patients receiving the Xeloda and cisplatin combination therapy had similar overall survival and progression free survival as those treatedwith5FUandcisplatinthusshowingshowingXelodaandcisplatintobeatleast aseffectiveas5FUandcisplatin.Xelodacaneffectivelyreplacetheoldstandardi.v.5 FU,incombinationwithcisplatin,asfirstlinetherapyforadvancedstomachcancer. PhaseI/IIclinicaltrialsofS1pluscisplatinforadvancedgastriccancerhaveyieldedgood responses and the treatment well tolerated. In a phase III trial from Japan, [S1 Plus cisplatin versus S1 alone, an RCT In the Treatment for Stomach cancer (SPIRITS) trial], 305 chemotherapynaive patients with advanced gastric cancer were enrolled at 38 centresandrandomlyassignedtoS1pluscisplatinorS1alone.24Inpatientsassignedto

S1 plus cisplatin, S1 (4060 mg depending on patient's body surface area) was given orally, twice daily for 3 consecutive weeks, and 60 mg/m(2) cisplatin was given intravenously on day 8, followed by a 2week rest period, within a 5week cycle. Those assignedtoS1alonereceivedthesamedoseofS1twicedailyfor4consecutiveweeks, followedbya2weekrestperiod,withina6weekcycle. Medianoverallsurvival wassignificantlylonger inpatientsassigned toS1 plus cisplatin (13.0 months [IQR 7.621.9]) than in those assigned to S1 alone (11.0 months [5.619.8]; hazard ratio for death, 0.77; 95% CI 0.610.98; p=0.04). Progressionfree survival was significantlylongerinpatientsassignedtoS1pluscisplatinthaninthoseassignedtoS1 alone (median progressionfree survival 6.0 months [3.312.9] vs 4.0 months [2.16.8]; p<0.0001). Additionally, of 87 patients assigned S1 plus cisplatin who had target tumours, one patient had a complete response and 46 patients had partial responses, i.e., a total of 54% (range 4365). Of 106 patients assigned S1 alone who had target tumours,onepatienthadacompleteresponseand32hadpartialresponses,i.e.,atotal of31%(2341).ThegroupassignedtoS1pluscisplatinwasassociatedwithmoregrade3 or4adverseeventsincludingleucopenia,neutropenia,anaemia,nausea,andanorexia,in thaninthegroupassignedtoS1alone.ThusS1pluscisplatinholdspromiseofbecoming astandardfirstlinetreatmentforpatientswithadvancedgastriccancer. IntraperitonealChemotherapy Arecentsystematicreviewandmetaanalysistodeterminetheeffectivenessandsafety of adjuvant intraperitoneal chemotherapy for patients with locally advanced resectable gastric cancer found thirteen reports of randomized controlled trials (RCTs).25 Ten reports were judged to be of fair quality and subjected to metaanalysis. A significant improvementinsurvivalwasassociatedwithhyperthermicintraoperativeintraperitoneal chemotherapy(HIIC)alone(hazardratio[HR]=0.60;95%CI=0.43to0.83;p=0.002)or HIICcombinedwithearlypostoperativeintraperitonealchemotherapy(EPIC)(HR=0.45; 95%CI=0.29to0.68;p=0.0002).Therewasatrendtowardssurvivalimprovementwith normothermicintraoperativeintraperitonealchemotherapy(p=0.06),butthiswasnot significant with either EPIC alone or delayed postoperative intraperitoneal chemotherapy. Intraperitoneal chemotherapy was also found to be associated with

higher risks of intraabdominal abscess (RR = 2.37; 95% CI = 1.32 to 4.26; p = 0.003) and neutropenia(RR=4.33;95%CI=1.49to12.61;p=0.007).Thusthismetaanalysisindicates that HIIC with or without EPIC after resection of advanced gastric primary cancer is associatedwithimprovedoverallsurvivalatthecostofincreasedriskofintraabdominal abscessandneutropenia. References: 1. CunninghamD,AllumWH,StenningSP,ThompsonJN,VandeVeldeCJ,Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, Smith DB, Langley RE, Verma M, WeedenS,ChuaYJ,MAGICTrialParticipants.Perioperativechemotherapyversus surgery alone for resectable gastroesophageal cancer.N Engl J Med. 2006 Jul 6;355(1):1120. HartgrinkHH,vandeVeldeCJ,PutterH,SongunI,TesselaarME,KranenbargEK, de Vries JE, Wils JA, van der Bijl J, van Krieken JH; Cooperating Investigators of TheDutchGastricCancerGroup.Neoadjuvantchemotherapyforoperablegastric cancer:longtermresultsoftheDutchrandomisedFAMTXtrial.EurJSurgOncol. 2004Aug;30(6):6439. Janunger KG, Hafstrm L, Glimelius B.Chemotherapy in gastric cancer: a review andupdatedmetaanalysis.EurJSurg.2002;168(11):597608. WuAW,XuGW,WangHY,JiJF,TangJL.Neoadjuvantchemotherapyversusnone for resectable gastric cancer. Cochrane Database Syst Rev. 2007 Apr 18;(2):CD005047. Sakuramoto S, Sasako M, Yamaguchi T, Kinoshita T, Fujii M, Nashimoto A, FurukawaH,NakajimaT,OhashiY,ImamuraH,HigashinoM,YamamuraY,Kurita A,AraiK;ACTSGCGroup.AdjuvantchemotherapyforgastriccancerwithS1,an oralfluoropyrimidine.NEnglJMed.2007Nov1;357(18):181020. JeungHC,MoonYW,RhaSY,YooNC,RohJK,NohSH,MinJS,KimBS,ChungHC. Phase III trial of adjuvant 5fluorouracil and adriamycin versus 5fluorouracil, adriamycin, and polyadenylic polyuridylic acid (poly A:U) for locally advanced gastriccanceraftercurativesurgery:finalresultsof15yearfollowup.AnnOncol. 2007Nov20[Epubaheadofprint] Oba K, Morita S, Tsuburaya A, Kodera Y, Kobayashi M, Sakamoto J.Efficacy of adjuvantchemotherapyusingoralfluorinatedpyrimidinesforcurativelyresected gastriccancer:ametaanalysisofcentrallyrandomizedcontrolledclinicaltrialsin Japan.JChemother.2006Jul;18(3):3117. NittiD,WilsJ,DosSantosJG,FountzilasG,ContePF,SavaC,TresA,CoombesRC, Crivellari D, Marchet A, Sanchez E, Bliss JM, Homewood J, Couvreur ML, Hall E, Baron B, Woods E, Emson M, Van Cutsem E, Lise M; EORTC GI Group; ICCG.Randomized phase III trials of adjuvant FAMTX or FEMTX compared with surgery alone in resected gastric cancer. A combined analysis of the EORTC GI GroupandtheICCG.AnnOncol.2006Feb;17(2):2629. Hermans J, Bonenkamp JJ, Boon MC, Bunt AM, Ohyama S, Sasako M, Van de Velde CJ.Adjuvant therapy after curative resection for gastric cancer: meta analysisofrandomizedtrials.JClinOncol.1993Aug;11(8):14417

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benefitwithdocetaxelplusfluorouracilandcisplatincomparedwithcisplatinand fluorouracil in a phase III trial of advanced gastric or gastroesophageal cancer adenocarcinoma:theV325StudyGroup.JClinOncol.2007Aug1;25(22):32059. Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, DanielF,OatesJ,NormanAR;UpperGastrointestinalClinicalStudiesGroupofthe National Cancer Research Institute of the United Kingdom. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008 Jan 3;358(1):3646. Kang YK, Shin WK, Chen DB, et al. Randomized phase III trial of capecitabine/ cisplatin(XP)vs.continuousinfusionof5FU/cisplatin(FP)asfirstlinetherapyin patients (pts) with advanced gastric cancer (AGC): efficacy and safety results [abstract].2006ASCOAnnualMeetingProceedings.JClinOncol2006;24(Suppl 18):LBA4018. Koizumi W, Narahara H, Hara T, Takagane A, Akiya T, Takagi M, Miyashita K, Nishizaki T, Kobayashi O, Takiyama W, Toh Y, Nagaie T, Takagi S, Yamamura Y, Yanaoka K, Orita H, Takeuchi M. Lancet Oncol. S1 plus cisplatin versus S1 alone forfirstlinetreatmentofadvancedgastriccancer(SPIRITStrial):aphaseIIItrial. LancetOncol.2008Feb15;[Epubaheadofprint] Yan TD, Black D, Sugarbaker PH, Zhu J, Yonemura Y, Petrou G, Morris DL.A systematic review and metaanalysis of the randomized controlled trials on adjuvant intraperitoneal chemotherapy for resectable gastric cancer. Ann Surg Oncol.2007Oct;14(10):270213.

ROLEOFRADIOTHERAPYINGASTRICCANCER INTRODUCTION The standard therapy for gastric carcinoma is radical surgical excision. Adequate gastrectomy requires that the surgical margins are free of tumour and that the lymphadenectomyextendsbeyondinvolvednodes(ROresection).The5yearsurvivalof patientswithcompletelyresectednodepositivegastriccancerrangesfrom15%to25%.In these patients and in those with extension of tumor through the serosa, locoregional relapse in the gastric bed, regional nodes, or anastomosis will occur in 50%60% 12. In

approximately20%,thelocoregionalareaistheonlysiteofinitialfailure.Thehighrateof recurrence after curative resection makes it important to consider postoperative adjuvanttherapyfor patientswithgastriccancer.Despitethelargeamountofpublished trialsandametaanalysis3thereportedresultsareconflictingandnouniformtreatment modalityhasbeenwidelyadoptedandimplemented.Onlyrecentlyhasadjuvantchemo radiationemergedasstandardtherapywithsignificantimprovementinrelapsefreeand overallsurvivalfollowingthepublicationofthelandmarkarticlebyMacDonaldetal4. Ametaanalysis19ofliteraturedataofradiotherapyalsoconfirmedthebenefitofadjuvant chemoradiation. PREOPERATIVERADIOTHERAPY Theaimofpreoperativeradiationtherapyistodecreasethebiologicalpotentialoftumor cells and to increase the operation radicality as well as to eradicate subclinical micro metastases. Preoperative radiotherapy has been investigated in several trials and its outcome is controversial.57. Hence preoperative radiotherapy as of now can be recommendedonlyinatrialsetting. NEOADJUVANTCHEMORADIATION Theuseofchemoradiotherapyintheneoadjuvantsettinghasbeenwidelyappliedinthe treatment of esophageal and rectal carcinoma. The most salient argument for its investigation in the treatment of gastric cancer is the greater likelihood that patients would be able to tolerate the treatment better and it could potentially facilitate R0 resectionandreducelocalrelapses.SeveralphaseIIItrialshavebeendonetoassessthe feasibility of neoadjuvant chemoradiation in potentially resectable gastric cancer 8. Recentlyamultiinstitutionaltrial9showedasubstantialpathologicalcompleteresponse rate plus pathological partial response rate is possible in localized gastric carcinoma patients treated with induction chemotherapy followed by preoperative chemo radiotherapy. The concept of preoperative chemoradiation is attractive but as of now canbeundertakenonlyinaninvestigationaltrialsetting. INTRAOPERATIVERADIOTHERAPY(IORT)

Itisaspecialradiotherapeutictechniquewhereinalinearacceleratorthatproduceshigh energyelectronbeamsisusedtodeliverprecise,highlyconcentrateddosesofradiation directly to the tumor site while avoiding adjacent normal tissues. A relatively high biologically effective single dose is administered, but the maximum tolerable dose is limited to 1535 Gy. Although intraoperative radiotherapy1012 has shown to favorably affect locoregional control without any improvement in overall survival, this technique hasnotgainedwideacceptancebecauseitisaspecializedprocedurerequiringexpertise andisavailableonlyinaveryfewcenters.Henceitisnotrecommendedasaroutine. ADJUVANTCONCURRENTCHEMORADIATION Early trials did not yield a definitive conclusion with regard to the benefit or lack of benefit of adjuvant chemoradiation1314. A renewed interest in gastric cancer treatment has arisen after the publication of the landmark US Intergroup trial0116 4.This trial reportedtheresultscomparingtheeffectofpostoperativechemoradiotherapywiththat ofsurgeryalone.Themedianoverallsurvivalinthesurgeryonlygroupwas27months,as comparedwith36monthsinthechemoradiotherapygroup. Thethreeyeardiseasefree and overall survival was 48% and 50% respectively in the chemoradiotherapy group. It stronglysupportedtheintegrationofthistreatmentprotocolaspartofstandardcarefor patients who have undergone curative resection for highrisk adenocarcinoma of the stomachandgastroesophagealjunction.Anupdate15oftheresultsofINT0116analysis performed in 2004 with 7 years median followup not only confirms the benefits from postoperative chemoradiation but also shows that chemoradiation does not produce significant longterm toxicity. However, there remain concerns regarding the optimal chemotherapyregimen,theoptimalmethodofradiotherapydeliveryandacutetoxicity ofthistreatment1618. Nevertheless this trial has changed the standard of care following potentially curative resection of gastric cancer from observation alone to adjuvant combined chemo radiotherapy. METAANALYSISOFLITERATUREDATA

A systematic review and metaanalysis to determine if there is a benefit of adjuvant radiotherapy, with or without chemotherapy, compared with surgery alone has been recently published19. The authors concluded that in patients with resectable gastric carcinoma, the available evidence from the literature data is sufficient to conclude the following: (1) radiotherapy as a single or combined with chemotherapy adjuvant significantly reduces 3year and 5year mortality compared with surgery alone;(2) the largest reduction in 5year overall mortality was in studies of postoperative CRT; (3) treatmentrelated mortality in the postoperative followup was not significantly increasedbyCRT,despitethehigherrateofsideeffects;and(4)preoperativeRTissafe anddefinitelyreduces3yearand5yearmortality. MODERNRADIOTHERAPY Modernradiotherapyhasevolvedfromtechniquesusingbonyanatomybasedprimarily on plain (two dimensional) xray images, handdrawn blocking and hand calculations towards specialized planning incorporating threedimensional reconstructions of computed tomography(CT) images and computer optimization algorithms. In parallel technical advances in radiation therapy delivery have also evolved including 3D conformal radiotherapy (3DCRT), Intensity modulated radiotherapy (IMRT) and Image guided radiotherapy (IGRT). The majority of protocols used for treatment of gastric cancer (including INT0116) have employed primarily parallelopposed anteroposterior posteroanterior(APPA)fieldarrangementswhichareassociatedwithsignificantacute normal tissue toxicity, particularly in relation to the kidneys and spinal cord. Current modern techniques of radiation delivery employ multiple radiation fields that conform more accurately to the highrisk volume, with the potential to produce superior dose distributionsandreducenormaltissuetoxicity. Leong et al 20 in their study used multiplefield conformal radiotherapy technique and compared this to the more commonly used APPA technique and reported that 3D conformal radiotherapy produces superior dose distributions and reduced radiation dosestothekidneysandspinalcordcomparedtoAPPAtechniques,withthepotential toreducetreatmenttoxicity.2122

Intensitymodulatedradiationtherapy(IMRT)furtherimprovestheconformitybetween the target volume and normal tissues achieved by the process of inverse planning. Several studies are investigating the role of intensity modulated radiotherapy in the treatmentofgastriccancer2325.Itsroleisstillinvestigational. Sincestomachisanabdominalorgan,immobilizationandanaccurateunderstandingof theinternalmotionoftheresidualstomachandnodalgroupsisessential.Translationand deformation resulting from the variable filling of hollow organs and the effects of respiration on target position are currently being studied. New tools such as image guidedradiotherapy,fourdimensionalCT 26,conebeamCTandactivebreathingcontrol areareasforfurtherstudy. TECHNIQUESOFRADIATIONTHERAPYPLANNING PREPLANNING It is important to review the preoperative radiological findings especially the preoperativeCTscan whichwillhelp to determine theextentof disease, the involvement of regional lymph nodes and spread if any to adjacent organs. The preoperativetumorextentwillformthebasisforradiotherapytreatmentvolumeofthe tumor bed. Also important are to note the intra operative and the histopathological findings.Thenutritionalstatusisofimportanceinthesepatientsastheyarelikelytobe nutritionally deprived after the radical nature of the surgery. Patients with total gastrectomy require a more aggressive nutrition supplementation compared to partial gastrectomyandaproportionofthesepatientswillrequireafeedingtubetotoleratethe toxicityofthechemoradiotherapy. SIMULATION CTsimulationand3Dtreatmentplanningisstronglyrecommended. Emptystomach. Supinepositionwitharmsoverhead. Immobilization device. (Thermoplastic mould or a full body vacloc and a knee rest).

I.Vcontrast/Oralcontrast(forbettertargetdelineationinordertodocumentthe positionofthestomach,distalesophagus,duodenumandlymphnodes). CTcutsaretakenat5mmintervalsfromthetopoftheheartsuperiorlytoL4L5 interspaceinferiorlywith3alignmentfiducialsforpatientsetup.

CONTOURINGGUIDELINES The radiation oncologists who are planning three dimensional radiotherapy should be well versed with the recommendations published by International Commission of RadiationUnits(ICRU)27. The clinical target volume (CTV) includes the entire residual stomach, anastomotic site and thelymphnode groups.Thestructures tobeincludedinthe clinical targetvolume areoutlinedbelowsitewise28. A.Proximalonethird/Cardia/GastroesophagealJunctionPrimaries 35cmmarginofdistalesophagus,mediallefthemidiaphragm,adjacentpancreaticbody shouldbeincluded.Nodalareasatriskincludeparaesophageal,perigastric,celiacand suprapancreaticlymphnodes. B.Middleonethird/Bodyprimaries Bodyofpancreasisincluded.Nodalareasatriskincludeperigastric,celiac,splenichilar, portahepatic,suprapancreaticandpancreaticoduodenallymphnodes. C.Distalonethird/Antrum/PylorusPrimaries HeadofPancreas,35cmmarginofduodenalstumpshouldbeincluded.Nodalareasat riskincludeperigastric,celiac,portahepatic,suprapancreaticandpancreaticoduodenal lymphnodes. Thetypicalconstraints29usedforplanningaregivenbelow. Nomorethan5%ofthespinalcordwithinthefieldsmayreceivemorethan4500 cGy,andnoportionofthespinalcordmayreceivemorethan5000cGy.

Nomorethan60%ofthelivermayreceivemorethan3000cGy. Ifpossible,bothkidneysshouldbeshieldedsuchthatnomorethan33%ofeach kidney receives more than 2250 cGy. In the event if this is not possible, it is recommendedthatarenalscanbedonetoseethefunctioningofbothkidneys.It isthenpermissibleforonekidneytoreceiveupto4500cGybutnomorethan33% ofthesecondkidneymayreceivemorethan2250cGy.

Nomorethan30%oftheheartmayreceivemorethan4000cGy.Themaximum fieldsizeis400cm2 buteveryattemptshouldbemadetouseshieldingtoreduce actualvolumetolessthan225cm2(15x15cm).

AdequatemarginsaregiventoCTVtoobtainplanningtargetvolume(PTV).Radiationwill typicallybegivenusing5to7fields.Multileafcollimator(MLC)willbeusedforshielding and wedges will be used to improve dose homogeneity. Lung corrections will be used when lung is within the treatment field. Central axis isodose distributions and dose volumehistogramswillbeusedtodeterminedosetoplanningtargetvolumeandcritical structures. Dose will be prescribed to isocenter. Treatment will be delivered with high energyphotons,typicallywithmixedenergy6MV/18MVphotonbeams. Beamseyeview willbeusedtoconfirmsetupatconventionalsimulation.Electronicportalimageswillbe takenatthetimeofradiationdeliverytoconfirmsetuperrors. Radiationdoseprescribedis45Gyin25fractionsover5weeks.

 Thedetailedguidelines 30regardingthestructurestobeincludedintheradiationportals basedontumorstageandnodalinvolvementisgiveninatabularformasfollows: Impact of Site of Primary Lesion and TN Stage on Irradiation Treatment Volumes EGJunction SiteofPrimary Remaining Stomach andTNStage EGjunction T2N0with invasionof subserosa T3N0 Bed NodalVolumes Tolerance Organ Structures Heart, Lung, Nstage If allows Tstage Spinal cord, dependent dependent exclusionof Kidneys, 2/3Rkidney Medialleft Variable None or hemidiaphragm; perigastric, dependent on surgical adjacent body periesophageal pathologic of findings pancreas Variable Medialleft None or dependent hemidiaphragm; perigastric, on surgical adjacent body periesophageal pathologic of mediastinal, findings pancreas celiac Preferablebut AsforT3N0plus Nodes related to site of dependenton site(s)of adherencewith adherence, surgical +/perigastric, 35cmmargin pathologic periesophageal findings mediastinal, celiac Preferable Not indicated Periesophageal, for T1, as above mediastinal, for T2 into perigastric, subserosa celiac Preferable AsforT3,T4N0 As for T12N+ and T4N0 Tumor Volumes

T4N0

T12N+

T34N+

 Impact of Site of Primary Gastric Lesion and TN Stage on Irradiation Treatment VolumesCardia/ProximalOneThirdofStomach Site of Primay and TN stage Cardia/ Proximal 1/3rd of stomach T2N0with invasionof subserosa T3N0 Remaining Stomach Tumor Volumes Bed NodalVolumes Tolerance Organ Structures Kidneys, Spinalcord, Liver, Heart, Lung

T4N0

T12N+

Preferred, but spare 2/3 of one kidney (usuallyRt.) Variable dependent on surgical pathologic findings Variable dependent onsurgical pathologic findings Variable dependent onsurgical pathologic findings Preferable

Tstage dependent Medial Lt. hemidiaphragm, adjacent body of pancreas (+/ tail) Medial Left hemidiaphragm, adjacent body of pancreas (+/ tail) AsforT3N0plus site(s) of adherence with35 cmmargin Not indicated for T1, as above forT2into subserosa

Nstagedependent

Noneorperigastric

T34N+

Preferable

AsforT3,T4N0

Noneorperigastric optional: periesophageal, mediastinal, celiac Nodesrelatedtosite of adherence, +/ perigastric,celiac periesophageal mediastinal Perigastric, celiac, splenic, suprapancreatic, +/periesophageal, mediastinal, pancreaticoduodenal, portahepatic As for T12N+ and T4N0

 Impact of Site of Primary Gastric Lesion and TN Stage on Irradiation Treatment VolumesBody/MiddleOneThirdofStomach Site of Remaining Stomach Primay andTNStage Body/midI/3 ofstomach T2N0with invasionof subserosa esp.postwall T3N0 Yes,butspare 2/3 of one kidney Yes Tumor Bed NodalVolumes Volumes Tstage dependent Body of pancreas (+/ tail) Tolerance Organ Structures Nstage dependent, Kidneys, spare 2/3 of one spinal cord, liver kidney None or perigastric; optional celiac, splenic, suprapancreatic, pancreaticoduodenal, portahepatis None or perigastric; optional celiac, splenic, suprapancreatic, pancreaticoduodenal, portahepatis Nodes related to site of adherence +/ perigastric, celiac, splenic, supra pancreatic, pncreaticouodenal, portahepatic Perigastric, celiac, splenic, suprapancreatic, pancreatico duodenal,porta hepatic As for T12N+ and T4N0

Yes

Body of pancreas (+/ tail)

T4N0

Yes

As for T3N0 plus site(s) of adherence with 35 cm margin

T12N+

Yes

Not indicated forT1

T34N+

Yes

As for T4N0

T3,

 Impact of Site of Primary Gastric Lesion and TN Stage on Irradiation Treatment VolumesAntrum/Pylorus/DistalOneThirdofStomach Site of Remaining Stomach Primary andTNStage Pylorus/distal 1/3stomach T2N0with invasionof subserosa Yes, but spare2/3of one kidney (usuallyL) Variable dependent onsurgical pathologic findings Variable dependent onsurgical pathologic findings Preferable but dependent on surgical pathologic findings Preferable Tumor Bed NodalVolumes Volumes Tstage dependent Head of pancreas, (+/body),1st and 2nd duodenum Head of pancreas, (+/body),1st and 2nd duodenum As for T3N0 plus site(s)of adherence with35 cmmargin Nstagedependent Tolerance Organ Structures Kidneys. liver spinalcord

T3N0

T4N0

Noneorperigastric; optional: pancreaticoduodenal, porta hepatis, celiac, suprapancreatic Noneorperigastric; optional: pancreaticoduodenal, porta hepatis, celiac, suprapancreatic Nodes related to site(s) of adherence +/perigastric, pancreatico duodenal, portahepatis,celiac, suprapanc

TI2N+

T34N+

Preferable

Not indicated Perigastric, forT1 pancreaticoduodenal, portahepatis,celiac, suprapancreatic; Optionalsplenic hilum As for T3, AsforT12N+and T4N0 T4N0

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