UnitTwentyFour.StimulationofTumorGrowthbyNutritionSupportMICHAELH.TOROSIAN,MDFromtheDivisionofSurgicalOncology,DepartmentofSurgery,UniversityofPennsylvaniaSchoolofMedicine,PhiladelphiaABSTRACT.Controversyexistsregardingtheuseofnutritionsupportinthecancerpatient.Althoughnutritionsupportcanclearlyimprovehostnutritionalstatusandrestoreimmunoconfidence,theefficacyofnutritionsupporttoreducemorbidityandmortalityassociatedwithantineo-plastictherapyisquestionable.Apotentialconcernwiththeuseofnutritionsupportinthetumor-bearinghostisstimulationofprimarytumorgrowthandmetastasis.Numerousanimalstudiesclearlydemonstratethatoralandparenteralnutritioncansignificantlystimulatetumorcellproliferationanddistantmetastasis.Althoughcellularkineticstudiesinhumanshaveshownalterationsafterparenteralnutrition,objectivemeasuresoftumorgrowth.Metastasisandtumorproteinsynthesishasnotbeenaffectedbyparenteralnutrition.Thischaptersummarizestheresearchandclinicalworkregardingtheeffectofnutrientsontumorigenesis,primarytumorgrowth,andmetastasisinbothanimalandhumantumors.(JournalofParenteralandEnteralNutrition16:72S-75S)Theeffectofnutritionsupportinthecancerpatientremainscontroversial.Althoughextensivenutritionalandmetabolicalterationshavebeendemonstratedinthecancerpatient,apotentialconcernwiththeuseofnutritionsupportinthispatientpopulationisstimulationoftumorgrowth.Previousstudiesclearlyhavedemonstratedanincreasedincidenceofspontaneoustumordevelopmentinanimalmodelsassociatedwithincreasedcaloricandfatdiets.Incontrast,protein-caloriedeprivationcausesareductioninspontaneoustumorigenesisandadecreasedrateofestablishmentoftransplantedtumors.Furthermore,numerousanimalstudieshaveshownaccelerationoftumorgrowthandtumormetastasisoccursduringperiodsofnutritionalrepletion.Therelativebenefitsofnutritionsupportinthecancerpatientregardinghostsurvivalareinconclusive.Clinicalstudiessimilarlyhavebeencontroversialregardingtheefficacyofnutritionsupporttoreducemorbidityandmortalityassociatedwithsurgery,chermotherapy,orradiationtherapyinthecancerpatient.Significantlyreducedcomplicationscanonlybedemonstratedinseverelymalnourishedcancerpatients.However,inadequatenumbersofpatients,inappropriatepatientpopulations,suboptimallevelsofnutritionsupport,andheterogeneityofpatientpopulationsflawthemajorityofthesestudies.Nevertheless,therelativerisksandbenefitsoftheuseofnutritionsupportinthecancerpatienthavenotbeenclearlydefined.Thisreviewwilllocusonbothlaboratoryandclinicalstudiesthatexaminetheeffectofnutritionsupportontumordevelopment,primarytumorgrowth,andtumormetastasis.TUMORIGENESISANDTUMORESTABLISHMENTPreviousanimalstudieshavedemonstratedthatprotein-calorierestrictioncansignificantlyreducetheincidenceofspontaneoustumorigenesis.Inaddition,tumorestablishmentandgrowthratesoftransplantedtumorsaresignificantlydecreasedunderconditionsofprotein-calorierestriction.TannenbaumandSilverstonein1953publishedanextensivereviewdemonstratingthatproteinand/orcaloriedeprivationsignificantlyinhibitedspontaneoustumorigenesisinnumeroustumorsystemsinmouseandratmodels.Greenetalin1950documenteddelayedestablishmentoftheWalker-256carcinosarcomatransplantedinprotein-depletedrats.RossandBrasin1971reportedareducedincidenceofspontaneousbenignandmalignanttumorsinCOBSratswithunderfeeding.Thispatternoftumorigenesiswasestablishedearlyinlifeinthismodelandremainedstablewithsubsequentnutrientalterations.Nutrientadministrationcanalsoeffectthegrowthofcarcinogen-inducedtumors.Whitein1961reviewednumerouscarcinogen-inducedmalignanciesinmiceandratsandreportedthatprotein-caloriedeprivationreducedtheincidenceofsuchmalignancies.MooreandTittledocumentedsimilarfindingsindimethylbenzanthracene-inducedbreasttumorsinSprague-Dawleyrats.Thus,itisclearinnumerousanimalmodelsthatprotein-calorierestrictionisassociatedwithadecreasedincidenceofspontaneousandcarcinogen-inducedtumors,inhibitionofprimarytumorgrowthanddecreasedestablishmentoftransplantedtumors.Fewclinicalstudieshavebeenreportedtocorroboratethesefindingin-patients.Numerousassociationshavebeenmadebetweenhighcaloricintake,highfatintakeandobesity,andthedevelopmentofseveralhumantumors.Inparticular,hormone-sensitivetumorssuchasbreastcarcinoma,ovariancarcinoma,andcolorectalcancerareassociatedwiththesenutritionalfactors.Thisrationaleformsthebasisforthedevelopmentofcurrentchemopreventiontrials,whichhavebeendesignedtodeterminetheeffectofspecificexternalinterventionsontheincidenceofhumanmalignancies.Furthermore,thesefindingshaveledtothegeneralrecommendationsoftheAmerican.CancerSocietyandNationalCancerInstitutethatdecreasedfatintakeandincreasedfiberintakemaybeassociatedwithreducedincidenceofhumantumors.PRIMARYTUMORGROWTHANDMETASTASISAnimalModelsNumeroustumor-bearinganimalstudieshavedemonstratedthattumorgrowthandmetastasiscanbesignificantlystimulatedduringperiodsofnutritionsupport.Tumorvolume,tumorweight,cellularmitoticindex,DNA,RNA,andproteinsynthesisandcellcyclechangeshavebeenusedasparametersoftumorgrowth.Bothoralandintravenousroutesofnutrientadministrationhavebeenassociatedwithalterationsoftumorgrowth.In1976,CameronandPavlatcomparedtotalparenteralnutrition(TPN)withoraldietsandstudiedgrowthoftheMonishepatomainBuffalorats.A2-weekperiodofparenteralnutritionresultedinincreasedtumorvolume,increasedtumormitoticindex,andincreasedtumor:hostweightratiointhismodel.Usingthissametumorsystem,Cameronin1981demonstratedadramaticincreaseinH-thymidinelagelingindexoftumorcellsafterinitiatingtotalparenteralnutrition.Dalyetalin1978comparedwiththerestricteddiet,theoralproteinandcarbohydratedietandTPNcausedanincreaseintumorvolumebutwithnochangeinthetumor:hostweightratio.Thus,therewasstimulationoftumorgrowthbutnotoutofproportiontohostweightgain.IntheWalker256carcinosarcomamodelinSprague-Dawleyrats,changefromarestrictedtooralprotein/carbohydratedietresultedinanincreaseintumorvolumeafteronly48hoursofthischange.Parenteralnutrientsweresimilarlyfoundtoacceleratetumorgrowthinadditionaltumormodels.Steigeretalin1975infusedparenteralaminoacidswithorwithouthypertonicdextrosefor10daysinLewis/WistarratswithAC-33mammarytumorimplants.Increasedtumorproteincontentwasobservedinanimalsreceivingparenteralaminoacidswithorwithouthypertonicdextrosecomparedtocontrolanimals.Aproportionalincreaseinhostweightwasobservedinanimalsreceivingparenteralnutrientswithnochangeinthetumor:hostweightratio.Oram-Smithetalin1977studiedfourparenteralsolutionsinthissameanimal/tumormodel.Theseinvestigatorscomparedparenteralaminoacidsalone,hypertonicdextrosealone,combinedparenteralaminoacidsandhypertonicdextroseandacontrolsolutionof2.5%dextrose.TumorproteinsynthesisratesweremeasuredusingN-glycineinfusiontechniquesanddemonstratedincreasedtumorproteinsynthesisin.allparenteralnutrientgroupscomparedwiththecontrol2.5%dextroseanimals.Torosianetaldemonstratedincreasedtumorsize,increasedtumorweight,andincreasedtumorcellproliferationofAC-33mammarytumorcellsinLewis/WistarratsreceivingTPN.Afteronly2hoursofinitiatingTPN,asignificantincreaseinthepercentageofS-phase,orDNAsynthesizing,tumorcellswereseen.Improvedanti-tumoractivitytocycle-specificagents(methotrexate,adriamycin)occurredduetothisburst'inDNAsynthesisfollowingshort-termTPN.Aspredictedbytheflowcytometrykinetics,noincreaseintumorresponsewasobservedinthistumorsystemtocyclenonspecificchemotherapy(cyclophosphamide).Thisphenomenonoccurredindependentofhostnutritionstatusandwasduetothesubstrate-inducedproliferativechangesintumorgrowthkinetics.Furtherstudiesdemonstratedthatthissubstrate-directedresponsewasprimarilyduetotheaminoacidcomponentofTPN.Isolatedanimalstudieshaveconcludedthatnosignificantstimulationoftumorgrowthoccurswithperenteralnutrition.Kishietalin1982comparedTPNwith5%dextrosefor7daysinWistarratswithWalker-256carcinosarcomaimplants.AlthoughthisstudyconcludedthatTPNdidnotacceleratetumorgrowth,asmallnumberofanimalswerestudiedandagreaterthantwofoldincreaseintumorweightoccurredinanimalsreceivingTPN.Kingetalin1985comparedTPNwithanoraldietinhepatoma"bearingACI"Nrats.AlthoughTPNdidnotincreasetumorproteincontentorH-thymidineincorporationinthisstudy,theproteinintakeofcontrolanimalsreceivingoraldietswas25%greaterthanthatoftheexperimentalgroupreceivingparenteralnutrition.Furthermore,bothglucose-basedandfat-basedTPNincreasedtumorweightcomparedwithanimalsreceivingoralnutrition.TumormetastasismayalsobeinfluencedbytheadministrationofTPN.In1987,aseriesofstudiesbyMahaffeyetalandBrvantetalreporteddecreasedlungmetastasesinparenterallyfedmicewithsubcutaneousLewislungcarcinomaimplants.Inthesestudies,decreasedpulmonarymetastasisoccurredwithinfusionofeitherTPNorcontrolelectrolytesolutions.Theminvestigatorssuggestedthatparenteralfluidload(notnutrientcontent)correlatedwithalterationsinpulmonarymetastasisinthismodel.Theyhypothesizedthatchangesincirculatinglevelsofprostaglandinsorothersolublefactorsmayhaveaccountedforthesedifferences.Torosianetalin1991comparedthreeparenteralnutrientsolutionstotwooraldietsinLobundratswithPA-Ⅲprostateadenocarcinomaimplants.TheTPNsolutionsconsistedofcarbohydratealone;combinedcarbohydrateandaminoacid;orcarbohydrate,aminoacids,andlipid.Astandardproteinorprotein-depleteddietwasusedasanoraldietarycontrolandtheseanimalsreceivedisovolemicparenteralfluidinfusions.ThisstudydemonstratedsignificantaccelerationofprimarytumorgrowthandlungmetastasisinanimalsreceivingTPNorthestandardoraldietcomparedwithproteindepletedcontrols.CombinedTPNwithdextrose,aminoacids,andlipidsstimulatedtumormetastasistothegreatestdegreeinthismodel.ArecentstudyinvestigatedadditionalTPNsolutionsintheMAC-33mammaryadenocarcinomainLewis/Wistarrats.ThistumorisaspontaneouslymetastasizingvariantoftheAC-33tumororiginallyinducedinthisratstrainwiththechemicalcarcinogen,β-aziridinopropionamide.ControlanimalsreceivingelectrolytesolutionwerecomparedwithanimalsgivenTPNsolutionscontainingglucose,long-chaintriglycerides,oracombinationofmedium-andlong-chaintriglycerides.IncreasedprimarytumorvolumewasobservedwithallTPNsolutionscomparedwiththecontrolelectrolytesolution.Incontrast,lungmetastasesweregreatestinanimalsreceivingtheTPNsolutioncontaininglong-haintriglycerides.Anintermediateleveloflungmetastaseswereobservedinglucose-basedTPNandareductioninmetastaseswereseeninanimalsreceivingTPNwithcombinedmedium-chainandlong-chaintriglycerides.Theseresultssuggestthatprimarytumorgrowthandtumormetastasismayresponddifferentlytonutrientadministrationandthatvariousnutrientsmayhavedifferentialeffectsontheprocessoftumormetastasis.HumanStudiesFewclinicalstudieshavebeenreportedtodefinetheeffectofnutritionontumorgrowthincancerpatients.Nixonetalin1981comparedTFNwithoraldietsinpatientswithmetastaticcoloncancer.Althoughnoobjectivestimulationoftumorgrowthcouldbedetermined,decreasedsurvivalwasobservedinpatientsreceivingTPN.Mullenetalin1980performedaprospective,randomizedstudyof25cancerpatientswithuppergastrointestinalcancers.Thesepatientswererandomizedtoreceiveeitheranoraldietortotalparenteralnutritionfor7to10daysbeforesurgery.Onthedayofsurgery,N-glycinewasparenterallyinfusedandtumorbiopsiesobtainedtodeterminefractionalproteinsynthesisratesatthetimeofsurgery.Nochangeinfractionalrateoftumorproteinsynthesiswasobservedbetweenpatientsreceivingtotalparenteralnutritionortheoraldietpreoperatively.Baronetalin1986studiedheadandneckpatientsbeforeandafterreceiving7to10daysofTPN.Inthisstudy,headandnecktumorswereaspiratedbeforeandafterreceivingparenteralnutrition,andtumorcellswereanalyzedbyflowcytometrytodeterminecellularproliferationkinetics.AnincreaseinthenumberofhyperdiploidcancercellswasseenafterTPNcomparedwithpre-TPNbaselinelevels.Franketalin1991studiedheadandneckcancerpatientsafter7daysofTPN.ComparedwithvaluesobtainedbeforeinitiatingTPN,increasedincorporationofbromodeoxyuridineintotumorcellswasseenafterTPN.Thesestudiesindicatethepotentialtoacceleratetumorcellproliferationinsquamouscellcancersoftheheadandneckafter7toIOdaysofTPN.Theabilityofthesecellularkineticalterationstoimprovetumorresponsetocycle-specificchemotherapyhasnotbeenstudiedinclinicalpopulations.SUMMARYThus,theeffectofexogenousnutrientstostimulatetumorgrowthandaltercellcyclekineticsremainscontroversial.Numerousanimal/tumormodelsclearlydemonstratethatoralandparenteralnutritioncansignificantlystimulatetumorcellgrowthandmetastasis.AlthoughcellularkineticstudiesinhumanshaveshownalterationsfollowingTPNadministration,ab3ectivemeasuresoftumorgrowthandtumorproteinsynthesishavenotbeenalteredbyTPN.Certainlytherearesignificantdifferencesbetweenanimaltumorsandhumanmalignancies,whichmayinfluencetheoutcomeofthesestudies.First,tumor-doublingtimeinanimaltumorsisrapidandrangesfrom2to7days.Incontrast,themostrapiddoublingtimeofhumantumorsis30daysandtypicalmalignanciesmaydoubleinseveralmonthstoyears.Second,tumorburdenmayoccupyasmuchas60%to70%ofweightinanimalmodels.Indistinction,hu