Combination cancer therapy: Presidential address.

Abstract

TheUniversityofTexas,M.D.AndersonHospitalandTumorinstitute,TexasMedicalCenter,Houston,Texas77025FirstIwanttothankyoufortheprivilegeandhonorofservingasyourPresidentduringthispastyear.Ithasbeenaturbulentandanimportantyearforcancerresearchandacceleratedsupportisinprocess.Iwouldliketotakethisopportunitytopresentsomeoftheconceptualandpracticaladvancesthathavebeenmadeincancerchemotherapyinthepast15to20yearsandtooutlinefutureprojections.In1955IarrivedattheNationalCancerInstitute.Theneedforthedevelopmentofsystemictreatmentforcancer,theencouragementfrommysuperiors,andtheopportunitytoobservetheverydramaticeffectthatcouldbeachievedoccasionallyintheleukemiasthroughtreatmentdevelopedbyDr.S.FarberandDr.J.H.Burchenalconfirmedmyinterestinmedicaloncologyandchemotherapy.Ihavebeenextraordinarily fortunateinthesuperiors,associates,andtraineeswithwhomIhavebeenassociated.Iwouldliketomentionthreespecifically.WhenIarrivedattheNationalCancerInstitute,itwasDr.GordonZubrodwhoprovided thefriendliness, stimulation, guidance, andopportunitytowork,andhehascontinuedtodoso.Fivemonthsaftermyarrival,agentlemanappearedinmyofficeandannouncedthathisnamewasEmilFreireich.Iallowedthat,asidefrombeingsomewhatlong,thiswasindeedaveryexcellentnameandthatanyonewithanamelikethathadto1Presentaddress:Children'sCancerResearchFoundation,Inc.,35BinneyStreet,Boston,Mass.02115.ReceivedAugust23,1972;acceptedAugust23,1972.begood.Iofferedhimajobonthespot,whichwaseasilyoneofthesmartestthingsIeverdid;wehavebeenworking,playing,andfightingtogethereversince.LastbutnotleastIwantedtointroducemywifeElizabeth.Unfortunately,shecouldnotattendbecauseoftheurgencyofherworkonbehalfofattainingpeaceinIndo-China.Seventeenyearsagothechemotherapistwasisolatedfromhisfellowcliniciansinotherdisciplinesrelatingtocancermainlybecausehehadrelativelylittletooffer.Hewasalsoisolatedfromthebridgingandfromthebasicscientists,partiallybecausethefieldwasinitsveryearlystagesofdevelopmentbutlargelybecausemostscientists,clinicalandotherwise,werescepticalconcerningthefutureofcancerchemotherapy.AschematicdiagramofdrugtreatmentcategoriesofdisseminatedcancerispresentedinChart1.Ourgoalistoridthepatientofhisneoplasticcells.Usingrathercrudetechniques,suchasChalklycounts,todeterminethenumberofneoplasticcellsatautopsy,wefoundthatpatientswithdisseminatedneoplasticdiseasehaveapproximately onetrillionorIO12cells(8).Similarvalueshavebeenobtainedviamoresophisticatedtechniquesinmyelomabydividingthetotalparaproteinproductionbytheamountofparaproteinproducedbyindividualcells(23).Theinitialcategoryiscalledremissioninductionwhereinthegoalistoproducecompleteremission,thatis,toeliminateallclinicalevidenceofthedisease.Thisnecessitatesatleasta99%reductioninneoplasticcellsor,touse acolloquialism, 2-logorgreaterreductioninthenumberofneoplasticcells.Oncethisisachieved,treatment duringremissionisinitiated. Forrelativelyhomogeneouspopulationsoftumorcells,aIst-orderkineticeffectoftreatmentobtains.Thismeansthatittakesjustasmuchtreatmenttoreducethenumberofneoplasticcellsfromamilliontoathousand(lessthan1mgoftissue)asitdoestoreducethenumberofneoplasticcellsfromIO12toIO9(1kgoftumor).Thus,theproductionofcompleteremissionrepresentsonlythedestructionofthetopoftheexponentialiceberg,andcontinuedtreatmentinremissionisnecessary.Asthenumberofcellsarereducedthereiscytokineticandmoredirectexperimentalevidencethattheslopeofthecurvewithtreatmentmayinfactbecomemoresteep,mainlybecausealargerproportionofthecellsentercycle.ThereisalsoexperimentalevidencethatnegotiatingthefinalhurdlefromalmostcompleteeradicationofneoplasticcellstocompleteeradicationmaynecessitateanalteredapproachtoDECEMBER1972 2593