Combination cancer therapy: Presidential address.

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,theproductionofcompleteremissionrepresentsonlythedestructionofthetopofthe"exponentialiceberg,"andcontinuedtreatmentinremissionisnecessary.Asthenumberofcellsarereducedthereiscytokineticandmoredirectexperimentalevidencethattheslopeofthecurvewithtreatmentmayinfactbecomemoresteep,mainlybecausealargerproportionofthecellsentercycle.ThereisalsoexperimentalevidencethatnegotiatingthefinalhurdlefromalmostcompleteeradicationofneoplasticcellstocompleteeradicationmaynecessitateanalteredapproachtoDECEMBER1972 2593