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Pulmonary Complications of Cancer Treatment Beth Zigmund, MD 1/12/2010 Objectives PulmonaryComplicationsofCancer Treatment (Preliminary PreliminaryVersion) Version) BethZigmund,MD • Developawarenessofthemyriadpulmonarycomplications ofcancertreatmentandofchallengeinmakingcorrect diagnosis • DescribeRadiationandChemotherapyͲInduced Complications • RadiationͲInducedComplications:RadiographicPatterns – Conventionalwisdom – Challengesofcurrentdeliverytechniques – Patternsofinjury – Challengesofnoveltherapies PulmonaryComplicationsofCancer Treatment TUESDAY • ChemotherapyͲInducedPulmonaryComplications PulmonaryComplicationsofCancer Treatment • RadiationͲInducedPneumonopathy • Radiation RadiationͲͲInduced InducedPneumonopathy Pneumonopathy • ChemotherapyͲInducedPneumonopathy • Chemotherapy ChemotherapyͲͲInduced InducedPneumonopathy Pneumonopathy • Surgical • Surgical • Infectious:CommunityͲaquired,Atypical, Aspiration • Infectious:CommunityͲaquired,Atypical,Aspiration • Pulmonaryemboli • Pulmonaryemboli PulmonaryComplicationsofCancer Treatment Lung Cancer Other Cancers PulmonaryComplicationsofCancer Treatment Lung Cancer Other Cancers 313 1/12/2010 ElevatedRiskintheLungCancer Patient • Primaryneoplasmispulmonary:lungsurgeryprimarycurativemodality • Underlyinglungdisease CostofBetterTreatments Aimtolengthensurvival,improvepalliation Multimodality,multiregimen treatmentnow standard • Meanagemoreadvanced:~70% ~70%diagnosedat65yearsofageorgreater* – Decreasingtissuemass – Impaireddrugclearance – GreaternumberofcoͲmorbidities • Surgery • Chemotherapy • Radiationtherapy MountingToxicity TUESDAY *Ries LAGetal.SEERCancerStatisticsReview1975Ͳ2000. http://seer.cancer.gov/csr/1975_2000 New,escalatingrespiratorysymptoms Recurrence or Progression Drug Toxicity Diagnostc Quandry Recurrence or Progression Radiation Toxicity Drug Toxicity Diagnostc Quandry Radiation Toxicity Infection Infection (CaseExample) RadiationͲ RadiationͲInducedToxicity Radiotherapyindicatedinabout64%ofNSCLCpatientsoverall: ~46%initially,18%laterinillness Radiotherapyindicatedinabout54%ofSCLCpatientsoverall: 45%initially,9%forrecurrenceorprogression Tyldesley Setal.Estimatingtheneedforradiotherapyforlungcancer:anevidenceͲbased, epidemiologicapproach.Int JRadiat Oncol Biol Phys2001;49:973Ͳ985 314 2 1/12/2010 RadiationTherapyRisks • IrradiationofnormallungmajordoseͲlimitingfactor • Typicaldose:60to70Gy totumorandlocalnodalmetastases • Invariablysomedamagetonormallung • Threshold for pneumonitis rangesfrom5to20Gy Thresholdforpneumonitis ranges from 5 to 20 Gy • 50Ͳ90%ofpatientsundergoinglungirradiationdevelopradiographicorpulmonary functionabnormalities* • Mechanismstillnotwellunderstood *Tsoutsou etal.Int JRadiat Oncol Biol Phys.2006:66(5):1281Ͳ93. FactorsInfluencingRisk • Volumeofnormallungirradiated • Cumulativedose • Sizeoffractionsdelivered,scheduleofdelivery Size of fractions delivered schedule of delivery • Comcomitant chemotherapy:certainagentsin particular • PreviousIrradiation:lowersthreshold • Geneticfactors? TUESDAY RadiationInducedLungToxicity • Improvinggeometricaccuracyofdelivery systems – conformalRT – intensitymodulatedRT y StagesofInjury Acute,exudative Acute, exudative stage:Radiation pneumonitis 0Ͳ2monthsaftertreatment Steroidresponsive • Complicationshavenotbeeneliminated.Ex: Pneumonitis reportedin5Ͳ15%ofpatients receivingexternalbeamradiationtherapyfor lungcancer Organizing,proliferativestage:Radiation pneumonitis 2Ͳ9moaftertreatment Steroidresponsive Chronic,fibroticphase:Radiationfibrosis >9moaftertreatment,stableafter24mo Notsteroidresponsive;supportivetherapy RadiologicManifestations:The ConventionalW onventionalWisdom ConventionalRT (ClinicalCaseImageslides) (ClinicalExampleImageSlide) Geographicmargins Confinedtotheradiation portal 3 315 1/12/2010 (CurrentRTTechniques:ImageSlides) ChemotherapyͲͲInducedComplications Chemotherapy TUESDAY Direct Di t Effects ChemotherapyͲInducedComplications Infection DrugToxicity:ADifficultDiagnosis • Directeffectsoftherapy:Incidencerangesfrom1to30%, dependingonagent • Overlap:Intercurrent infection,progressionoftumor,fluid overload,pulmonaryedema,pulmonaryembolism Di t Direct Effects Infection • Multidrugregimens:Difficulttoascribetoaparticularagent • Nonspecificradiologicfindings,multiplepatterns • Lessfrequentthanradiationtoxicity,butcanbefloridand mayhavehighermortalityrate • Consultwithreferringclinician! (Imageslide– caseexample) Agents(NSCLCandSCLC) • Toxicitywelldescribedincertainestablishedagents:mitomycin, bleomycin • Novelchemotherapeuticagents – – – – – – Antimetabolites:gemcitabine Taxanes:paclitaxel,docetaxel Topoisomerase IInhibitors:topotecan,irinotecan I Inhibitors: topotecan irinotecan Topoisomerase IIInhibitors:etoposide TyrosineKinase EGFRInhibitors:erlotinib,gefitinib VascularEndothelialGrowthFactorInhibitor:bevacizumab • CombinationregimensnowthestandardforbothSCLCandNSCLC • Clinicaltrialscontinuetorevealtoxicityprofilesofvarious combinationregimens • Higherresponseratesmaybeoffsetbygreatertoxicity 316 4 1/12/2010 Class Agents Observed Toxicities Class Agents Observed PulmonaryToxicities PlatinumAgents Cisplatin Carboplatin Minor exceptwhenusedincombination PlatinumAgents Cisplatin Carboplatin Minor exceptwhenusedincombination; variouspatternsincombination regimens Taxanes Paclitaxel Docetaxel NSIP, InterstitialFibrosis,HP,DAD, CapillaryLeakEdema,Eosinophilic Pneumonia Taxanes Paclitaxel Docetaxel NSIP, InterstitialFibrosis,HP,DAD, CapillaryLeakEdema,Eosinophilic Pneumonia Antimetabolites Gemcitabine NSIP, InterstitialFibrosis,DAD, DAH, VenoͲocclusiveDisease Antimetabolites Gemcitabine NSIP, InterstitialFibrosis,DAD, DAH, VenoͲocclusiveDisease Tyrosinekinase EGFR Inhibitors Gefitinib Erlotinib DAD,DAH Tyrosinekinase EGFR Inhibitors Gefitinib Erlotinib DAD,DAH Topoisomerase Inhibitors Etoposide Topotecan Irinotecan NSIP, BronchiolitisObliterans,DAD Topoisomerase Inhibitors Etoposide Topotecan Irinotecan NSIP, BronchiolitisObliterans,DAD MonoclonalAntibodies Bevacizumab DAH MonoclonalAntibodies Bevacizumab DAH www.pneumotox.com www.pneumotox.com Dimopoulou I,Bamias A,Lyberopoulos P,etal.Pulmonarytoxicityfromnovelantineoplastic agents.AnnOncol 2006;17:372Ͳ379. Dimopoulou I,Bamias A,Lyberopoulos P,etal.Pulmonarytoxicityfromnovelantineoplastic agents.AnnOncol 2006;17:372Ͳ379. TUESDAY (ImageslidesͲvariouspatterns,various agents) PulmonaryDrugToxicity:Treatment • Removeoffendingagent • Steroids • Supportivetreatment Summary (CaseExampleImageSlide) Summary • Longdifferentialdiagnosisincancerpatientwith respiratorycomplaints,lungcancerpatientin particular • Radiation RadiationTherapy:continuedchallengedespite Therapy: continued challenge despite improvementsindeliverytechniques,confusing radiologicpatterns • Chemotherapy:widespectrumofabnormalities, challengeposedbynewagentsandcombination regimens 5 317 1/12/2010 KeyReferences SpiroSG,DouseJ,ReadC,etal.ComplicationsofLungCancer Treatment.Semin Respir Crit CareMed2008;29:302Ͳ318. ParkKJ,ChungJY,ChunMS,Suh JH.RadiationͲinducedlungdisease andtheimpactofradiationmethodsonimagingfeatures. Radiographics 2000;20:83Ͳ98. Dimopoulou I,Bamias A,Lyberopoulos P,etal.Pulmonarytoxicityfrom novelantineoplastic agents.AnnOncol 2006;17:372Ͳ379. Abeloff Metal.Abeloff’s ClinicalOncology,4th Edition.Philadelphia: ChurchillLivingstone,2008. TUESDAY www.pneumotox.com 318 6