RENAL CELL CARCINOMAAnother 147most fascinating148 cancer entity - PDF document

RENAL CELL CARCINOMAAnother “most fascinating” cancer entity. Dr Christoph OingThe Christie NHS Foundation TrustManchester, UK CONFLICT OF INTEREST DISCLOSURE C

hristoph OingPersonal financial interestsHonoraria speaker activity: Medac(2018), IPSEN (2017)Institutional financial interestsNoneNonfinancial interests / Leadership rol

e medical societies nonremuneratedChairman “JungeDGHO” of the German Society of Hematologyand Oncology (DGHO)ESMO YOC memberOtherTravel and conference attendanc

e: IPSEN (2017) PATHOPHYSIOLOGY RISK CLASSIFICATION TREATMENT RENAL CELL CARCINOMA Macroscopic hematuriaLower back painPalpable lumbar massAnemiaFatigueIncidentally, asym

ptomatic (ultrasound, MR)KIDNEY TUMOURSClinical presentation Classic triad15% pts RCC suspected:Abominopelvic CT (contrastenhanced) or MRI Chest XrayBone scan (if clinica

lly indicated) Who needs a biopsy? If surgery anyways But you need a biopsy...To assess indeterminate (small) renal massesTo select most suitable therapy strategy (“

Treat or not to treat”)KIDNEY TUMOURSDiagnostic work Many different histologies90% of kidney cancers RCCDifferent clinical behaviourClear cell carcinomaPapillary typ

e IPapillary type IIChromophobeCollective ducts OthersKIDNEY CANCERClassification ~4% ~13,000 new cases each year in the UK4,619 kidney cancer deaths in 2016 in the UK~40

0,000 new cases each year worldwide~175,000 kidney cancer deaths worldwideApproximately 3% of all adult cancers: = 1.5 : 1KIDNEY CANCEREpidemiologyhttps://www.cancerresea

rchuk.org/healthprofessional/cancerstatistics/statisticscancertype/kidneycancerBray F et al. ClobalCancer Statistics 2018. CA Cancer J Clin 2018; 68:394424 New cancer& de

athsNo. 16 Smoking (x4)ObesityChemical exposureVHL disease (23%, clear cell RCC)MET germline mutations (80% papillary type I RCC)Familial (hereditary leiomyomatosis, etc.

)KIDNEY CANCERRisk factors & primary prevention nhssmokefree KIDNEY CANCERStaging 8th Ed. KIDNEYCANCERClinical stages T1 N0 M0T2 N0 M02 N1 M0T3 anyT4 anyanyany KIDNEY CAN

CERPrognosis Stageyear survivalratehttps://www.cancer.org/cancer/kidneycancer/detectiondiagnosisstaging/survivalrates.hrml Clinical behaviourPrognosisTreatment decisionma

king„Renal CellCarcinoma“ ≠ ccRCCSubtypingcantricky(i.e. eosinophilicRCC, RCC NOS, familial casesKIDNEYTUMOURSSubtypingcriticalCritical Most frequent histology (

6075%)~90% driven by mutations or hypermethylation of the VHLgene on 3p26 (sporadic ccRCC)Pseudohypoxia via lost HIF1a degradationConstitutively active VEGF signalling RE

NAL CELL CARINOMAClear cell carcinoma CLEAR CELL RCCResult of angiogenesis Strongly hypervascular tumors RISK CLASSIFICATION RENAL CELL CARCINOMARisk classification M1 di

sease KlatteT & Stewart GD. Nat Rev Urol2019; 16:332 RENAL CELL CARCINOMAMotzer RJ et al. J Clin Oncol 2002; 20:28996. MSKCC risk classification mosmosmos Median OS Prop

ortion survivingYearsafter IFN initiation RENAL CELL CARCINOMAHeng et al. Lancet Oncology 2013IMDC risk classification 7.8 mos22.5 mos43.2 mos CLEAR CELL„Same, same

but different“ OkitaK et al. Clin GenitourinCancer 2019; 17:e440Inflammatoryreactionledreclassificationinthigherriskcategoryrelevant subsetpatients RENAL CELL CARCIN

OMAThus a matter of classification...OkitaK et al. Clin GenitourinCancer 2019; 17:e440 MSKCCIMDC Commonly spreads to lymph nodes, lung, and bonePrognostic role for site o

f metastasisAtypicPancreatic M1 special entitiy?Thyroid M1 special entitiy?Oligometastatic (incl. Bone, Lung, Liver)Better outcomes Metastasectomy!?Different disease? Bo

ne M1 or liver M1 poor prognosisRENAL CELL CARCINOMAClinical behaviour TREATMENT RENAL CELL CARCINOMAPrinciples of cancer treatment TREATMENT LOCALISEDDISEASE RENAL CELL

CARCINOMATreatment localised disease (stage I / II) CapitanioU & MontorsiF. Renal Cancer. Lancet 2016; 387:894906. RENAL CARCINOMARadicalnephrectomyOnly if organsparing a

pproach not feasible (i.e. ≥ cT3)LND controversial in cN+ adds staging information, no survival benefitAlso for cytoreductive nephrectomy in Stage IV patients No RCT ph

ase III data supporting use of adjuvant systemic treatmentConflicting trial results for TKITRACSUNITINIB vs. PLACEBOOS immatureASSUREPAZOPANIB vs. PLACEBONo OS benefitPRO

TECTSUNITINIB vs. PLACEBONo OS benefitToxicity↑ / QoL↓ vs. uncertain clinical benefitAdjuvant sunitinib available for high risk patients in the USpT3 tumors │ N1

diseaseIO to come?! (NIVO or DURVATREME vs. PLACEBO)CLEAR CELL RCCAdjuvant therapy TREATMENT ADVANCEDDISEASE SURGERY CLEAR CELLCytoreductivenephrectomy Sunitinib aloneNep

hrectomyplus SunitinibRole of CN in TKI era questionableStill recommended for good risk patientsCertainly no option for poor risk patients / high metastatic burdenFlaniga

n RC et al. New EnglJ Med 2001; 345:1655MéjeanA et al. New EnglJ Med 2018; 379:41727. RADIOTHERAPY Low responseratestoconventionalRT (i.e. 2 Gy / fractionHigh responsest

ohighdoserate schedulesStereotacticAblative Radiotherapy(SABR) (i.e. 26 Gy / 1 fraction40 Gy / 5 fractionsCausesbreak down bloodsupplySufficientlocalcontrollowtoxicityRar

ely used for primary RCCRegularly used for metastases (e.g. brain, bone)CLEAR CELLExternal Beam Radiotherapy IMMUNOTHERAPYOLDFASHIONED“ RCC are strongly immunogenic

tumorsHistorical treatment (and still in some US centers...)High dose ILHigh dose Interferon Provides durable responses in 10% of patientsExtremely toxic (ILMassive capil

lary leakage, SIRS, organ failure due to cytokine stormRENAL CELL CARCINOMAImmunotherapy ANTIANGIOGENICTHERAPY CLEAR CELL RCCTackling Neoangiogenesis Rini B et al. Clin C

ancer Res 2007Celldeathfromnutrient/ oxygenstarvation Growth factorbindingGrowth factorsignalingExtracellularcompartmentCellmembraneCytoplasm AntiVEGF tyrosine kinase inh

ibitorsBlock intracellular activation of VEGF pathwayOrally availableGood penetration of bloodbrain barrierCLEAR CELL RCCAvailable drugs: TKI CLEAR CELL1ststandardSunitin

ib ORR 31% vs. 6% Unselected untreated ccRCC patients (~7% MSKCC poor risk) Motzer RJ et al. JCO 2009; 27:358490. Sunitinib (SutentTM50mg caps OD, 4w on 2w offSide effect

s: fatigue, handfoot syndrome, stomatitisPazopanib (VotrientTM800mg ODSide effects: diarrhoea, hair discolorationAxitinib (InlytaTM5mg BIDSide effects: diarrhoea, dysphon

ia, fatigueTivozanib (FotivdaTM1,340µg OD, 3w on 1w offSide effects: dysphonia, diarrhoea, fatigueCLASS EFFECTS: HYPERTENSION, HYPOTHYROIDISMCLEAR CELL RCCTKI First line

IMMUNOTHERAPY„MODERN WARFARE AntiCTLA4 monoclonal antibodies (Ipilimumab)First generationHigh incidence of autoimmune toxicityModerate efficacyAnti1 and antiL1 mono

clonal antibodies (Nivolumab, Pembrolizumab, Avelumab, Atezolizumab)Second generationLess toxicMore efficientCombination therapyHigher response rate but also toxicityCLEA

R CELL RCCImmune checkpoint inhibitors 2019 CLEAR CELL RCCA new standard Motzer RJ et al. New Engl J Med 2018; 378:127790. 20% respondersto1i arelongtermrespondersiRECIST

importantWhentostoptreatmentWhentoconsidercurestageIV RCC?measureforproper responsepredictionAlso PDL1 negative tumoursrespondCombinationswithpromising results1i + CTLAL1

i + TKIL1i + VEGFiCLEAR CELLEvolution concepts IO TKI IO CLEAR CELL RCCEAU guideline 2019 NONCLEAR CELL RCCLimited evidence, limited optionsPapillarytype I RCCMETdrivenCo

nsiderCabozantinibPapillarytype II RCCConsiderantiVEGFR TKIChromophobeConsiderTemsirolimusmTORiCollective ductmedullaryChemotherapyaccordingurothelialcancers Kidneytumour

scomprisedifferent entitiesConsidercarefullyyoubiopsyChallenge yourpathologistClear CellRenal CellCarcinomamostcommonsubtypeccRCCrelatedVHL inactivationPseudohypoxiaAngio

genesisveryimportantforccRCCgrowthLN, lungscommonsitesformetastaticspreadTAKE HOMEMESSAGERCC characteristics TAKE HOMEMESSAGERCC treatmentConventionalchemoradiotherapyine

ffectiveOrgansparingsurgerywheneverpossible in localiseddiseaseccRCC‘sAchilles‘ AngiogenesisImmunogenicityroleforadjuvant systemicTKITotal resectionforoligometa

staticdiseasefeasibleCytoreductivenephrectomymorein riskmRCCpatientsTKI still standardcare forriskmetastaticccRCCTKI and PD1i keysuccessin intermediate / riskccRCC EMUCyo