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Certain patients should be managed differently
- 1. RENALCELLCARCINOMA Another “most fascinating” cancer entity. Dr ChristophOing TheChristieNHSFoundation Trust Manchester, UK
- 2. CONFLICTOFINTERESTDISCLOSURE DrChristophOing Personal financialinterests • Honorariaspeakeractivity:Medac(2018),IPSEN(2017) Institutionalfinancialinterests • None Non-financialinterests/ Leadershiprolemedicalsocietiesnon-remunerated • Chairman“JungeDGHO”oftheGermanSocietyofHematologyandOncology (DGHO) • ESMOYOCmember Other • Travelandconferenceattendance:IPSEN(2017)
- 4. Macroscopichematuria Lowerbackpain Palpablelumbarmass Anemia Fatigue Incidentally,asymptomatic(ultrasound, MR) KIDNEYTUMOURS Clinicalpresentation Classictri X ad10-15%of pts
- 5. Diagnostic work-up RCCsuspected: AbominopelvicCT(contrast-enhanced)or MRI Chest X-ray Bonescan(if clinically indicated) Whoneedsabiopsy? If surgeryanyways No Butyouneedabiopsy ... Toassessindeterminate(small)renalmasses Toselectmostsuitable therapystrategy(“Treatornotto treat”) KIDNEYTUMOURS
- 6. Classification Manydifferent histologies 90%of kidneycancersRCC Different clinical behaviour Clear cell carcinoma PapillarytypeI PapillarytypeII Chromophobe Collectiveducts Others KIDNEYCANCER 75% 10% 5% 1% ~4%
- 7. KIDNEYCANCER Epidemiology Newcancer cases &deaths20182 ~13,000newcaseseachyear intheUK1 4,619kidneycancer deathsin2016intheUK1 ~400,000newcaseseachyearworldwide2 ~175,000kidneycancerdeathsworldwide2 Approximately3%ofall adultcancers ♂ : ♀ =1.5: 1 No. 16 1 https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/kidney-cancer 2 BrayFetal.ClobalCancerStatistics2018.CACancerJClin2018;68:394-424
- 8. KIDNEYCANCER Riskfactors &primary prevention Smoking(x4) @nhssmokefree Obesity Chemical exposure VHLdisease(2-3%, clear cell RCC) METgermlinemutations(80%papillarytypeI RCC) Familial (hereditaryleiomyomatosis, etc.)
- 10. KIDNEYCANCER Clinicalstages T1 N0 M0 T2 N0 M0 T1-2 N1 M0 T3 Nany M0 T4 Nany M0 Tany Nany M1 I II III IV
- 11. KIDNEYCANCER Prognosis Stage 5-year survival rate I 81% II 74% III 53% IV 8% https://www.cancer.org/cancer/kidney-cancer/detection-diagnosis-staging/survival-rates.hrml
- 12. Clinical behaviour Prognosis Treatmentdecisionmaking „Renal Cell Carcinoma“≠ ccRCC Subtypingcanbetricky (i.e.eosinophilicRCC,RCCNOS,familial cases) KIDNEYTUMOURS Subtypingis critical #BCritical
- 13. Clearcell carcinoma Most frequent histology (60-75%) ~90%drivenbymutationsorhypermethylationoftheVHLgeneon 3p26(sporadicccRCC) Pseudohypoxiavialost HIF1adegradation ConstitutivelyactiveVEGFsignalling RENALCELLCARINOMA
- 19. CLEARCELLRCC „Same,same– butdifferent“ OkitaKetal.ClinGenitourinCancer2019;17:e440-6. • Inflammatoryreactionledtoreclassificationintoahigherriskcategoryofa relevant subset of patients
- 21. PancreaticM1 ThyroidM1 special entitiy? special entitiy? Oligometastatic(incl. Bone, Lung, Liver) Better outcomes Metastasectomy!? Different disease? BoneM1or liver M1 poor prognosis Clinicalbehaviour Commonlyspreadstolymphnodes,lung,andbone Prognosticrolefor siteof metastasis Atypic RENALCELLCARCINOMA
- 22. TREATMENT
- 25. RENALCELLCARCINOMA Treatmentlocalised disease(stage I / II) CapitanioU&MontorsiF.RenalCancer.Lancet2016;387:894-906.
- 26. RENALCARCINOMA Radicalnephrectomy Onlyif organ-sparingapproachnotfeasible(i.e.≥ cT3) LNDcontroversial in cN+ addsstaging information,nosurvival benefit Alsofor cytoreductivenephrectomyin StageIVpatients
- 27. S-TRAC ASSURE PROTECT SUNITINIBvs. PLACEBO PAZOPANIBvs. PLACEBO SUNITINIBvs. PLACEBO OSimmature NoOSbenefit NoOSbenefit Adjuvanttherapy NoRCTphaseIII datasupportinguseofadjuvantsystemictreatment Conflictingtrial resultsforTKI Toxicity↑ / QoL↓vs. uncertainclinical benefit Adjuvantsunitinib availableforhighrisk patientsin theUS pT3tumors │ N1disease IOtocome?!(NIVOorDURVA±TREMEvs.PLACEBO) CLEARCELLRCC
- 29. SURGERY
- 30. CLEARCELLRCC Cytoreductive nephrectomy Sunitinibalone NephrectomyplusSunitinib FlaniganRCetal.NewEnglJMed2001;345:1655-9. MéjeanAetal.NewEnglJMed2018;379:417-27. RoleofCNinTKI eraquestionable Still recommendedforgoodrisk patients Certainlynooptionforpoorrisk patients / highmetastaticburden
- 31. RADIOTHERAPY
- 32. External BeamRadiotherapy Lowresponseratestoconventional RT(i.e. 2Gy/ fraction) BUT Highresponsestohigh-dose-per-rateschedules StereotacticAblativeRadiotherapy(SABR)(i.e.26Gy/ 1fractionor 40Gy/ 5fractions) Causesbreakdownof bloodsupply Sufficientlocalcontrolandlowtoxicity Rarelyusedfor primaryRCC Regularlyusedfor metastases(e.g. brain, bone) CLEARCELLRCC
- 34. Immunotherapy RCCarestronglyimmunogenictumors Historical treatment(andstill insomeUScenters...) HighdoseIL-2 HighdoseInterferonα2 Providesdurableresponsesin10%of patients Extremelytoxic(IL-2) Massivecapillary leakage,SIRS,organfailure duetocytokine storm RENALCELLCARCINOMA
- 36. CLEARCELLRCC TacklingNeo-angiogenesis RiniBetal. ClinCancerRes2007 X Cell deathfromnutrient/ oxygenstarvation Growthfactor binding↓ Growthfactor signaling↓ Extracellular compartment Cell membrane Cytoplasm
- 37. Availabledrugs: TKI Anti-VEGFtyrosinekinaseinhibitors Blockintracellular activationof VEGFpathway Orallyavailable Goodpenetrationof blood-brainbarrier CLEARCELLRCC
- 38. CLEARCELLRCC 1st-line standardSunitinib ORR31%vs. 6% UnselecteduntreatedccRCCpatients(~7%MSKCCpoorrisk) MotzerRJetal.JCO2009;27:3584-90.
- 39. TKI – First line Sunitinib(SutentTM) 50mgcapsOD, 4won 2woff Sideeffects:fatigue,hand-footsyndrome,stomatitis Pazopanib(VotrientTM) 800mgOD Sideeffects:diarrhoea,hairdiscoloration Axitinib(InlytaTM) 5mgBID Sideeffects:diarrhoea,dysphonia,fatigue Tivozanib(FotivdaTM) 1,340µgOD, 3won 1woff Sideeffects: dysphonia, diarrhoea, fatigue CLASSEFFECTS: HYPERTENSION, HYPOTHYROIDISM CLEARCELLRCC
- 41. Immunecheckpoint inhibitors2019 Anti-CTLA-4monoclonalantibodies(Ipilimumab) First generation Highincidenceof auto-immunetoxicity Moderateefficacy Anti-PD-1andanti-PD-L1 monoclonalantibodies(Nivolumab,Pembrolizumab, Avelumab,Atezolizumab) Secondgeneration Lesstoxic Moreefficient Combinationtherapy Higher responseratebut alsotoxicity CLEARCELLRCC
- 43. 15-20%responderstoPD-1iarelongtermresponders iRECISTimportant Whentostoptreatment? Whentoconsider acureof stageIVRCC? Nomeasureforproperresponseprediction AlsoPD-L1negativetumoursrespond Combinationswithpromisingresults PD-1i +CTLA-4i PD-L1i +TKI PD-L1i +VEGFi CLEARCELLRCC Evolutionof concepts IO TKI IO
- 45. NON-CLEARCELLRCC Limitedevidence,limitedoptions Papillary typeI RCC MET-driven Consider Cabozantinib Papillary typeII RCC Consider anti-VEGFRTKI Chromophobe RCC Consider T emsirolimus (mTORi) Collective duct / medullary RCC Chemotherapy according to urothelial cancers
- 46. RCCcharacteristics Kidney tumourscompriseabunge of different entities Consider carefully if youneed abiopsy Challenge your pathologist Clear Cell Renal Cell Carcinomamost common RCC subtype ccRCCrelatedtoVHLinactivation andPseudohypoxia Angiogenesis veryimportant for ccRCCgrowth LN, lungs andbones commonsites for metastaticspread TAKEHOMEMESSAGEI
- 47. TAKEHOMEMESSAGEII RCCtreatment Conventional chemo-andradiotherapy ineffective Organ-sparingsurgery whenever possible in localised disease ccRCC‘sAchilles‘ heel:Angiogenesis andImmunogenicity Norolefor adjuvant systemicTKI Totalresection for oligometastatic disease if feasible Cytoreductive nephrectomy nomoreinpoor riskmRCCpatients TKIstill standard of carefor goodrisk metastatic ccRCC TKIandPD-1i ± keyto successin intermediate / poorrisk ccRCC