Updateof NMIBC management. Critical

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1 Updateof NMIBC management. Critical analysisof EAU Guidelines Eduardo Solsona Service of Urology. Instituto Valenciano de Oncología Valencia. Spain

2 Disclosures Adisory Boards -Sanofi -Janssen -Astellas -Bayer -Combat

3 Stratification of NMIBC EAU Risk Groups: therapeutic decision

4 Schedule Therapeutic Recommendations(TR): Low Risk Intermediate Risk High Risk Very High Risk Alternatives to BCG

5 Treatment Recommendations(TR): Low Risk Immediate Instillation followed by multiple Instllations - 2 random trials: Single immediate instillation vs idem follwed by multiple instillations in patients with predominant at Low Risk Author Pts Agent(mg) Single TUR + Immediate instillation Multiple p Tolley 223 MMC (40) 42.9% 30.8% 0.06 Selvagi 340 EPI (50) 31.8% 24.0% 0.11 At Low Risk, Immediate single instillation is enough

6 TR: LowRisk Pre-operativeInstillation(electromotive-EMDA device) -Randomtrial: 374 pts(ta-1): Md FU=86ms; pre-operativemmc (EMDA) VS. peri-operative MMC VS. TURB alone p<.0001 Pre-operative instillation signficantly reduced recurrence Advantage: include all pts Concerns: - No difference between TUR alone and Immediate instillation - Single trial, some methodological problems Di StasiS LancetOncol(2011) 12:871

250 pts(ta-1) Low-Intermediate Risk: Md.

7 TR: LowRisk ContinuousSalineBladderIrrigation(CSBI) - Random trial: CSBI (24hs) VS. Immediate Instillation MMC). 250 pts(ta-1) Low-Intermediate Risk: Md. FU= 36ms. No differencebetweencsbi and Immediate Instillation in Low Risk Onoshi T Eur Urol(2016) Suppl 204

8 TR: Intermediate Risk

9 Immediate single instillation in Intermediate Risk - Random trial: 113 pts of NMIBC: Intermediate(100); Low(13) one immediate postoperative instillation of pirarubicin(php)30mg (Group A), or additional THP 30mg weekly for 8 weeks (Group B). TR: Intermediate Risk 2-yr recurrence-free survival Group Global Intermediate EORTC score 5-9 A B Intermediate Risk: Immediate instillation followed by more instillations better than one single immediate instillation NayaY. EurUrolsuppl(2016) suppl210

Optimization of the schedule TR: Intermediate Risk Randontrial: 119 ptsoptimizationvs 111 standard Optimization: urinealkalinization (Na + bicarbonate, 1gx12hs.

10 Optimization of the schedule TR: Intermediate Risk Randontrial: 119 ptsoptimizationvs 111 standard Optimization: urinealkalinization (Na + bicarbonate, 1gx12hs.) concentration(20-50ml); urine( restrict fluids 6hs.) Pts Recurrence -free Interval Optimization % 11.8ms Standard % 29.1ms Duration: MMC 1h intravesicalbetterthan½h 2 Optimization of the instillation improves the results 1 Au JL J NatlCancerInst(01) 93: 598; 2 Giesbers AA BJU (1989) 63: 176

11 TR: Intermediate Risk

12 TR: Intermediate Risk TR: Intermediate Risk Dosis & Maintenance: EORTC trial: 1355 pts;bcg (1/3d vs FD) / (1 vs 3yrs) Recurrence rate Group/doses 1yr 3yrs Intermediate: - 1/3D -FD 55.2% 37.7% 44.4% 43.0% High Risk - 1/3D 40.2% 40.3% - FD 50% 33.5% PRIMARY OBJECTIVE: No DIFFERENCE between BCG doses & duration PLANNED STRATIFICATION: FD 3yrs SUPERIOR TO 1/3D 1yr NO PLANNED STRATIFICATION: -HIGH RISK: FD 3yrs SUPERIOR TO FD 1yr - INTERMEDIATE RISK: FD 1yr SUPERIOR TO 1/3D 3yrs - Toxicity NO DIFRERENCE neither dose nor maintenance Oddens J Eur.Urol(2013) 63:462

13 Dose: StandarorLow(1/3D). TR: Intermediate Risk -2 CUETO trials: BCG (81) vs BCG (27mg): 500 (Ta-1, Tis) & 155 pts(t1g3) 1,2 p= BCG: Standar VS Low dose: - NO DIFFERENCE In recurrence& progression(intermediate Risk) -TREND TO WORSE In HighRisk(T1G3) with1/3 dose - LESS toxicity: local (p=0.009)& systemic (p=0.043) - NO DIFFERENCE in progression 1 Martinez-Piñeiro JA BJU Inter. 2002; 89: ; 2 Martinez-Piñeiro J.A. J.Urol(05) 174:1242

14 Maintenance vs NO Maintenance TR: Intermediate Risk -SWOG ramdomtrial: 384 ta-1 pts(tis, 1 recurrence/yr; 3 tms(6ms) - Induction(6 wks) maintenance schedule: 3 weekly(at 3,6,12,18,24,30,36ms) Maintenance: recurrence& worsening-fs en Ta-1 (p<.05) y CIS (p<.01) Only 16% complete the whole schedule Worsening-free survival? Methodology critisized LammD J Urol(2000) 163,

15 Maintenance vs NO Maintenance TR: Intermediate Risk - CUETO ramdom trial: 397 Ta-1 pts(intermediate-high risk groups). Scheme: Induction(6 wks) maintenanceschedule: 1 weekevrey3 month 3yrs There is no difference between Maintenance VS NO maintenance in recurrence& progression Martinez-Piñeiro L. Eur Urol 68 (2015)

16 TR: High Risk Group NO PLANNED STRATIFICATION: -HIGH RISK: FD 3yrs SUPERIOR TO FD 1yr. Compliance: 62%

17 TR: High Risk Group

18 TR: VeryHighRiskGroup Predictive factor for Progession: High Risk: HG (G3) T1+TIS+ other factor Author(yr) Therapy Categoriaes Pts Md. FU Progression Sylvester(06) Chemoth. T1G3,Tis, Multiple, >3cm % Solsona(06) BCG T1G3,Tis, Multiple, >3cm yrs 64.5% Gontero(15) BCG T1G3,Tis, 70 a, 3cm yrs 52% Palou(15) BCG T1G3, female o TIS Pr yrs 40%

19 TR: VeryHighRiskGroup

20 BCG-REFRACTORY TUMOUR TR: VeryHighRiskGroup Response tobcg at 3ms: 199 highriskpatients 72.4% progressionat 5yrs afterfailurebcg (1 st cycle) with pathology: T1,G3,Tis, Pr+ Literature overview. Multivariate analysis: Solsona(00) HR= 4.3; p=.000, Hölmang(04) HR=3.01;p<.0001, Herr(07) HR=2.7; p=.001, Griffiths(02) HR= 3.78; p=.001, Sylvester(06) HR=3.11; p<.0001, CUETO (07) HR=4.6; p<.001),guilianelli(07) p=.002 Solsona E. J.Urol(2000) 164:685

21 TR: VeryHighRiskGroup BCG-REFRACTORY TUMOUR 2 nd cycle of BCG. Phase II trial (IVO): 414 T1 pts receiving BCG 1 BCG Pts RC RP NR(T1,G3,Tis,Pr+) Progression 1 cycle (84.4%) 23 (5.4%) 43 (10.1%) 34 (79%) 2 cycle 58* 35 (60.3%) 4 (6.9%) 19 (32.2%) 17 (89.4%) BCG failureafter1 cyclewithworsepathology CTx BCG failure after 2 consecutive cycles Mandatory CTx 1 Solsona E EurUrol(2006 ) Suppl;

22 TR: VeryHighRiskGroup RECURRENCE OR REFUSE CTx or NON-HG REFRACTORY-BCG -2 nd cycleof BCG 1 st cycleof BCG 2 nd cycleof BCG 374 (84.4%) RC Progresión 26 (6.9%) 35 (60.3%) RC Progresión 20 (57%) (5.4%) RP (6.9%) RP 19 (32.2%) NR 43 (10.1%) NR 8 (T 2) (excluidos) 2 nd cycleof BCG can achieve60% of new CR 1 Solsona E EurUrol(2006 ) Suppl;

23 RECURRENCE OR REFUSE CTx or NON-HG REFRACTORY-BCG Phase II trial: 1.007pts (45%) after BCG failure 2 -Scheme: IFNα(50x10 6 UI) + BCG (1/3D) + maintenance3, 9, 15ms BCG failure (interval) Recurrence-free survival(2yrs) NO failure 59% <6ms 34% 6-12ms 41% 12-24ms 53% >24ms 66% Global 45% 2 JoudiFN UrolOncol82006) 24: 344; 3 TR: VeryHighRiskGroup IFNα+BCG (1/3D) EFECTIVE after BCG failure (better with disease-fre interval >12ms)

24 TR: VeryHighRiskGroup RECURRENCE OR REFUSE CTx or NON-HG REFRACTORY-BCG PhaseII: Valrubicin: 90 pts TIS fallobcg (Md. Sgto=30ms) 3-19(21%) RC; 7 (7.7%) tasalibrerecidiva; 44 (56%) CTx Randomized phase II: GEM vsbcg: 80pts. alto riesgotrasfallobcg GEM BCG p Pts Recidiva 52.2% 87.5%.002 Intervalo 3.9ms 3.1ms.9 Progresión 33% 37%.12 Valrubicin approved by FDA GEM mightbeanalternative SteinbergG J Urol(2000) 163: 1 Di Lorenzo G. Cancer(2010) 116:1893

25 TR: VeryHighRiskGroup RECURRENCE OR REFUSE CTx or NON-HG REFRACTORY Phase II trials after BCG failure: Chemo-Hyperthermia (CHT) Category Pts. (% BCG) RC DFS (yr) Progression Halachmi T1G % (4yrs) 7.9% Arends Inter-High 160 (81%) 47% (2yrs) 4.3% Van der Heijden Inter-High 41 58% (2yrs) 0 Witjes TIS 34 92% 51% (27ms) 11% (CTx) Ayres High 38 50% (2yrs) 3% Lombardia Ta (?) 62% (2yrs) 2% Nativ Ta % (2yrs) 3% 569 pts: DFS (2yrs)= 53%; Progresión (2yrs)= 4.4% CHT Effective after BCG failure Van der Heijden AG. EurUrol(2004) 46: 65-72; Hallacmi.UrolOncol(2011) 29: 259

26 Chemo-Hyperthermia(CHT) TR: Alternative to BCG RandomizedphaseIII trial: -CHT+MMC vs BCG; pts Intermediate- High Risk ITT Per-Protocol Eficacy: CHT thanbcg Toxicity higher with BCG -CHT lesslocal & systemic -CHT highin spasms, urethral stenosis, catheterism, bladder pain, alergy Arends TJH: Eur Urol(2016)in press)

27 Electromotive MMC (EMDA) TR: Alternative to BCG PhaseIII trial (BCG/ MMC-EMDA VSBCG): 212 pts(t1); mdsgto= 88 ms. Toxicidad: No difference between both arms Recidiva: 62% VS 48% (p=.002) Progresión: 28% VS 12% (p=.002) Alternating BCG/ MMC-EMDA SUPERIOR to BCG alone Di StasiSM LancetOncol(2006) 7: 43-51; EurUrol (2015, Abstract

28 TR: Alternative to BCG Phase III trial (INFα-2b+ BCG-1/3d): 144 Ta-1, TIS pts; FU to 17yrs Scheme: BCG (6 weekly)vsbcg (1/3D) + IFNα-2b (10 MU) (6) 3-weekly (6) Local & systemic toxicity with the combination VS BCG INFα+ BCG (1/3D) recurrencerate. Alternative to BCG EsuvaranathanK. J Urol2014:191(4 Suppl):e571(abs.MP56-19)

Toxicity(G3) Local Systemic BCG 10.9% 4.7% MMC (30mg)/BCG 55.9% 6.8% MMC(10mg)/BCG 28.4% 13.9% p <0.05

29 TR: Alternative to BCG CUETO-93003, phase III trial: 405 pts Ta-1,TIS; md FU= 7.1yrs Scheme: BCG (6 weekly) VS MMC 24hs before BCB (6weekly) 3 forthnightly instillations Subgroup analysis Toxicity(G3) Local Systemic BCG 10.9% 4.7% MMC (30mg)/BCG 55.9% 6.8% MMC(10mg)/BCG 28.4% 13.9% p <0.05 <0.05. MMC+ BCG: 43% recurrence risk but no progression MMC+BCG higher toxicity than BCG Pts with recurrent T1 tumorsthe best candidates for this schedule SolsonaE. UrolUrol(2015 ) 67: 508

30 New Agents Genomic predictive factors: microrna profiling in urine samples Knowles MA. Nat Rev Cancer(2015)15:25 Mengual L. Int. J. Cancer: 133, 2631 (2013)

31 New Agents Agente Fase II Descripción rad-ifn/syn3 (Instiladrin) RAD001(Everolimus) I/II II INF-α2btransfected ito urothelial cells via adenovirus vector Intravesical Gemcitabine + oral Everolimus Dovitinib II Oral Dovitinib(TKIs) for patients with FGF3 overexpressio/mutationsunitinib Sunitinib II Oral Sunitinib(TKIs) EN3348 III Mycobacterial cell wall-dna complex VS MMC ALT-801 I/II Recombinat protein IL-2+ anti-p53-receptor DTA-H19/PEI II dsdnaplasmid-diphteriatoxingen underh19 regulation(upregulated in tumour cell) CG0070 II GM-CSF tranfected into urthelial cells via adenovirus vector nab-rapamicin I/II Intravesical nanoparticle albumin-boundrapamicin (mtor inhibitor)

32 3.HIGH RISK: FD 1-3yrs Take Home Messages 1. LOW RISK: One Immediate Instillation 2. INTERMEDIATE RISK: Immediate instillation + conventional scheme 1yr or BCG (1/3D) 1-3yrs orbcg (FD) 1yr 4. VERY HIGH RISK: CTxorBCG ifctxisrefused 5. BCG FAILURE: REFRACTORY (T1,G3,Tis, PR+) CTx Non-HG REFRACTORY orrecurrence: 2 nd cyclebcg or INFα+ BCG (173D) orcht orgem 6. ALTERNATIVE BCG: CHT (MMC) ormmc (EMDA)+ BCG orinf-α+ BCG (1/3D) ormmc+bcg

Intravesical Therapy for Bladder Cancer

Intravesical Therapy for Bladder Cancer Alexandre R. Zlotta, MD, PhD, FRCSC Professor, Department of Surgery (Urology), University of Toronto Director, Uro-Oncology, Mount Sinai Hospital Director, Uro-Oncology