Critical Evaluation of Early Post-operative Single Instillation Therapy in NMIBC

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1 Critical Evaluation of Early Post-operative Single Instillation Therapy in NMIBC Levent N. Türkeri MD, PhD Professor of Urology Acıbadem University Faculty of Medicine Istanbul

2 Conflict of Interest No relevant COI For this presentation

3 Risk Stratification Recurrence and Progression Risk 1 Recurrence (%)* Progression (%)** Risk Group 1 year 5 year 1 year 5 year Low Intermediate High Recurrence Risk* Low risk = EORTC recurrence score 0 Intermediate risk = EORTC recurrence score 1-9 High risk = EORTC recurrence score Progression Risk** Low risk = EORTC recurrence score 0 Intermediate risk = EORTC recurrence score 2-13 High risk = EORTC recurrence score EORTC: European Organisation for Research and Treatment of Cancer 1. Babjuk M et al. Guidelines on non-muscle invasive bladder cancer. EAU March 2011.

4 Early Single Dose Instillation 1 Group Recurrence Rate % Change p value TUR alone 48.4% TUR + SI 36.7% 11.7% < Single tm TUR alone 47.1% TUR + SI 35.8% 11.3% Multiple tm TUR alone 81.5% TUR + SI 65.2% 16.3% 0.06 tm: tumour TUR: Transurethral resection SI: Single instillation 1. Sylvester RJ et al. J Urol 2004; 171:

5 Early Single Dose Instillation 1 Forest Plot of Recurrence by Treatment Study Publ Year Treatment Events/Patients Statistics OR & Cl (1-OR) TUR Alone TUR+Chemo (O-E) Var. (TUR+Chemo : TUR Alone) % ±SD Epirubicin 153/325 99/ Mitomycin C 129/221 95/ Thiotepa 46/123 52/ Pirarubicin 34/79 21/ Total 362/ / (48.4%) (36.7%) 39% ±8 Reduction TUR+Chemo Better TUR Alone Better Test for Heterogeneity 2 =9.19, df=3: p=0.03 Treatment Effect: p= TUR: Transurethral resection 1. Sylvester RJ et al. J Urol 2004; 171:

6 Management of NMIBC Low Risk Group 1 Comparison of Guideline Recommendations for Low Risk Disease 24 EAU Guidelines (2017) TURBT Single immediate post operative instillation of chemotherapy (grade A) NCCN Guidelines (2017) TURBT Consider single immediate postoperative instillation of chemotherapy (category 2A), and/or FICBT Guidelines (2005) TURBT Single immediate post operative instillation of chemotherapy (grade A) AUA Guidelines (2016) TURBT Single immediate postoperative instillation of chemotherapy (moderate recommendation; grade B) FICBT: First International Consultation on Bladder Tumors NCCN: National Comprehensive Cancer Network TURBT: Transurethral resection of bladder tumour NMIBC: non-muscle invasive bladder cancer Brausi M et al. J Urol 2011; 186:

7 EAU Guidelines 2018

8 Meta-Analysis Who did not benefit from the instillation? Patients with a prior recurrence rate > 1 recurrence per year, Patients with a recurrence score > 5 Sylvester RJ. et al. Eur Urol 2016;69:

9 European Gemcitabine Trial (2009) vs SWOG Trial (2018) 38.7* 37.1* * European Trial (2009)

10 It only works in low risk disease Major Problem Missing information about stage and grade at the time of instillation Hypothetical Case: Table 5 W eigh ts used to calculate th e recurren ce an d progression scores Factor Recurrence Progression Num ber of tum ors 0 Single to Tum or size < 3cm cm 3 3 Prior recurren ce rate Prim ary rec/yr 2 2 > 1 rec/yr on in pr of Single Primary 3 cm Pathology: T1 HG Tcategory Ta T1 1 4 CIS No 0 0 Yes 1 6 Grade G1 0 0 G G3 2 5 Total score Total points= 6 0 Fig O = pa

11 Continuous Bladder Irrigation with Saline

12 Effect of Post-operative Irrigation Nonrandomized comparison of 1592 patients Overall relative risk reduction 31% HR: 0.69 (95% CI, ; p < 0.001) Single instillation: relative risk reduction 35% HR: 0.65; 95% CI, ; p < Adjustment for the randomized treatment and EORTC recurrence risk score post-op irrigation reduced the relative risk of recurrence by 21% HR: 0.79 (95% CI, ; p = 0.004). Sylvester RJ. et al. Eur Urol 2016;69:

13 Effect of Post-operative Irrigation

14 RCT with Con t Bladder Irrigation European Study Gem 2g (2009) Japanese Study MMC 30 mg (2017) Böhle A. et al. Eur Urol 2009;56: Onishi T. et al. BJU Int 2017; 119:

15 Overlay of Recurrence-free Survial Curves European (2009) vs SWOG (2018) data No Con t irrigation Gem (Europe) Con t irrigation Gem (SWOG)

16 PSI: No Effect on Progression Sylvester RJ. et al. Eur Urol 2016;69:

17 Alarming Fact: Increased Mortality with PSI Increase in the risk of death by 26% with immediate instillation (HR: 1.26) Sylvester RJ. et al. Eur Urol 2016;69:

18 Drugs Used for Instillation Sylvester RJ. et al. Eur Urol 2016;69:

Argument Against Routine Use of PSI PSI is effective only in low risk patients Recurrences (if any) will be small papillary tumors (median size 3 mm) Sylvester RJ.

19 Argument Against Routine Use of PSI PSI is effective only in low risk patients Recurrences (if any) will be small papillary tumors (median size 3 mm) Sylvester RJ. Eur Urol 2016;69: (Strongly recommend a post hoc analysis of SWOG 2018 to find out the median size and grade of recurrences) These can be managed effectively by active surveillance or office fulguration Soloway MS. Urol Oncol. 2006;24:58-61 Effective reduction of recurrences by continuous bladder irrigation with saline post operatively

20 Significantly Innocent Looking

21 Significantly Mortal

22 Hippocratic Oath

Controversies in the management of Non-muscle invasive bladder cancer

Controversies in the management of Non-muscle invasive bladder cancer Sia Daneshmand, MD Associate Professor of Urology (Clinical Scholar) Director of Urologic Oncology Director of Clinical Research Urologic