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
Conflict of Interest No relevant COI For this presentation
Risk Stratification Recurrence and Progression Risk 1 Recurrence (%)* Progression (%)** Risk Group 1 year 5 year 1 year 5 year Low 15 31 0.2 0.8 Intermediate 24-38 46-62 1-5 6-17 High 61 78 17 45 Recurrence Risk* Low risk = EORTC recurrence score 0 Intermediate risk = EORTC recurrence score 1-9 High risk = EORTC recurrence score 10-17 Progression Risk** Low risk = EORTC recurrence score 0 Intermediate risk = EORTC recurrence score 2-13 High risk = EORTC recurrence score 14-23 1. Babjuk M et al. Guidelines on non-muscle invasive bladder cancer. EAU March 2011. EORTC: European Organisation for Research and Treatment of Cancer
Early Single Dose Instillation 1 Group Recurrence Rate % Change p value TUR alone 48.4% TUR + SI 36.7% 11.7% <0.0001 Single tm TUR alone 47.1% TUR + SI 35.8% 11.3% 0.0005 Multiple tm TUR alone 81.5% TUR + SI 65.2% 16.3% 0.06 tm: tumour TUR: Transurethral resection 1. Sylvester RJ et al. J Urol 2004; 171: 2186-90. SI: Single instillation
Early Single Dose Instillation 1 Forest Plot of Recurrence by Treatment Events/Patients Statistics OR & Cl (1-OR) Study Publ Year % ± SD Treatment TUR Alone TUR+Chemo (O-E) Var. (TUR+Chemo : TUR Alone) Epirubicin 153/325 99/317 -26 36.7 Mitomycin C 129/221 95/206 -13.2 26.6 Thiotepa 46/123 52/124 2.8 14.8 Pirarubicin 34/79 21/81 -6.8 9.1 39% ± 8 Total 362/748 267/728 -43.2 87.3 Reduction (48.4%) (36.7%) TUR+Chemo TUR Alone Better Better Test for Heterogeneity Treatment Effect: p =0.00000 2 =9.19, df=3: p =0.03 TUR: Transurethral resection 1. Sylvester RJ et al . J Urol 2004 ; 171:2186-90. 5
24 Management of NMIBC Low Risk Group 1 Comparison of Guideline Recommendations for Low Risk Disease EAU Guidelines (2017) FICBT Guidelines (2005) TURBT TURBT Single immediate post operative Single immediate post operative instillation of chemotherapy instillation of chemotherapy (grade A) (grade A) NCCN Guidelines (2017) AUA Guidelines (2016) TURBT TURBT Consider single immediate Single immediate postoperative postoperative instillation of instillation of chemotherapy chemotherapy (category 2A), (moderate recommendation; and/or grade B) FICBT: First International Consultation on Bladder Tumors NCCN: National Comprehensive Cancer Network TURBT: Transurethral resection of bladder tumour Brausi M et al. J Urol 2011; 186: 2158-67. NMIBC: non-muscle invasive bladder cancer
EAU Guidelines 2018
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;69:231 – 244
European Gemcitabine Trial (2009) vs SWOG Trial (2018) 38.7* 37.1* * European Trial (2009)
4 6 6 –4 7 7 – – – – – – – – – – – – – identified five five five Harrell’s five It only works in low risk disease – five confidence patient’s Factor Recurrence Progression Major Problem Num ber of tum ors 0 Single 0 0 2 to 7 3 3 Missing information • 8 6 3 about stage and grade at Tum or size 3 < 3 cm 0 0 the time of instillation 3 cm 3 3 0 Prior recurrence rate Prim ary 0 0 Hypothetical Case: 1 rec/yr 2 2 > 1 rec/yr 4 2 T category Single • 1 Ta 0 0 • Primary T1 1 4 3 cm • 0 CIS No 0 0 Yes 1 6 Pathology: T1 Grade • G1 0 0 • HG 2 G2 1 0 G3 2 5 – 0–17 0–23 Total score Total points= 6
Continuous Bladder Irrigation with Saline
Effect of Post-operative Irrigation Nonrandomized comparison of 1592 patients Overall relative risk reduction 31% HR: 0.69 (95% CI, 0.59 – 0.88; p < 0.001) Single instillation: relative risk reduction 35% HR: 0.65; 95% CI, 0.58 – 0.74; p < 0.001. 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, 0.67 – 0.93; p = 0.004). Sylvester RJ. et al. Eur Urol 2016;69:231 – 244
Effect of Post-operative Irrigation
RCT with Con’t Bladder Irrigation European Study Gem 2g (2009) Japanese Study MMC 30 mg (2017) Böhle A. et al. Eur Urol 2009;56:495-503 Onishi T . et al. BJU Int 2017; 119: 276 – 282
Overlay of Recurrence-free Survial Curves European (2009) vs SWOG (2018) data No Con’t irrigation Gem (Europe) Con’t irrigation Gem (SWOG)
PSI: No Effect on Progression Sylvester RJ. et al. Eur Urol 2016;69:231 – 244
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;69:231 – 244
Drugs Used for Instillation Sylvester RJ. et al. Eur Urol 2016;69:231 – 244
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;69:231 – 244 (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
Significantly Innocent Looking
Significantly Mortal
Hippocratic Oath
Recommend
More recommend
