Early Post-operative Single Instillation Therapy in NMIBC Levent N. - - PowerPoint PPT Presentation

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 Risk1

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

• 1. Babjuk M et al. Guidelines on non-muscle invasive bladder cancer.

EAU March 2011.

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

EORTC: European Organisation for Research and Treatment of Cancer

Early Single Dose Instillation1

• 1. Sylvester RJ et al. J Urol 2004; 171: 2186-90.

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 SI: Single instillation

5

Early Single Dose Instillation1

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 99/317

• 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 Total 362/748 267/728

• 43.2

87.3 (48.4%) (36.7%)

• 1. Sylvester RJ et al. J Urol 2004; 171:2186-90.

39% ±8 Reduction

TUR+Chemo Better TUR Alone Better

Test for Heterogeneity 2=9.19, df=3: p=0.03

Treatment Effect: p=0.00000

Forest Plot of Recurrence by Treatment

TUR: Transurethral resection

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)

Management of NMIBC Low Risk Group1

Comparison of Guideline Recommendations for Low Risk Disease

Brausi M et al. J Urol 2011; 186: 2158-67.

FICBT: First International Consultation on Bladder Tumors NCCN: National Comprehensive Cancer Network TURBT: Transurethral resection of bladder tumour NMIBC: non-muscle invasive bladder cancer

24

EAU Guidelines 2018

Who did not benefit from the instillation ? Patients with a prior recurrence rate > 1 recurrence per year, Patients with a recurrence score > 5

Meta-Analysis

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)

five five five identified Harrell’s five five confidence patient’s

4 6 6 –4 7 7

– – Factor Recurrence Progression

Num ber of tum ors Single 2 to 7 3 3 8 6 3 Tum or size < 3 cm 3 cm 3 3 Prior recurrence rate Prim ary 1 rec/yr 2 2 > 1 rec/yr 4 2 T category Ta T1 1 4 CIS No Yes 1 6 Grade G1 G2 1 G3 2 5 Total score 0–17 0–23

–

– – – – – – – – – – – –

3 1 2

Total points= 6

Major Problem

• Missing information

about stage and grade at the time of instillation Hypothetical Case:

• Single
• Primary
• 3 cm

Pathology:

• T1
• HG

It only works in low risk disease

Continuous Bladder Irrigation with Saline

Sylvester RJ. et al. Eur Urol 2016;69:231–244

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).

Effect of Post-operative Irrigation

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

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

• ut the median size and grade of recurrences)

These can be managed effectively by active surveillance or office fulguration Effective reduction of recurrences by continuous bladder irrigation with saline post operatively

Argument Against Routine Use of PSI

Soloway MS. Urol Oncol. 2006;24:58-61

Significantly Innocent Looking

Significantly Mortal

Hippocratic Oath