Trends in bladder cancer treatments Professor Morgan Rouprêt Pitié-Salpétrière Hospital University Paris 6, Paris, France

Disclosures Consultant and advisory role, Ipsen Consultant and advisory role, Sanofi Pasteur Member of the EAU- guidelines panel NMIBC Head of the French association- guidelines panel Bladder Cancer

95% are Urothelial Carcinomas Renal pelvis Ureter UTUC 5-10% Bladder Cancer 90-95% Siegel R, CA Cancer J Clin, 2012

Bladder cancer There are 104.000 new cases per year in Europe Smoking increases the risk by 2 to 5-fold 2/3 of patients with bladder urothelial cell carcinoma are Ta, T1 or CIS (NMIBC) and 1/3 MIBC. Recurrence and progression are the two main problems in the management of NMIBC

Medico-Economic 5th most expensive cancer on a global perspective Bladder Cancer Time Consuming (nurses, urologists) Costly +++ (TURBT, Urinary culture, cytology, cystoscopy,…) Range 96 000 - 187 000 $ / patient Botteman, Pharmacoeconomics 2001 60% treatment et 30% follow-up & complications Avritscher, Urology 2006 5th most expensive cancer on a global perspective THE most expensive Ca/ patient

MEDIAN AGE at diagnosis Classification Classification TNM Bladder Cancer NMIBC MIBC Frequency at diagnosis NMIBC : 70-80% MIBC : 20-30% MEDIAN AGE at diagnosis 65 years

NMIBC vs. MIBC

Mortality Bladder Cancer database Surveillance Epidemiology and End Results (SEER) NCI, USA

Mortality Bladder Cancer database Surveillance Epidemiology and End Results (SEER) NCI, USA

STOP SMOKING

GUIDELINES

BC: daily practice

NON MUSCLE INVASIVE BLADDER CANCER

NMIBC Stratification: Why and How? PROGNOSIS PRACTICE Recurrence Progression Specific survival Blue light Day care Surveillance TREATMENTS IPOI 2nd TURBT adjuvant instillation early cystectomy

Stratification  PROGNOSIS EORTC CUETO Scores Stage Grade Size Number Past BCa CIS Stage Grade Number Past BCa CIS Sexe Age Probability of RECURRENCE and of PROGRESSION Sylvester R et al. Eur Urol. 2006 Fernandez-Gomez J et al. J Urol. 2009

Stratification  PROGNOSIS EORTC CUETO Scores Recurrence 17 1 4 5 9 10 Recurrence 16 5 6 7 9 10 Progression 23 6 7 13 14 2 Progression 16 4 5 6 7 9 10 LOW HIGH LOW HIGH RISK GROUP Sylvester R et al. Eur Urol. 2006 Fernandez-Gomez J et al. J Urol. 2009

Stratification  PROGNOSIS EORTC CUETO Scores Stage Grade Size Number Past BCa CIS Stage Grade Number Past BCa CIS Sex Age STATISTICAL WEIGHT FOR THE RISK OF PROGRESSION Sylvester R et al. Eur Urol. 2006 Fernandez-Gomez J et al. J Urol. 2009

NMIBC Stratification PROGNOSIS PRACTICE TREATMENTS Recurrence Progression Blue light Day care Surveillance TREATMENTS IPOI 2nd TURBT Adjuvant instillation Early cystectomy

NMIBC – risk stratification group Low risk: primary, unique Ta low grade <3 cm Intermediate risk: Ta low grade, multifocal and/or recurrent, low grade High risk: CIS; TI tumour; High grade; multiple/ recurrent large > 3 cm Ta, G1, G2 tumours EAU GUIDELINES

TURBT crucial step mandatory must be complete In the OR, under anesthesia

？ ？ ？ Causal lesions of intravesical recurrence are “the endoscopic invisible lesions” Tiny lesion Flat lesion Concomitant flat lesion ？ ？ ？ To detect these invisible lesions

Concomitant flat lesion ALA-PDD visualization of bladder lesions Tiny lesion Flat lesion Concomitant flat lesion

Current European guidelines and the recommendations PDD in NMIBC: The value of fluorescence cystoscopy for improvement of the outcome in relation to progression rate or survival remains to be demonstrated

If feasible, tissue preservation would be better TURB TUR en bloc F #witjes #EAU15

BLADDER INSTILLATION : BCG or CHEMOTHERAPY

BCG strains: are all the same? Not clear! Connaught may be superior Morbidity similar Neuzillet Y t al, Prog en Urol 2015

Non-grade 3 NMIBC that failed to BCG N= 34 patients Chemo-Hyperthermia with MMC that employs conductive heating: Unithermia Non-grade 3 NMIBC that failed to BCG N= 34 patients 5 patients toxicity grade 3 No recurrence at one year: 59 % Median followup 41 m: 35.3 % recurrence and 23.5 % progression Soria F et al, World J Urol 2015

NMIBC Treatment - - TURBT TURBT 2nd TURBT NMIBC low risk IPOIC + Surveillance TURBT MMC x8 ± + 1/month 2 years NMIBC intermediate risk Failure BCG x6 + 3 BCG x3 + BCG m - - BCG x3 + BCG maintenance TURBT 2nd F/u cystoscopy NMIBC High risk TURBT NMIBC interm. BCG x6 Cystoscopy BCG x6 NMIBC High risk Failure CT MIBC MIBC MIBC

MUSCLE INVASIVE BLADDER CANCER

What would be a « Triple A » Radical Cystectomy ?

Length of time

Lymphadenectomy

Influence of hospital surgical volume complications, post-operative care, nursing, immunonutrition,..

Radical Cystectomy

Surgical approach Oncological outcomes= similar? ?

WE NEED MORE BASIC RESEARCH

Boormans and Zwarthoff, Bladder cancer 2016

Checkpoint clinical trails in bladder cancer NMIBC MIBC metastatic BCa Low grade High grade Neoadjuvant Adjuvant BCG refractory 1st line Fit for cisplatin 2nd line and more Unfit for cisplatin Pembrolizumab MPDL3280A Cisplatin refractory Maintenance Pembrolizumab (Phase III) MPDL3280A (Phase III) MEDI4736 AMP-514 MSB0010718C MGA271 ongoing Pembrolizumab / BCG Nivolumab + ipilimumab Nivolumab/carbozantinib + ipilimumab Pembrolizumab/radiation MPDL3280A + Bevacizumab MEDI0680 + MEDI4736

Bladder Cancer: treatments NMIBC TURBT Instillation Stratification MIBC Cystectomy Neo adjuvant chemo NEW DRUGS Immunotherapy Molecular status

Professor Morgan Rouprêt Trends in bladder cancer treatments Professor Morgan Rouprêt Paris, France morgan.roupret@aphp.fr Twitter @MRoupret