Intravesical Therapy for Bladder Cancer

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1 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 Fellowship Program, University of Toronto Staff, Division of Surgical Oncology, Princess Margaret Hospital, University Health Network Toronto, Ontario

2 Key Learning Objectives By participating in this session, health care professionals will: Learn about the recent advances in intravesical therapy for non-muscle invasive bladder cancer Examine new data regarding differences in BCG strains, EMDA for BCG failures, imaging of residual disease and new predictive markers and risk stratification including histological variants

Toronto, Toronto, Ontario, Canada Mount Sinai and

3 Intravesical Therapy for Bladder Cancer Alexandre R Zlotta, MD PhD FRCSC Professor, University of Toronto, Toronto, Ontario, Canada Mount Sinai and Princess Margaret Hospitals, University Health Network

4 Disclosures Advisor, grants Sanofi-Aventis Sanofi-Pasteur Amgen Astellas- CUA grants

5 BCG works but there are BCG failures!!!! Recurrence rates: 33-74% Progression rates: 7-49% Toronto experience: 1/3 recurrence without progression, 1/3 no rec no progression, 1/3 progression

6 A prospective randomized single-institution trial with treatment of 142 high-risk NMIBC patients with BCG Connaught or Tice

7 Patients and BC characteristics

8 Recurrence-free survival Progression-free survival

9 CONCLUSIONS Treatment with BCG Connaught prevented recurrences more efficiently than BCG Tice. Comparison of the immunogenicity of the two strains in mice indicated superior immunogenicity of BCG Connaught.

10 Can we identify the cats from the lions?

12 Results of multivariate analysis Most Important Prognostic Factors Recurrence Progression Nb of tumors Carcinoma in situ Prior rec rate Grade Tumor size T category (Sylvester et al, 2006)

13 T1m (minimal) T1e (extensive) pt1e: Invasion > 0.5 mm

14 New substaging New substaging T1a,b,c substaging T1a,b,c substaging

15 J Urol 2013; 189 (6):

17 Uni and multivariable analyses bladder cancer specific survival

18 RESULTS AND MESSAGE Progression rates at 10 yr ranged from 17% to 52%. Most important prognostic factors for progression: age, tumor size, and concomitant CIS Most important prognostic factors for BCa-specific survival and OS: age and tumor size. T1G3 patients 70 yr with tumors 3 cm and concomitant CIS should be treated more aggressively because of the high risk of progression

19 Clinical Outcomes of ct1 Micropapillary Bladder Cancer Willis et al, MD Anderson J Urol patients with micropapillary bladder cancer, including 72 staged with ct1n0m0 40 received primary intravesical BCG 26 underwent up-front radical cystectomy Of patients who received BCG 75%, 45% and 35% experienced disease recurrence, progression and lymph node metastasis, respectively!!!!! 5 year survival BCG: 60% 5 year survival cystectomy: 100% 5 year survival delayed cyst after recurrence: 60% 5 year survival delayed cyst after progression: 24%

21 Intravesical chemotherapy The Renaissance

22 The International Bladder Cancer Group emphasizes the importance of distinguishing recurrence from treatment failure Recurrence refers to reappearance of disease (any grade, T category, or CIS) after completion of therapy Treatment failure is defined as any recurrence or progression that occurs during intravesical therapy.

23 Intravesical Gemcitabine Author Dalbagni Dalbagni Bartoletti Mohanty Di Lorenzo Addeo Treatment modality IV Gemcitabine IV Gemcitabine IV Gemcitabine IV Gemcitabine IV Gemcitabine IV Gemcitabine n= n=high risk n='failure s' F/U (mo) (0-35) weeks (6-22) Efficacy and Comment 50% CR with a 1 year RFS of 21%. 37% needed a cystectomy Phase I stage of above study with 7/18 (39%) CR Recurrence in 32.5% of BCG failures vs. 21% BCG naïve group 43.7% of high risk failures developed recurrence vs. 25% of intermediate risk failures 60% CR. 3 patients (8.75%) progressed (all G3pT1 previously) Recurrence and 2-yr DFS better for GC vs BCG (p=0.002 and p<0.008, respectively) Recurrence free 72% GC vs. 61% MMC. DFS in favour of GC (p=0.0021)

26 Overall Survival Cancer Specific Survival

27 Intravesical Docetaxel/Paclitaxel/ BCG interferon Author Treatment modality n= n=high risk N=failures F/U (mo) McKiernan IV Docetaxel weeks Laudano IV Docetaxel Barlow IV Docetaxel Bassi IV Paclitaxel week McKiernan IV Paclitaxel weeks Joudi BCG + Interferon-α Efficacy and Comment Phase I study with a mean of 3 previous courses BCG. 56% CR but only 22% durability Long term follow-up of McKiernan [24]. 61% failed treatment. Median DFS 13.3 months Maintenance regime with 10/13 (77%) CR and 6 (46%) disease free at end of follow-up Phase I tolerability study. Nine (60%) patientshad no CIS on post treatment biopsy Only 28% (n=5 )had no evidence of disease at 6 week post treatment evaluation Of BCG failure group, 45% disease free vs. 59% BCG

28 Recurrence rates in patients receiving intravesical BCG and IFN characterized by whether they never received BCG (BCG-N) or had tumor recurrence after prior BCG (BCG-F), Joudi et al, 2006

29 Thermochemotherapy/phototherapy Author Treatment modality n= N high risk N 'failures' F/U (mo) Efficacy and Comment Witjes Thermochemot herapy % CR and 51% disease free after mean 27mo f/u Nativ Thermochemot herapy (2-74) Overall DFS 85% and 56% after 1 and 2 years but decreased efficacy if no maintenance Halachmi Waidelich Berger Breyer Thermochemot herapy Photodynamic therapy Photodynamic therapy MMC + Gemcitabine (2-49) 36 (12-51) 23.7 (1-73) KM estimated probability of recurrence 50.7% at 2-yrs for BCG failure cohort vs 42.9% 3/5 CIS patients and 4/19 with papillary tumours disease free In BCG failure group, 4/10 (40%) recurrence free with mean f/u 11.8 months % CR

30 More than 80% of pts previously treated with BCG Almost half of all those who received CHT showed no evidence of disease at 2 years

32 Device assisted instillations: EMDA (di Stasi Lancet Oncol 2006)

33 Methods 81 mg BCG infused over 120 min once a week for 2 weeks, followed by 40 mg electromotive mitomycin (intravesical electric current 20 ma for 30 min) once a week as one cycle for three cycles (n=107) Maintenance in the combo arm: 40 mg electromotive mitomycin once a month for 2 months, followed by 81 mg BCG once a month as one cycle for three cycles

34 OVERALL TREATMENT EFFICACY Recurrence BCG alone (n=105) BCG/MMC (n=107) P value Patients (%) 61/105 (58.1) 45/107 (42.1) Median disease- mos (CI) 21 (15-54) 69 (55-86) Progression to muscle invasive disease Patients (%) 23/105 (21.9) 10/107 (9.4) Median time to progr. (CI) 16.0 ( ) 37.5 ( ) Mortality Death from any cause (%) 34/105 (32.4) 23/107 (21.5) Death from bladder ca (%) 17/105 (16.2) 6/107 (5.6)

36 BACKGROUND In July 2012: Sanofi Pasteur announced it was halting production of ImmuCyst, BCG Connaught strain after inspectors found mould in the sterile manufacturing area of the Toronto plant following a flood. The Toronto facility was the only one in the world manufacturing ImmuCyst, the market leader in many countries including the UK, US and Canada This halt led to a severe worldwide shortage of BCG as other manufacturers struggled to keep up with demand.

37 Multiple simultaneous problems! Although the problem appeared to be improving slowly MSD, OncoTICE manufacturer announced that it expected severely reduced OncoTICE supplies throughout 2015 due to a combination of increased demand and a manufacturing issue. Sanofi Pasteur indicated that ImmuCyst should be available from the second quarter of Production of the RIVM BCG strain by Medac (Germany) has been on hold for some time during the fourth quarter of 2014

38 Clinical recommendations 1. BCG maintenance can be stopped after 1 yr- Patients in years 2 and 3 of maintenance without CIS can be reassured that this option is safe in terms of progression although there is a slightly higher risk of recurrence 2. Patients with CIS could be offered a reduced dose of BCG for years 2 and if possible, patients should be offered a one-third dose of BCG for induction and maintenance courses up to 1 yr. Based on a randomised EORTC trial which showed no difference in progression rates between fulldose and one-third dose BCG. Recurrence rates, however, will be higher.

39 4. if administering one-third dose BCG is not possible for practical reasons Induction course of MMC that should be followed by maintenance Optimal MMC maintenance regimen unknown, but following confirmation of response at cystoscopy, monthly instillation from months 3 12 would be a pragmatic option.s

40 5. patients should not be offered only a single BCG instillation instead of three instillations for each BCG maintenance cycle because this has been shown to be less effective

41 6. in circumstances in which BCG supplies have run out or are insufficient to allow reduced doses Patients with lowest risk high-risk NMIBC (HG Ta) can be offered an induction course of MMC followed by maintenance High-risk NMIBC patients with T1 or CI should be offered intravesical chemotherapy using DAT with thermotherapy- DISCUSSION EMDA in Canada? If already failed MMC or no access, gemcitabine 2000 mg in 50 ml once a week for 6 wk. In case of local toxicity, dose reduced to 1000 mg in 50 ml.

Management options for high-risk, BCG-refractory NMIBC. Alan M. Nieder, M.D. Columbia University Division of Urology Mount Sinai Medical Center

$Management options for high-risk, BCG-refractory NMIBC. Alan M. Nieder, M.D. Columbia University Division of Urology Mount Sinai Medical Center$ Management options for high-risk, BCG-refractory NMIBC Alan M. Nieder, M.D. Columbia University Division of Urology Mount Sinai Medical Center Bladder Cancer in U.S. 4 th most common cancer in men 9 th