1.  1) For intravesicle therapy:  A) Mitomycin C instillation dose is 40mg for 2 hour  B) Oncotice BCG instillation dose is 81mg for 2hours  C) ImmuCyst BCG instillation dose is 12.5mg for 1 hours  D) ImmuCyst BCG instillation dose is 81mg for 2hours  E) Oncotice BCG instillation dose is 12.5mg for 1 hour MCQ

2.  2) BCG treatment: A) Lamm’s protocol use 28 doses BCG over a period of 3 years B) SWOG trial protocol uses maintenance BCG for 1 year only C) BCG maintenance drop out rate is as high as 84% according to SWOG trial D) There is good evidence to suggest that Immuncyst BCG is more effective than Oncotice BCG E )In superficial bladder cancer BCG reduces progression but not recurrence, whereas mitomycin C reduces recurrence but not progression

3.  3) BCG toxicity :  A) EORTC and CUETO suggest reduced dose BCG reduces the incidence of severe systemic toxicity compared to standard dose BCG  B) BCG can be administered in patients with macroscopic haematuria  C) Patient with microscopic haematuria is a contraindication for BCG instillation  D) Presence of leukocyte or asymptomatic bacteriuria is not a contraindication for BCG application  E) Patient with symptomatic UTI can have BCG provided prophylactic antibiotic is given

4.  4) Long term (e.g. 15 years) outcome after BCG for patient with high risk non-muscle invasive bladder cancer. Which of the following is the best answer?  A) ~50% progression rate  B) ~27% alive with intact bladder  C) 1/3 die of cancer progression  D) 1/3 develop recurrence in upper tract / prostate  E) All of the above

5.  1) For intravesicle therapy:  A) Mitomycin C instillation dose is 40mg for 2 hour -F  B) Oncotice BCG instillation dose is 81mg for 2hours -F  C) ImmuCyst BCG instillation dose is 12.5mg for 1 hours-F  D) ImmuCyst BCG instillation dose is 81mg for 2hours-T  E) Oncotice BCG instillation dose is 12.5mg for 1 hour-F

6.  2) BCG treatment: A) Lamm’s protocol use 28 doses BCG over a period of 3 years-F (27 doses over 3 yrs) B) SWOG trial protocol uses maintenance BCG for 1 year only-F (used Lamm’s) C) BCG maintenance drop out rate is as high as 84% according to SWOG trial-T D) There is good evidence to suggest that Immuncyst BCG is more effective-F than Oncotice BCG E )In superficial bladder cancer BCG reduces progression but not recurrence, whereas mitomycin C reduces recurrence but not progression -F

7.  3) BCG toxicity :  A) EORTC and CUETO suggest reduced dose BCG reduces the incidence of severe systemic toxicity compared to standard dose BCG –F (CUETO- fewer patients have toxicity but incident of severe systemic toxicity was similar. EORTC- no difference in toxicity)  B) BCG can be administered in patients with macroscopic haematuria -F  C) Patient with microscopic haematuria is a contraindication for BCG-F instillation  D) Presence of leukocyte or asymptomatic bacteriuria is not a contraindication for BCG application - T  E) Patient with symptomatic UTI can have BCG provided prophylactic antibiotic is given -F

8.  4) Long term (e.g. 15 years) outcome after BCG for patient with high risk non-muscle invasive bladder cancer. Which of the following is the best answer?  A) ~50% progression rate  B) ~27% alive with intact bladder  C) 1/3 die of cancer progression  D) 1/3 develop recurrence in upper tract / prostate  E) All of the above –Best answer (MSKCC –cookson J urol 1997)

9. Viva Question-EAU guideline 2013 – intravesical therapy

10. Viva Question-EAU guideline 2013

11.  Low risk:  Single dose, immediate post op intravesicle instillation of chemotherapy, no difference between agents (standard treatment)  Absolute recurrence reduction 11.7% (RR 39%) Sylvester 2004 Meta- analysis  To maximised efficacy immediate instillation is recommended – all single instillation studies administered within 24 hrs  Finnbladder group (Kassinen 2002)- suggested by delaying instillation overnight the risk of recurrence is increased by two fold

12.  MITOMYCIN  Mechanism of acion - Antitumour antibiotic – DNA alkylating agent, causes cross links to complementary DNA strands – inhibits DNA synthesis  Dose - 40mg in 40ml sterile water  Side effects – skin rash, storage LUTS, bladder calcifications, myelosupression  Evidence – meta-analysis of 7 RCTs, 1476 pts, 36.7% of pts with one post op dose MMC had recurrence compared to 48.4% treated with TURBT alone (decrease of 39% in odds of recurrence) (Sylvester J Urol 2004). Mitomycin

13.  Contraindications  Bladder perforation  Bleeding requires irrigation  Previous allergy

14.  Intermediate Risk  One immediate installation of chemotherapy  Further intravesicle therapy  BCG or chemotherapy (Optimum schedule not defined)  For no more than 1 year  Choice between BCG and mitomycin C for 1 year  Mitomycin – only prevent recurrence not progression  BCG- more efficacious than Mitomycin for recurrence, reduce progression BUT more toxic

15.  High risk  BCG reduce recurrence and superior to MMC (meta-analysis Shelley BJUI 2004; Bohle J Urol 2003)  BCG reduce progression  (meta-analysis Sylvester J urol 2002- 4% absolute risk reduction for progression; 27% RR reduction)  BCG maintenance is required to achieve effect (Bohle urology 2004, J urol 2003 at least 1 year of maintenance BCG is required to obtain superiority of BCG over MMC for prevention of recurrence or progression)

16.  Microwave-induced hyperthermia  Electromotive drug administration (EMDA)  Considered as experimental treatment, as studies are small and evidence is limited Methods to improve efficacy of intravesicle chemo

18. What type/ dose of BCG do you use, what advice do you give and how do you treat complications

19.  Two BCG preparations licensed in the UK  ImmuCyst (Cambridge)  BCG Connaught  81mg dose (contains 0.4-3.7x10 7 CFU/ml BCG Connaught)  OncoTICE (Organon)  BCG-TICE  12.5mg (contains 0.4-1.6x10 7 CFU/ml BCG TICE)  Mechanism – poorly understood, probably immune response leads to cytokine production What type/ dose of BCG do you use, what advice do you give and how do you treat complications

20.  Both reconstituted with 50mls saline to make a 53ml volume preparation  Catheter then inserted  Ideally full bladder on catheterisation to wash out any lubricant  Instill BCG slowly via gravity  Pt should retain the fluid for as long as possible up to 2 hours  For first 15min, should lie prone, then allowed to get up  After 2hrs Patient can void in a seated position  Care should be taken with voiding for the next 4 hours  Void whilst sitting  Bleach toilet and leave for 15min  Condoms should be used within a week of treatment

21.  BCG – absolute contraindications:  During first 2 weeks after TUR  Macroscopic Haematuria  After traumatic catheterisation  In patient with symptomatic UTI *WCC or asymptomatic bacteriuria or microscopic haematuria are not contraindication. Prophylactic antibiotic is not required *BCG should be used with caution in immunocompromised patients

22.  1st year  X6 (induction)  X3 (at 3/12)  X3 (at 6/12)  X3 (at 12/12)  2 nd year  X3 (at 18/12)  X3 (at 24/12)  3 rd year  X3 (at 30/12)  X3 (at 36/12) Total= 27 doses Lamm’s Protocol used in SWOG &EORTC

23. BCG complications  Local  Cystitis  Haematuria  Prostatitis  Orchitis  Treatment  Analgesia  +/-Postpone BCG  Culture  Antibiotic  Restart BCG  Systemic  BCG sepsis  Treatments  If a systemic BCG infection occurs, an Infectious Diseases consultation should be sought.  BCG should be permanently discontinued  Mulitiple agents anti-tuberculosis therapy should be initiated promptly. Commonly, this will comprise  Isoniazid,  Rifampicin,  Ethambutol  Pyrazinamide

24.  Non specific Symptoms (Malaise, fever, Rash, arthralgia/ arthritis)  Anti-histamines or NSAIDs BCG complications

26.  1/3 dose and full dose BCG- no difference in toxicity  Intermediate-risk patient if BCG is used- should be treated with full dose for 1 year  High-risk patient should have full dose 3 years BCG to reduce recurrence compared with full dose 1 year BCG. However, there is no benefit in terms of progressions or deaths using 3 years or 1 year protocol. Final EORTC-GU cancers Group randomized study -European Urology 2013

27. When do you consider radical treatment in superficial bladder cancer

28.  Highest risk:  G3T1 with concurrent Bladder CIS  Multiple and /or large (>3cm) G3T1  recurrent G3T1  G3T1 with CIS in prostatic urethra  Micropapillary variant of urothelial ca  High risk disease unable to tolerate BCG  consider immediate cystectomy because:  TURBT staging accuracy: For T1 disease 27-51% of patients being upstaged to muscle invasive disease at cystectomy  5 years risk of Disease Progression can be as high as 45%  Retrospective study shows high risk non muscle invasive disease undergo early cystectomy has a high survival rate When do you consider radical treatment in superficial bladder cancer

29.  Fail BCG  BCG refractory tumour 1.If high grade, non muscle invasive tumour present at 3 months 2.If CIS is present at both 3 and 6 months 3.If high grade tumour appears during BCG therapy  BCG recurrence 1.Recurrence of high grade (G3) tumour after completion of maintenance BCG, despite initial response Others

30.  Intravesicle Interferon α and BCG  Intravesicle Gemcitabine  Thermochemotherapy  Electromotive drug therapy (EMDA)  Intravesicle Taxane chemo agent  Intravesicle Mitomycin C and gemcitabine  Photodynamic therapy  Sequential therapy- Sequential BCG and EMDA MMC (Small studies with some promising results but insufficient to formulate definitive recommendation) (D Yates European Urology 2012) Alternatives to cystectomy after BCG failure