1. Management of T1G3 Bladder cancer Dr Charles Chabert

2. T1G3 High grade lesion with invasion between epithelium & muscularis propria Gene alterations similar to T2 TCC Dilemma is to identify which will be cured by TUR & which will progress Turner E Urol 45 (2004) 401-405

3. Natural History T1G3 Paucity of data on natural history of untreated T1G3 Recurrence rates 50-70% Progression rate 25-50% Heney et al J Urol 1983; 130:1083-6

4. Diagnosis & Initial Management Is it really T1G3? Ensure muscle present Cold cut biopsies Flourescence endoscopic resection

5. Second TUR Retrospective review of concordance of 2 nd TURBT 2nd TURBT changed management in 33% If no muscle 49% upstaged to T2 J Urol 1999; 146: 316-8

6. Second TUR Residual tumour present in 33-37% Grade & stage predictive of residual tumour Biopsy abnormal urothelium Soloway et al Urol Clin N Am (2005) 133-145

7. Staging System Recommendation to substage T1 121 T1 G3 T1a : above muscularis mucosae T1b: below muscularis mucosae Only 6% not substaged 5yr survival 54% vs 42% Holmang et al J Urol 1997: 157; 800-3

8. Staging System Categorised to T1a, T1b & T1c No difference in 3 yr risk of recurrence Risk of progession 6%, 33% & 55% ROP x27 if T1c & CIS Smits et al Urol 1998;86:1035-43

9. Staging System Measured the depth of invasion 55 patients Measured from the BM to the deepest tumour cell Cutoff 1.5mm PPV >T2 95% Cheng et al. Cancer 1999:86:1035

10. Prognostic Features Early recurrence after TUR & BCG SizeMultifocalityCIS Prostatic Urethra LVI Depth of Lamina Propria Invasion Rodriguez J urol 2000;163:73-8

11. Perioperative Cytotoxic Chemotherapy 60-80% recurrence at 5 years If high grade, there is risk of progression

12. Perioperative Cytotoxic Chemotherapy Meta-analysis: One-dose immediate postop cytotoxic chemotherapy Sylvester et al J Urol2004: 171;2186-90

13. Materials & methods Randomised trials with primary or recurrent Ta/T1 Exclusion of CIS Sylvester et al J Urol 171, June 2004

14. Materials & Methods Primary end point: % of patients with a recurrence in the 2 treatment arms Decrease in Odds of recurrence calculated without time to recurrence Sylvester et al J Urol 171, June 2004

15. Results 12 trials considered 5 exclusions; 4 inadequate randomisation 1 included CIS 7 trials entered into Meta-analysis Sylvester et al J Urol 171, June 2004

16. Trial Characteristics Accural between 1981-1994 Median F/U: 3.4 years (2-10.7 yrs) 3 trials included only primary patients 2 trials only single tumours Sylvester et al J Urol 171, June 2004

17. Trial Characteristics 4 different drugs used Epirubicin 3 trials Mitomycin C 2 trials Thiotepa 1 trial Pirarubicin 1 trial Sylvester et al J Urol 171, June 2004

18. Patient Characteristics 1517 eligible patients from 7 trials 1476 had F/U 748 (50.7%) TUR only & 728 (49.3%) TUR + instillation Sylvester et al J Urol 171, June 2004

19. Tumour Characteristics Predominantly low risk 89.2% primary tumours 84.3% single tumours 67.9% Ta 9.5% G3 Sylvester et al J Urol 171, June 2004

20. Recurrence 629 (42.6%) of 1476 patients 362 (48.4%) TUR & 267 (36.7%) TUR + Chemo Decrease of 39% in odds of recurrence Sylvester et al J Urol 171, June 2004

21. Toxicity Mild irritative bladder symptoms in 10% Systemic toxicity extremely rare Allergic skin reactions 1-3% Sylvester et al J Urol 171, June 2004

22. Summary NNT to prevent 1 recurrence: 8.5 One instillation cost effective Significantly reduces recurrence with minimal morbidity Sylvester et al J Urol 171, June 2004

23. Immunotherapy BCG results in local immunological response Helper T-cells Cytotoxic t-cell activation Soloway et al Urol Clin N Am (2005) 133-145

24. T1G3 BCG era “Rule of threes” 1/3 survive with bladder 1/3 survive without bladder 1/3 die of their disease Studer et al J Urol 2003; 169:96-100

25. Merits of BCG Davis et al 59% of 98 patients bladder retention at 10 years Herr HW 50% preservation with 15 year F/U Turner E Urol 45 (2004) 401-405

26. Merits of BCG Maintenance BCG SWOG data: reduced recurrence Poor tolerance with regimen 17% completion rate Lamm et al J Urol 2000;163:1124

27. Role of Cystectomy: Early vs Late Conservative management associated with lifelong risk of recurrence, progression & metastasis Studer et al J Urol 2003; 169:96-100

28. Role of Cystectomy: Early vs Late Series of 153 patients Recurrence rate 75% at 10 years 30% dead at 10 years Studer et al J Urol 2003; 169:96-100

29. Role of Cystectomy: Early vs Late Delay in treatment affects survival: Cystectomy within or greater 3 months 55% vs 34% 5 year survival May et al scand J Urol Neph 2004

30. Role of Cystectomy: Early vs Late Improved 15 year survival with early cystectomy Review of 90 patients Cut off 2 years Herr et al J Urol 2001,166:1296-9

31. Role of Cystectomy: Early vs Late Immediate cystectomy if : Young Deep T1 One additional poor prognostic feature

32. Summary Highly malignant tumour Variable & unpredictable behaviour Variable & unpredictable behaviour Accurate staging & re –TUR Intravesicle immunotherapy Early cystectomy