1. Radical Cystectomy As Early Primary Therapy for T1G3 Bladder Cancer Karim Touijer and Bernard H. Bochner. Memorial Sloan-Kettering Cancer Center

2. T1G3 Bladder Cancer “THE FACTS” Is a potentially lethal tumorIs a potentially lethal tumor This is NOT a superficial tumorThis is NOT a superficial tumor Understaging occurs frequentlyUnderstaging occurs frequently High recurrence rate and progression despite intravesical therapyHigh recurrence rate and progression despite intravesical therapy Poor markers available to accurately identify high risk lesionsPoor markers available to accurately identify high risk lesions Can be effectively CURED by early definitive surgery (radical cystectomy)Can be effectively CURED by early definitive surgery (radical cystectomy)

3. BLADDER CANCER: TWO PATHWAYS OF PROGRESSION NORMAL UROTHELIUM Ta 9qDel RAS T1T2-4 N+/M+ 9pDel (INK4A) (Presti et al, Ca Res 91; Cordon-Cardo et al, JNCI 92; Dalbagni et al, Lancet 93; Sarkis et al, JNCI 93; Cairns et al, Science 94; Orlow et al, JNCI 95; Li et al, Am J Path 96; Rabbani et al, JNCI 99; McShane et al, Ca Res 2000; Hernando et al, Int J Ca 2001; Sanchez et al, Ca Res, 2002; Veltman et al Ca Res, 2003 ) Tis T1T2-4 N+/M+ TP53 RB 5qDel, 3pDel 10qDel, 11pDel, 18qDel 14qDel

4. T1G3 Bladder Cancer Can we accurately detect this disease? Are we at risk for understaging?

5. T1G3 And TIS Bladder Cancer Clinical Understaging Author P stage > T1 Amling (Duke), 1994 37% Soloway (Florida) 1994 36% (60% for Tis) Stein (USC) 2001 39% 10 - 15% have positive nodes at cystectomy

6. Risk Of Understaging Is Influenced By Presence Of Muscle In TUR Specimen Dutta, J Urol 166:490, 2001 N=78 Herr, HW J Urol 162:74, 1999 A second TURBT required to identify extent of disease.

7. T1G3 Bladder Cancer Outcome Of Understaged Patients Disease Specific Outcomes Freeman et al, Cancer, 1995 179 patients (71% with T1 tumors) 53% failed intravesical therapy Understaged lesions do significantly worse Understaged lesions WILL NOT respond to bladder sparing approaches

8. Repeat TURBT May Help Reduce Understaging Dalbagni et al, UROLOGY 2002

9. T1G3 Bladder Cancer Natural History Recurrence and Progression Risk Recurrence RiskRecurrence Risk –Following TURBT, 69-80% risk of recurrence –Intravesical immunotherapy can delay recurrence and progression, but long-term will not alter natural history Progression RiskProgression Risk –33-50% will progress to muscle invasion

10. Can BCG Impact Ultimate Cancer- Specific Survival

11. BCG Can Delay Recurrence But May Not Impact Ultimate Cancer- specific Survival Recurrence-free survivalCancer-specific survival Orsola et al Eur Urol 48:231, 2005

12. T1G3 Bladder Cancer Long-term Results With BCG Cookson, J Urol 158:62, 1997 Pansodoro, Urology 59:227, 2002 Shahin, J Urol 169:96, 2003 Study # pts Med. F/u ProgressionCystectomy DOD DOD Cookson 86 86 15.3 yrs 53% 53% 36% 36% 34% 34% Pansodoro 81 81 6.3 yrs 15% 15% 8.6% 8.6% 6% 6% Shahin 92 92 5.3 yrs 30 % 30 % 29% 29% 23% 23%

13. T1G3 Bladder Cancer Long-Term Outcome Conservative BCG and Progression of Disease 1978-1981 86 patients with high risk non-muscle invasive disease (36 patients T1)1978-1981 86 patients with high risk non-muscle invasive disease (36 patients T1) Randomized to TURBT +/- BCGRandomized to TURBT +/- BCG Followed q3-6 months for 3 years then annuallyFollowed q3-6 months for 3 years then annually Evaluated progression and disease specific survivalEvaluated progression and disease specific survival

14. T1G3 Bladder Cancer Long-Term Outcome Conservative BCG and Progression of Disease

15. T1G3 Bladder Cancer Long-Term Outcome Conservative Disease Specific Survival Cookson J Urol 158:62, 1997 People not treated by cystectomy continue to die of bladder cancer!

16. T1G3 Bladder Cancer Long-Term Outcome Conservative Disease Specific Outcomes

17. T1 Bladder Cancer Characteristics Associated with Recurrence and Progression PathologicPathologic –High grade, multifocality, associated CIS, prostatic urethral involvement, size, sessile growth pattern, (Others unreliable and controversial: aneuplody, p53 alteration, lymphovascular invasion) ClinicalClinical –Failure of intravesical therapy (80% with disease at 3 months progress), endoscopically uncontrollable disease, disease within diverticuli MAJORITY