BLADDER CANCER

1. BLADDER CANCER • What proportion of deaths from bladder cancer could be improved if we could do a cystectomy earlier in the right people? • Do we allow the natural history of CIS to become evident with extravesical (prostate, upper tract) extension by delaying cystectomy with conservative treatment? • What is the importance of divergent histology on bladder cancer management? • What is the optimal integration of systemic chemotherapy along with cystectomy? • Partial cystectomy

2. BLADDER CANCER The patient and urologist must walk a tightrope to not remove the bladder too early but not remove it too late.

3. Study Objective • To determine the proportion of patients dying of bladder cancer with potentially avoidable deaths • If large—suggests aggressive therapy may save lives • If small—suggests tumor biology has already determined ultimate outcome David S Morris Alon Weizer, James Montie, Rodney Dunn, Zaojun Ye, Brent Hollenbeck Cancer: March 2009

4. Study Population • Patients with deaths directly caused by bladder cancer • Institutional data • 126 patients from 2001-2005 • 4 independent expert reviewers • Administrative data (SEER-Medicare) • 6,326 patients from 1992-2003 • Algorithms follow clinical course • i.e. look at those who died and make assumptions on those who could have lived

5. UM Institutional Data • 40 of 126 bladder cancer deaths potentially avoidable = 32% • Substantial agreement between reviewers • Kappa range 0.74 to 0.96 • All reviewers agreed on 30 of 40 patients, 3 of 4 agreed on additional 8 patients

6. Administrative Data • 3293/6326 (52%) of deaths occurred within 1 year of diagnosis • Estimated between 21% and 39% potentially avoidable • Based on delays in treatment • Majority were healthy patients who did not receive any form of definitive therapy

7. Conclusions • A significant proportion of bladder cancer deaths may be avoidable with “ideal” therapy • Estimated as 1/3rd by clinical and administrative data • “ideal” therapy requires better decision-making by the doctor and patient to predict the future • We can do a lot better with just clinical data now available to us • The delay in these patients is long, almost 5 years

8. Institutional Data:Survival Curves Diagnosis to Death Diagnosis to Treatment Curable Non-Curable 10 58 Potentially curable patients: Lived longer with disease (58 vs. 10 months) Longer delay between diagnosis and cystectomy (23 vs. 2 months)

9. Conclusions • The majority of deaths from bladder cancer occur within 1 year of diagnosis and thus the greatest benefit will likely come from other factors • Earlier detection/screening • Improved systemic therapy • Improving physician/patient decision-making with clinical data and understanding progression risk better may avoid 30-40% of bladder cancer deaths

10. BLADDER CANCER GOALS OF TREATMENT • LOW GRADE • HIGH GRADE CHANGE IN • RECURRENCE RATE • WORTHLESS ! • MUST ELIMINATE HIGH GRADE CANCER RECURRENCE RATE

11. INTRAVESICAL THERAPY • Change in paradigm: • Surveillance works for HG Ta or T1 or CIS ONLY if there is no progression. Once progression occurs, we have lost 20-30% survival.

12. BLADDER CANCER SURGERY Which are the most dangerous cancers? • CIS • Papillary Ca and CIS • T1 • High grade T1 with CIS: Answer: High grade T1 and CIS: knows how to invade and mucosa abnormal

13. CIS • CIS must be viewed as a potentially pan-urothelial disease. The longer the disease is allowed to persist, the greater the chance for: • Extravesical spread • Invasion

14. CIS: HOW DOES IT GET THERE? Cystectomy specimens • Intramural ureter: 35% • Prostatic ducts: 43% Late recurrences with CIS treated with BCG • Upper tracts: 25% (5 yrs) • Prostate: 24% (1 yr) • Seminal vesicles: 8 cases Pagetoid spread MUST be a mechanism

15. T1 BLADDER CAHOW DO WE DO ? • How many patients have residual tumor at second resection? Answer: 20-40% (Jakse et al, 2004) • Well, that’s when other people do the resection, not me. OK, what if it is only 10% ? That’s still 10% who will get insufficient treatment. HG T1 with focal micro-papillary

16. T1 BLADDER CA:OUR CONCEPTS • If TURBT & BCG works, everyone happy • If TURBT & BCG doesn’t’ work, I’ll find out before muscle invasion • Even if muscle invasion does occur, I can take out the bladder and results will not be as bad as usual T2

17. T1 BLADDER CAHOW DO WE DO IN A PINCH ? • “I’ll find the recurrence before it invades the muscle” Wrong ! Progression to T2 or greater occurs in 10-50% of cases. Jakse, 2004 Peyromaure, 2004 Thalmann, 2004 Serretta, 2003 Divrik, 2006 Herr, 2005

18. T1 BLADDER CANCERHOW DO WE DO ? • “Since I found the muscle-invading recurrence early, the patient will still do well”. Wrong ! • The literature doesn’t support this notion and patients do just as badly or worse. Herr and Sogani, J Urol 166:1296, 2001 Yiou et al, BJU 89:374,2002 Schrier et al, Eur Urol 45: 292-296, 2004

19. p = 0.05 Lee et al, UM, 2005

20. T1 BLADDER CANCER • “Well, it’s crazy to take the bladder out in everyone with a T1 cancer” • I agree !!! Let’s pick out the BAD T1 cancers Montie

21. EVILT1 BLADDER CANCER • Bad location (inaccessible to good TUR) • Multifocal T1 • Lymphovascular invasion (LVI) • Recurrent T1 on reresection • T1 after BCG • T1 without muscle in specimen 7. ? Abnormal markers 8. ? T1b Re-resect all T1 cancers, no matter who does the initial one

22. HIGH GRADE T1 AND CIS • Change in paradigm: • Surveillance works ONLY if there is no progression. Once progression occurs, we have lost 20-30% survival. IF NO CR, TAKE OUT BLADDER

23. Urothelial Divergent Histology • Definition: Bladder cancer with both urothelial and non-urothelial components, such as: • Squamous • Glandular (adeno) • Nested • Micropapillary • Plasmacytoid • Signet cell • Lymphoepithlioma • Small cell • Sarcomatoid

24. Pathological spectrum of mixed histology component: Rajal Shah MD 112 of 448 (25%) of TURBTs contained Mixed Histology Squamous and Glandular most common followed by Sarcomatoid, Micropapillary and Small cell

25. UC with mixed histology were uniformly (100%) high grade Only one tumor with mixed histology was non-invasive (99% demonstrated invasion of at least lamina propria –T1 disease) Results TURBT CYSTECTOMY (295 patients underwent cystectomy: 90 in mixed histology group and 205 in pure UC group)

26. Conclusions • Divergent differentiation common in TURBT~30% • Micropapillary as well other types of divergent differentiation present at TURBT is associated with high pathologic stage at cystectomy and usually with a poor prognosis • Response to BCG or systemic treatment uncertain but patients with T1 disease should be offered aggressively early radical cystectomy (currently well accepted with micropapillary variant) • Just in the last month, I have had 3 cases initially called urothelial but reclassified as divergent with micropapillary, small cell, or plasmacytoid/signet ring components on review at UM

27. Neoadjuvant Chemotherapy

28. INT 0080 Figure 1: Unadjusted Survival Curves by Treatment Arm 100 % Median At Risk Death in Months Cystectomy 154 100 46 80 % MVAC/Cystectomy 153 90 77 60 % 40 % Number of Patients at Risk at 2 Years at 5 Years 20 % Cystectomy 88 60 MVAC/Cystectomy 112 84 0 % 0 24 48 72 96 120 144 168 Months from Registration

29. INT 0080 Figure 3: Unadjusted Survival Curves Stratified by Treatment and T-Stage Classification 100 % Median At Risk Death in Months MVAC/Cyst T2 61 32 105 Cyst T2 61 33 75 80 % MVAC/Cyst T3-4a 92 58 65 Cyst T3-4a 93 67 24 60 % 40 % 20 % 0 % 0 24 48 72 96 120 144 168 Months from Registration This secondary analysis underpowered and thus can’t be used to say only treat T3 with neoadjuvant

30. CONFIRMATORY DATA FOR INT 0080 The Three Largest Studies • INT 0080 (MVAC) .74 (.55-.99)* • MRC/EORTC (CMV) .85 (.71-1.02)** • Nordic 1&2 (AC or CM) .80 (.64-.99)*** *p= 0.088 (2 sided), thus called non-sig; greatest benefit T3/T4 **p= 0.075 (2-sided), thus called non-sig; now significant at 7 years FU for both survival and locoregional control *** 11% survival advantage for T3/T4a, marginal for T1 and T2 UM philosphy: neoadjuvant chemo for all T2 unless reason not to

31. What about Partial Cystectomy? • Candidates: single tumor in space and time, no CIS, good location • With these criteria, only 2-3 % of patients qualify • Age is NOT an indication: a bad cancer operation in a 60 y/o does not become a good cancer operation in an 80 y/o

32. Partial Cystectomy Use is Decreasing % Subjects Undergoing Partial

33. Partial Utilization by Patient Age % Subjects Undergoing Partial

34. Bladder Cancer Outcomes • What proportion of deaths from bladder cancer could be improved if we could do a cystectomy earlier in the right people? 30% • Do we allow the natural history of CIS to become evident with extravesical (prostate, upper tract) extension by delaying cystectomy with conservative treatment? Yes, I bet

35. Bladder Cancer Outcomes • What is the importance of divergent histology on bladder cancer management? Very • What is the optimal integration of systemic chemotherapy along with cystectomy? All muscle invasive get neoadjuvant • Isn’t partial cystectomy safer in an older person? Not if it doesn’t get rid of all the cancer

36. BLADDER CANCER The patient and urologist must walk a tightrope to not remove the bladder too early but not remove it too late ---and do it right