1. High-Grade T1 Bladder Cancer: A Clinical Quandary Daniel Canter, M.D. Assistant Professor of Urology Emory University presentation created for:

2. Outline Background Background Incidence of High-grade T1 Disease Incidence of High-grade T1 Disease Importance of Re-resection Importance of Re-resection Recurrence and Progression Recurrence and Progression Clinical Understaging Clinical Understaging Patient Selection Patient Selection Morbidity/Mortality of Surgery Morbidity/Mortality of Surgery Risk Stratification Risk Stratification

3. Background Jemal et al. Ca Cancer J Clin 60: 277, 2010

4. Background

5. Background 70,520 new cases of bladder cancer in 2010 70,520 new cases of bladder cancer in 2010 14,680 deaths attributable bladder cancer in 2010 14,680 deaths attributable bladder cancer in 2010 Jemal et al. Ca Cancer J Clin 60: 277, 2010

6. Outline Background Background Incidence of High-grade T1 Disease Incidence of High-grade T1 Disease Importance of Re-resection Importance of Re-resection Recurrence and Progression Recurrence and Progression Clinical Understaging Clinical Understaging Patient Selection Patient Selection Morbidity of Surgery Morbidity of Surgery Risk Stratification Risk Stratification

7. Incidence of High-Grade T1 Disease 25% of bladder cancer presents as muscle-invasive disease or greater 1 25% of bladder cancer presents as muscle-invasive disease or greater 1 17,630 patients (expected) 17,630 patients (expected) Approximately 25% of non-muscle-invasive bladder cancer presents as high-grade T1 disease 2 Approximately 25% of non-muscle-invasive bladder cancer presents as high-grade T1 disease 2 13,222 patients (expected) 13,222 patients (expected) 1 Fedeli et al., J. Urol, 185: 72, 2011 2 Strope et al., Cancer, 116: 2604, 2010

8. High-Grade T1 Disease

9. Rule of 30%s 1 30% never recur 30% never recur 30% require deferred cystectomy 30% require deferred cystectomy 30% die of metastatic TCC 30% die of metastatic TCC 1 Cookson et al., J Urol, 158: 1, 1997

10. Outline Background Background Incidence of High-grade T1 Disease Incidence of High-grade T1 Disease Importance of Re-resection Importance of Re-resection Recurrence and Progression Recurrence and Progression Clinical Understaging Clinical Understaging Patient Selection Patient Selection Morbidity of Surgery Morbidity of Surgery Risk Stratification Risk Stratification

11. Importance of re-resection 1 1 Nieder et al., Urology, 66: 6, 2005 Risk of Understaging for Patients with High-Grade T1 disease StudyYear% Understaged Freeman199534% Pagano199135% Soloway199436% Amling199437% Herr199949% Ghoneim199762% Dutta200164%

12. Prognostic Importance of Re- resection 14% progression rate with less than T1 disease 14% progression rate with less than T1 disease 76% progression rate with residual T1 disease 76% progression rate with residual T1 disease 1 Nepple et al., Can J Urol, 3: 4, 2009

13. Outline Background Background Incidence of High-grade T1 Disease Incidence of High-grade T1 Disease Importance of Re-resection Importance of Re-resection Recurrence and Progression Recurrence and Progression Clinical Understaging Clinical Understaging Patient Selection Patient Selection Morbidity of Surgery Morbidity of Surgery Risk Stratification Risk Stratification

14. Recurrence and Progression 1 Probability of recurrence at 5 years: 50-70% Probability of recurrence at 5 years: 50-70% Probability of progression to muscle invasion: moderate to high Probability of progression to muscle invasion: moderate to high 1 NCCN Guidelines Version 2.2011

15. Recurrence and Progression 1 Predictive score based on Predictive score based on –Number of tumors –Tumor size –Prior recurrence rate –T category –CIS –Grade 1 Sylvester et al., Eur Urol, 49: 3, 2006

16. Progression 1 Predictive score > 9 or presence of CIS Predictive score > 9 or presence of CIS –2-year progression rate approximately 30% 1 Sylvester et al., Eur Urol, 49: 3, 2006

17. Outline Background Background Incidence of High-grade T1 Disease Incidence of High-grade T1 Disease Importance of Re-resection Importance of Re-resection Recurrence and Progression Recurrence and Progression Clinical Understaging Clinical Understaging Patient Selection Patient Selection Morbidity of Surgery Morbidity of Surgery Risk Stratification Risk Stratification

18. Patient with clinical high-grade T1 disease with metastases to the head of pancreas (Canter et al., Urology, in press)

19. Pathological Up-Staging at Time of Radical Cystectomy 1 51.4% had pT2 disease or greater 51.4% had pT2 disease or greater 33.4% had pT3 disease or greater 33.4% had pT3 disease or greater 16.2% of patients had lymph node metastasis (range=9-18% 2 ) 16.2% of patients had lymph node metastasis (range=9-18% 2 ) 6.3% of patients had positive surgical margins 6.3% of patients had positive surgical margins 1 Fritsche et al., Eur Urol, 57: 2, 2010 2 Kulkarni et al., Eur Urol, 57: 1, 2010

20. SeriesNo. of patients % Upstaging LN +Bladder-cancer survival Overall survival Herr and Sogani 35NR 92%NR Dutta et al78401278%64 Thalmann et al29411469%54 Masood et al3027NR88%NR Bianco et al6627978%NR Lambert et al10440NR93%87 Gupta et al167501882%69 Denzinger et al5426NR78%NR Total56326-50%9-18%69-93%54-87% Outcomes of Radical Cystectomy in Patients with High-Grade T1 Disease

21. Risk Stratification 1 Low-risk T1 Low-risk T1 –Unifocal disease –No associated CIS –Tumor accessible/resectable in full –Residual disease <T1 on restaging TURBt High-risk T1 High-risk T1 –Multifocal disease –Associated CIS –Tumor hard to access/not resectable in full –Residual disease >T1 on restaging TURBT 1 Nieder et al., Urology, 66: 6, 2005

22. Indications for Early Cystectomy 1 Morphologic features Morphologic features –solid –large tumor size –multifocality Pathologic characteristics Pathologic characteristics –depth of tumor invasion –associated CIS –presence of lymphovascular invasion Response to prior intravesical therapy Response to prior intravesical therapy Status of p53, Ki67, Cox-2, NMP-22 Status of p53, Ki67, Cox-2, NMP-22 1 Bochner, Urol Oncol, 27, 2009

23. Indications for Early Cystectomy 1 Youth Youth Extensive disease Extensive disease Incomplete resection Incomplete resection Multiple, early recurrences Multiple, early recurrences T1 with CIS T1 with CIS High-risk histology (micropapillary, small cell, etc.) High-risk histology (micropapillary, small cell, etc.) 1 Montgomery et al., Urol Oncol, 28, 2010

24. Outline Background Background Incidence of High-grade T1 Disease Incidence of High-grade T1 Disease Importance of Re-resection Importance of Re-resection Recurrence and Progression Recurrence and Progression Clinical Understaging Clinical Understaging Patient Selection Patient Selection Morbidity of Surgery Morbidity of Surgery Risk Stratification Risk Stratification

25. Hollingsworth et al. Journal of NCI, 2006

26. Source: National Cancer Institute

27. Prostate Cancer-Specific Mortality for Localized Prostate Cancer Eggener et al. J Urol 185: 2011

28. High-grade T1 Disease Why are more radical cystectomies not being done for high-grade T1 disease? Why are more radical cystectomies not being done for high-grade T1 disease?

29. Outline Background Background Incidence of High-grade T1 Disease Incidence of High-grade T1 Disease Importance of Re-resection Importance of Re-resection Recurrence and Progression Recurrence and Progression Clinical Understaging Clinical Understaging Patient Selection Patient Selection Morbidity of Surgery Morbidity of Surgery Risk Stratification Risk Stratification

30. Risk Factors for Bladder Cancer Age Age –Incidence increases with age –Median age=73 years Gender Gender –M:F=3:1 History of cigarette smoking History of cigarette smoking History of external beam radiation History of external beam radiation

31. Miller et al. J Urol 169: 2003 Impact of Co-Morbidity CSS OS p=0.01 24% of patients had a CCI > 2

32. Aghazadeh et al. J Urol 185: 1, 2011 90-day Mortality Rate after Radical Cystectomy based on Hospital Discharge Status Home without services = 4% Home without services = 4% Home with services = 4.8% Home with services = 4.8% Transferred to facility = 20.5% Transferred to facility = 20.5%

33. Early Complications Examination of 1142 consecutive patients who underwent cystectomy at MSKCC Examination of 1142 consecutive patients who underwent cystectomy at MSKCC Complications occurred in 64% of patients (735/1142) within 90 days of surgery Complications occurred in 64% of patients (735/1142) within 90 days of surgery Major complications (Clavien grade III-V) occurred in 13% of patients Major complications (Clavien grade III-V) occurred in 13% of patients Shabsigh et al. Eur Urol, 55: 1, 2009

34. Early Complications 6,577 patients from NIS from 1998 to 2002 6,577 patients from NIS from 1998 to 2002 2.57% in-hospital mortality rate 2.57% in-hospital mortality rate 28.1% complication rate, digestive system most common (16.1%) 28.1% complication rate, digestive system most common (16.1%) Age and co-morbid conditions predictors of complications; high-volume centers and women were associated were lower risk of complications Age and co-morbid conditions predictors of complications; high-volume centers and women were associated were lower risk of complications Konety et al. Urol, 68(1), 2006

35. Long-term Complications after Radical Cystectomy 1,057 patients 1,057 patients 1,453 conduit-related complications in 643 (61%) patients 1,453 conduit-related complications in 643 (61%) patients 2.3 complications/patient 2.3 complications/patient Shimko et al. J Urol, 185: 2, 2011

36. High-grade T1 Disease How can we choose better? How can we choose better?

37. Outline Background Background Incidence of High-grade T1 Disease Incidence of High-grade T1 Disease Importance of Re-resection Importance of Re-resection Recurrence and Progression Recurrence and Progression Clinical Understaging Clinical Understaging Patient Selection Patient Selection Morbidity of Surgery Morbidity of Surgery Risk Stratification Risk Stratification

38. Charlson Co-Morbidity Index (CCI)

39. http://www.medal.org/OnlineCalculators/ch1/ch1.13/ch1.13.01.p hp www.urologymatch.com or

40. Competing Risks Nomograms www.cancernomograms.com

41. www.cancernomograms.com

42. www.cancernomograms.com

43. www.cancernomograms.com

44. Conclusions High-grade T1 bladder is a heterogeneous disease with an aggressive biologic behavior in the majority of patients High-grade T1 bladder is a heterogeneous disease with an aggressive biologic behavior in the majority of patients Radical cystectomy is not without risk, carrying a high amount of morbidity and mortality Radical cystectomy is not without risk, carrying a high amount of morbidity and mortality Risk stratification is imperative Risk stratification is imperative These tools exist and can help to objectify treatment decision-making (i.e, early cystectomy versus delayed cystectomy) These tools exist and can help to objectify treatment decision-making (i.e, early cystectomy versus delayed cystectomy)

45. Conclusions Considering the aggressive phenotype of high- grade T1 bladder cancer and the fact that many patients will have extravesical/nodal disease at the time of “early cystectomy”, is it justified to defer early definitive treatment in this group of patients when medically fit? Considering the aggressive phenotype of high- grade T1 bladder cancer and the fact that many patients will have extravesical/nodal disease at the time of “early cystectomy”, is it justified to defer early definitive treatment in this group of patients when medically fit?