High-Grade T1 Bladder Cancer: A Clinical Quandary

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

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

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

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

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

7. Incidence of High-Grade T1 Disease 1Fedeli et al. , J. Urol, 185: 72, 2011 2 Strope et al., Cancer, 116: 2604, 2010 • 25% of bladder cancer presents as muscle-invasive disease or greater1 • 17,630 patients (expected) • Approximately 25% of non-muscle-invasive bladder cancer presents as high-grade T1 disease2 • 13,222 patients (expected)

8. High-Grade T1 Disease

9. Rule of 30%s1 1Cookson et al., J Urol, 158: 1, 1997 30% never recur 30% require deferred cystectomy 30% die of metastatic TCC

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

11. Importance of re-resection1 1Nieder et al., Urology, 66: 6, 2005

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

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

14. Recurrence and Progression1 1NCCN Guidelines Version 2.2011 Probability of recurrence at 5 years:50-70% Probability of progression to muscle invasion:moderate to high

15. Recurrence and Progression1 • Predictive score based on • Number of tumors • Tumor size • Prior recurrence rate • T category • CIS • Grade 1Sylvester et al., Eur Urol, 49: 3, 2006

16. Progression1 • Predictive score > 9 or presence of CIS • 2-year progression rate approximately 30% 1Sylvester et al., Eur Urol, 49: 3, 2006

17. Outline • Background • Incidence of High-grade T1 Disease • Importance of Re-resection • Recurrence and Progression • Clinical Understaging • Patient Selection • Morbidity of Surgery • 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 Cystectomy1 1Fritsche et al., Eur Urol, 57: 2, 2010 2Kulkarni et al., Eur Urol, 57: 1, 2010 • 51.4% had pT2 disease or greater • 33.4% had pT3 disease or greater • 16.2% of patients had lymph node metastasis (range=9-18%2) • 6.3% of patients had positive surgical margins

20. Outcomes of Radical Cystectomy in Patients with High-Grade T1 Disease

21. Risk Stratification1 • Low-risk T1 • Unifocal disease • No associated CIS • Tumor accessible/resectable in full • Residual disease <T1 on restaging TURBt • High-risk T1 • Multifocal disease • Associated CIS • Tumor hard to access/not resectable in full • Residual disease >T1 on restaging TURBT 1Nieder et al., Urology, 66: 6, 2005

22. Indications for Early Cystectomy1 • Morphologic features • solid • large tumor size • multifocality • Pathologic characteristics • depth of tumor invasion • associated CIS • presence of lymphovascular invasion • Response to prior intravesical therapy • Status of p53, Ki67, Cox-2, NMP-22 1Bochner, Urol Oncol, 27, 2009

23. Indications for Early Cystectomy1 • Youth • Extensive disease • Incomplete resection • Multiple, early recurrences • T1 with CIS • High-risk histology (micropapillary, small cell, etc.) 1Montgomery et al., Urol Oncol, 28, 2010

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

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

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

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

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

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

34. Early Complications Konety et al. Urol, 68(1), 2006 • 6,577 patients from NIS from 1998 to 2002 • 2.57% in-hospital mortality rate • 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

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

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

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

38. Charlson Co-Morbidity Index (CCI)

39. http://www.medal.org/OnlineCalculators/ch1/ch1.13/ch1.13.01.phphttp://www.medal.org/OnlineCalculators/ch1/ch1.13/ch1.13.01.php or www.urologymatch.com

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 Radical cystectomy is not without risk, carrying a high amount of morbidity and mortality Risk stratification is imperative 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?