1. Surgical Management of Urothelial Carcinoma A 21 st Century Approach Douglas S. Scherr, M.D. Clinical Director, Urologic Oncology Weill Medical College of Cornell University

2. 38 300 14 900 Estimated new cancer cases. 10 leading sites by gender, US, 2000

3. 8 100 4 100 Estimated cancer deaths. 10 leading sites by gender, US, 2000

4. Epidemiology 5 th most common cancer in men 12,000 cancer related deaths/year 70% present as superficial TCC “Superficial” = Ta, Tis, T1 Men>Women

5. Epidemiology 2.8% lifetime risk in caucasian men 0.9% lifetime risk in African American men 1% risk in caucasian women 0.6% African American women Carcinogens implicated in bladder cancer – could have 40 year latency period

6. Risk Factors for Transitional Cell Carcinoma Cigarette smoking: 2-4 fold increase risk 4-Aminobiphenyl O-toluidine Arylamine exposure 2-Naphthylamine Benzidine 4-Aminobiphenyl Chemotherapy – cyclophosphamide Pelvic radiation therapy

7. Overview Role of TUR Neoadjuvant Chemotherapy Surgical Principles of Importance Minimally Invasive Techniques -Robotics -Prostate Sparing Techniques Future Horizons

8. TUR vs. TUR + BCG T1, GIII 153 patients (92 TUR+BCG, 61 TUR alone) 23% in BCG arm had co-existing CIS compared with 10% in TUR alone arm (p=0.04) 5.3 year median follow up Recurrence rate: a.) BCG: 70% b.) TUR alone: 75% Time to recurrence: a.) BCG: 38 months b.) TUR alone: 22 months Progression Rate: a.) BCG: 33% b.) TUR alone: 36% Cystectomy Requirement: a.) BCG: 29% b.) TUR alone: 31% Overall Survival: No significant difference Shahin et al. J Urol 169: 96-100, 2003

9. Overall SurvivalTime to cystectomy Recurrence Free Survival Progression Free Survival Shahin et al. J Urol 169: 96-100, 2003

10. Neoadjuvant Chemotherapy Meta-Analysis Analysis of data from 2688 individual patients from 10 randomized trials Clinical stage T2-T4a disease Platinum based chemotherapy with a significant benefit to overall survival –13% reduction in risk of death –5% absolute benefit at 5 years Overall survival increased from 45% to 50% No evidence for single agent CDDP Lancet 2003; 361: 1927-34

11. Neoadjuvant Chemotherapy Meta-analysis Lancet 2003; 361: 1927-34

12. Neoadjuvant Chemotherapy Meta-analysis Lancet 2003; 361: 1927-34

13. Neoadjuvant Chemotherapy Meta-analysis

15. N Engl J Med 349;9 859-66 August 28, 2003

16. Patient Characteristics N Engl J Med 349;9 859-66 August 28, 2003

17. MVAC Toxicities  Grade 3 (n = 150) N Engl J Med 349;9 859-66 August 28, 2003

19. Grossman, H. B. et. al. N Engl J Med 2003;349:859-866 Survival among Patients Randomly Assigned to Receive Methotrexate, Vinblastine, Doxorubicin, and Cisplatin (M-VAC) Followed by Cystectomy or Cystectomy Alone, According to an Intention-to-Treat Analysis

20. Grossman, H. B. et. al. N Engl J Med 2003;349:859-866 Survival According to Treatment Group and Whether Patients Were Pathologically Free of Cancer (pT0) or Had Residual Disease (RD) at the Time of Cystectomy

21. Grossman, H. B. et. al. N Engl J Med 2003;349:859-866 Survival According to Treatment Group and Whether Patients Had Superficial Muscle Involvement (Stage T2 Disease) or More Advanced Disease (Stage T3 or T4a)

22. Conclusions Median survival of cystectomy alone was 46 mo c/w 77 mo for combination therapy (p=0.06 by two-sided stratified log rank test) In both groups, improved survival associated with the absence of residual cancer in the cystectomy specimen Significantly more patients in the combination group had no residual disease than patients in the cystectomy group (38% vs. 15%, p=<0.001) N Engl J Med 349;9 859-66 August 28, 2003

26. Diagnosis and Staging The “Re-Staging TURB” 78% of T1 tumors have residual tumor at the time of re-staging TURB 25-40% are upstaged to T2 If no muscle in first biopsy, approximately 50% of pts are upstaged to T2 If T1 is restaged and remains T1, only 13% are upstaged at time of cystectomy Herr et al. J Urol, 162: 74-76, 1999 Brauer et al. J Urol, 165: 808-10, 2001 Dalbagni et al, Urology, 10: 19-24, 2003 Dutta et al. J Urol, 166: 490-3. 2001

27. Radical Cystectomy for T1 TCC USC Experience: 208 pts with T1 disease Recurrence Free Survival Overall Survival 5 Year 10 Year 80% 75% 74% 51% Stein et al., J Clin Oncol, 19(3): 666-75, 2001

28. Early Vs. Late Cystectomy 90 pts who had TUR + BCG ultimately underwent cystectomy 41/90 had T1 disease Median Follow up of 96 mos Early cystectomy ( 2 years): 56% survival Herr and Sogani, J Urol, 166: 1296-9, 2001

29. Natural History T1, GIII TCC Natural history of T1, G3: -69-80% recurrence rate -33-48% progression rate “Rule of 30%” a.) 30% never recur b.) 30% die of metastatic TCC c.) 30% require deferred cystectomy

30. Was the Effect all Chemotherapy? Are surgical variables important? Post cystectomy survival predicted by: a.) age b.) stage c.) node status d.) negative surgical margins e.) >10 nodes removed Hazard ratio for death: a.) 2.7 for + surgical margin b.) 2.0 for <10 nodes removed Herr et al. JCO, 22(14): 2781, 2004

31. Extent of Lymphadenectomy Is there more to the node dissection than staging? 1936 Colston and Leadbetter performed studies on 98 cadavers “limited metastatic disease was restricted to the pelvic nodes” 1946 – Dr. Jewett “cardinal site of metastasis” Colston and Leadbetter, J Urol, 36: 669, 1936 Jewett et al. J Urol, 55: 366, 1946

32. Extent of Lymphadenectomy Node positive patients can enjoy long term survival 24% of grossly node positive disease survived 10 years without adjuvant therapy More nodes removed correlates with improved survival Sanderson et al. Urol Oncol., 22: 205, 2004

33. Extent of Lymphadenectomy Likely no staging advantage to extending the node dissection above the aortic bifurcation 33% of unsuspected nodes found at common iliacs Practice patterns vary widely: a.) 40% of cystectomies have no LND b.) 12.7% of LND had <4 nodes removed Lymph node density (# pos nodes/total # nodes) Konety et al. J Urol, 170: 1765, 2003

34. IMA Genitofemoral nerve Genitofemoral nerve Aortic Nodes Common Iliac Nodes Hypogastric and Obturator Nodes Extent of Pelvic Lymph Node Dissection

35. Survival By Number Of Lymph Nodes Removed Herr et al. JCO, 22(14): 2781, 2004

36. Herr, H. W. et al. J Clin Oncol; 22:2781-2789 2004 Postcystectomy survival by node status and number of nodes removed

37. Post Cystectomy Survival VariableHR*95% CIP Value Treatment RC v MVAC + RC10.7 to 1.40.97 Age ≥65 v < 65 years1.51.0 to 3.60.03 pT stage 3-4 v 0–22.31.5 to 3.60.0002 Node status positive v negative1.61.0 to 2.50.04 Margins Positive v negative2.71.5 to 4.90.0007 Nodes removed < 10 v ≥1021.4 to 2.80.0001 Herr, H. W. et al. J Clin Oncol; 22:2781-2789 2004

38. T1 Bladder Cancer “Superficial?” Balance between over treatment and under diagnosis Role of cystectomy Intravesical Therapy

39. Prostate Sparing Cystectomy Role for improved continence and potency Need to rule out prostate cancer or TCC of prostatic urethra Functional Results are good: a.) 97% complete continence b.) No episodes of retention c.) 82% maintained potency Vallancien et al. J Urol, 168: 2413, 2002

40. Prostate Sparing Cystectomy Incidence of Pca is 30-50% with approx. 48% are clinically significant 60% of CaP involve the apex (79% significant and 42% insignificant) 48% of prostates had urothelial ca involvement of which 33% had apical involvement 61% had no prostatic apical involvement of CaP or Urothelial ca.

41. (6/71-12/97) USC/Norris Bladder Cancer Experience in 1054 Patients Probability of Not Recurring According to Pathologic Group 051015 Years from Cystectomy 0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90 1.00 Probability of Not Recurring P <0.001 Organ Confined (n=594) Extravesical (n=214) Lymph Node (+) (n=246)

42. (6/71-12/97) USC/Norris Bladder Cancer Experience in 1054 Patients Probability of Survival According to Pathologic Groups 051015 Years from Cystectomy 0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90 1.00 Probability of Survival P <0.001 Organ Confined (n=594) Extravesical (n=214) Lymph Node (+) (n=246)

43. (6/71-12/97) USC/Norris Bladder Cancer Experience Patients with Positive Lymph Nodes (N=246): Probability of Not Recurring According to Pathologic Groups 051015 Years from Cystectomy 0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90 1.00 Probability of Not Recurring LN+: Organ Confined (n=75) LN+: Extravesical (n=171) P = 0.004

44. (6/71-12/97) USC/Norris Bladder Cancer Experience Patients with Positive Lymph Nodes (N=246): Probability of Survival According to Pathologic Groups 051015 Years from Cystectomy 0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90 1.00 Probability of Survival LN+: Organ Confined (n=75) LN+: Extravesical (n=171) P < 0.001

45. (6/71-12/97) USC/Norris Bladder Cancer Experience Probability of Not Recurring According to # of Lymph Nodes Involved 051015 Years from Cystectomy 0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90 1.00 Probability of Not Recurring P <0.001 Lymph Node - (n=808) 1-4 Lymph Nodes + (n=160) > 5 Lymph Nodes + (n=86)

46. (6/71-12/97) USC/Norris Bladder Cancer Experience Probability of Survival According to # of Lymph Nodes Involved 051015 Years from Cystectomy 0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90 1.00 Probability of Survival P <0.001 Lymph Node - (n=808) 1-4 Lymph Nodes + (n=160) > 5 Lymph Nodes + (n=86)

47. (6/71-12/97) USC/Norris Bladder Cancer Experience Incidence of Recurrence Following Surgery: Lymph Nodes Positive TCC (N=246) 051015 Years from Cystectomy 0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90 1.00 Incidence of Recurrence Distant Recurrence (f=113) Local Recurrence (f=28)

48. Dodd et al, JCO, 1999 Outcome of Postchemotherapy Surgery After MVAC for Advanced Transitional Cell Carcinoma

49. Role of Robotics In Bladder Cancer Decrease in hospital stay Lower morbidity Can it compete oncologically?

50. Conclusion Bladder cancer is a multidisciplinary disease Surgery plus chemotherapy are the cornerstone of therapy New advances in biomarkers and better characterization of T1 disease is necessary

51. Karakiewicz et al., Eur Urol, Vol 50:6, p. 1254-62, 2006