1. Radical cystectomy is the gold standard treatment for muscle-invasive bladder cancer with curative intent. Extended pelvic lymph node dissection provides better cancer control outcomes compared to limited dissection. 2. Post-operative complications are common after radical cystectomy but can be reduced at high-volume centers. Long-term oncologic outcomes depend on accurate staging and removal of all detectable cancer. 3. Nerve-sparing and organ-preserving techniques during radical cystectomy aim to improve urinary and sexual function, but long-term oncologic safety requires further study.

1. Localised invasive bladder cancer: Surgery George Thalmann Department of Urology University of Bern Switzerland

2. “ It is important to preface this discussion with the reality of the disease: high-grade invasive bladder cancer is a lethal disease and any short cuts/mistakes in the treatment can be lethal to the patient” Richard Hautmann

3. TNM Classification Bladder Muscle Mucosa Lamina propria Tis (Carcinoma in situ) Ta (urothelium) T1 (Lamina propria) T2a (superficial muscle) T2b (deep muscle) T4 (perivesical organs) T3b (perivesical fat -macro) T3a (perivesical fat -micro) Ta, T1, Tis Non muscle invasive bladder cancer T2a to T4 Muscle invasive bladder cancer

4. Staging Chest x-ray Uro-CT scan abdomen/pelvis Bone scan IVU when Uro-CT not possible

5. Staging

6. Staging LIMITATIONS OF IMAGING CT / MRI: under-/overstaging in ~30% false neg. rate 68% for LNs, 16% false pos. (Herr HW. J Urol 1996; 47: 785-791) PET: Limited role (urinary excretion of tracer) Lymph node staging accuracy ~80%

7. Staging Cystoscopy Tumor biopsy Bimanual palpation Paracollicular biopsies Bladder wash cytology

8. Clark PE, et al. ,Cancer: 104:36, 2005. Radical Cystectomy Gold Standard in the therapy of muscle-invasive bladder cancer Indication: Invasive bladder cancer N0 M0 Patient operable Elderly patients not to be excluded

9. Pelvic Lymph Node Dissection

10. Bladder Cancer Outcomes by Surgical and Pathologic Variables for the 268 Patients Undergoing Cystectomy SWOG 8710 H.W. Herr et al., J Clin Oncol 22:2781-2789, 2004 Survival Local Recurrence Variable At Risk Deaths 5-Year Survival (%) P No. of Pts. % P PLND None Limited Standard 24 98 146 17 63 79 33 46 60 .01 12 22 7 50 22 5 <.0001 Surgeon Urologist Urologic oncologist 153 115 98 61 48 58 .053 33 8 23 6 .06 Institution type Academic Community VA/military 137 84 47 72 52 35 57 54 40 .053 14 18 9 10 21 19 .02 Urinary diversion Ileal Conduit Continent stoma or orthotopic 191 77 126 33 48 63 .006 29 12 15 16 .93

11. Hautmann RE et al., J Urol 2006; 176: 486-92 Pelvic Lymph Node Dissection

12. 2 3 1 1 external iliac 3 internal iliac 2 obturator fossa Template of extended lymph node dissection Pelvic Lymph Node Dissection

13. LIMITED PLND: CC EXTENDED PLND: Bern Boundaries of Dissection {median 12 nodes: range 2-31} {median 22 nodes: range 10-43} Dhar N. et al., J. Urol 179: 873-878, 2008

14. Patients with pT2 and pT3 pN0 bladder cancer 2 consecutive series: CC 385 pts : median age 62 (31-84) Bern 394 pts : median age 67 (35-89) Follow-up: CC : median 45 months (1.1-166) Bern : median 59 months (1.3-229) No neoadjuvant radiotherapy/chemotherapy 1997 TNM system Dhar N. et al., J. Urol 179: 873-878, 2008

15. Results: Number of Pathological Positive Nodes Dhar N. et al., J. Urol 179: 873-878, 2008 Institution Stage # of Patients # with pN+ CC Limited pT 2 pN 0-2 200 15/200 (7.5%) Bern Extended pT 2 pN 0-2 150 24/150 (16%) CC Limited pT 3 pN 0-2 136 29/136 (21%) Bern Extended pT 3 pN 0-2 172 59/172 (34%)

16. RFS pT2&3 , pN 0-2 p< 0.001 Limited PLND Extended PLND Dhar N. et al., J. Urol 179: 873-878, 2008

17. RFS: pT2 pN 0-2 & pT3 pN 0-2 p< 0.001 Limited PLND Extended PLND Dhar N. et al., J. Urol 179: 873-878, 2008

18. RFS: pT2 pN 0 & pT3 pN 0 p< 0.001 Limited PLND Extended PLND Dhar N. et al., J. Urol 179: 873-878, 2008

19. RFS: pT2&3 pN + p< 0.001 Limited PLND Extended PLND Dhar N. et al., J. Urol 179: 873-878, 2008

20. Prognosticators of outcome pN1 vs pN2 Vieweg et al. J Urol 1999 Herr et al. J Urol 2003 Number pos. LN Lerner et al. J Urol 1993 Stein et al. JCO 2001 Ratio +LN/ tot LN Stein et al. J Urol 2003 Herr et al. J Urol 2003 Extracapsular Mills et al. J Urol 2001 extension

21. LNM LC LC Extracapsular extension of lymph node metastasis

22. Multivariate analysis for recurrence-free survival N = 101 Patients Variables p Value Hazard ratio 95% CI extracapsular extension or not 0.019 2.11 1.12 - 3.96 tumor stage 0.16 1.70 0.79 - 3.66  5 vs. <5 pos. nodes 0.43 1.36 0.62 - 3.00  20% vs. <20% pos. nodes 0.43 1.34 0.63 - 2.88

23. Overall survival of the entire cohort (n=507) Madersbacher S. et al., Journal of Clinical Oncology; 21(4):690-6, 2003 100 75 50 25 0 0 5 10 n = 507 probability of overall survival % years from cystectomy

24. Madersbacher S. et al., Journal of Clinical Oncology; 21(4):690-6, 2003 Overall survival of the entire cohort (n=507) 100 75 50 25 0 0 5 10 n = 507 probability of overall survival % years from cystectomy

25. Overall survival stratified according to tumor stage in lymph node negative patients Madersbacher S. et al., Journal of Clinical Oncology; 21(4):690-6, 2003 pT3pN0 (n = 120) pT1pN0 (n = 75) pT4pN0 (n = 46) pT2pN0 (n = 125) 100 75 50 25 0 Overall survival % 5 10 years from cystectomy 0

26. Recurrence-free survival in organ-confined, non organ confined and lymph node positive patients Madersbacher S. et al., Journal of Clinical Oncology; 21(4):690-6, 2003 pT1-4 pN+, n = 124 pT1-2 pN0, n = 217 pT3-4 pN0, n = 166 years from cystectomy 0 5 10 100 75 50 25 0 probability of recurrence free survival [%]

27. Madersbacher S. et al., J Clin Oncol; 21(4):690-6, 2003 Hautmann RE et al, J Urol; 176: 486-492, 2006 Stein JP et al., J Clin Oncol; 1;19(3):666-75, 2001. Radical Cystectomy Results of large series: Bern: 5 y recurrence-free survival all (4% pTa/pTis) 62% Ulm: 5 y recurrence-free survival all 59% UCLA: 5 y recurrence-free survival all (20% pTa/pTis) 68% Bern: 5 y recurrence-free survival organ-confined, LN- 73% Ulm: 5 y recurrence-free survival organ-confined, LN- 53-82% Bern: Local recurrence-free survival all 92% Ulm: Local recurrence-free survival all 96/84% Bern: Local recurrence-free survival organ-confined 97% Ulm: Local recurrence-free survival organ-confined 96%

28. Radical Cystectomy Results of large series: Positive LNs average ~25% Long term survival 20-30% Bern: 80% of all recurrences were attributable to distant metastases and 64% of LN+ progressed. Madersbacher S. et al., J Clin Oncol; 21(4):690-6, 2003 Fleischmann A et al., J Clin Oncol, 23(10):2358-65, 2005 Hautmann RE et al, J Urol; 176: 486-492, 2006 Stein JP et al., J Clin Oncol; 1;19(3):666-75, 2001.

29. Local recurrence and distal failure in pN+ bladder cancer patients after radical cystectomy n patients with pN+ 124 local recurrence only 16 (13%) distant recurrence 64 (51%) NED 44 (36%) Radical Cystectomy Good local control: improvement of survival depends on reducing distant (micro)metastases.

30. Bochner Prognosticators of outcome Internat. Bladder Cancer Nomogram Consortium; JCO 24:3967-3972.

31. Prognosticators of outcome JCO 24:3967-3972.

32. Timing of Cystectomy Patients treated within 3 months: Better RFS, DSS and OS TNM status similar, more vascular invasion in group > 3 months (Hara I et al., Jpn J Clin Oncol 2002; 32: 14-18) Treatment delay > 12 weeks: OS: 62% vs 35% (p=0.05, HR 1.93 CI 0.99-3.76) Extravesical or LN+: 84% vs 42% (Sanchez-Ortiz RF et al., J Urol 2003, 169: 110-115) Treatment > 90 days: pT3 81 vs 52% (Chang SS et al., J Urol 2003; 170: 1085-7)

33. Mortality rate 1-2% Overall early complication rate 25 - 30% Blood transfusions 30 - 50% (preoperative anemia) Radical Cystectomy Gold Standard in the therapy of muscle-invasive bladder cancer Indication: Invasive bladder cancer N0 M0 Patient operable Elderly patients not to be excluded

34. Complications of cystectomy Mortality 1 – 2% in major centers Morbidity How to prevent Cardiovascular preop work – up, monitor blood (stroke, MI) pressure Pulmonary embolism low molecular heparin started on the eve of surgery, stockings, mobilisation, bipolar coagulation Ileus Prostigmine, Metoclopramide

35. Morbidity (cont.d) How to prevent Lymphoceles ligatures distally, drainage Pyelonephritis, Remove stents on day 5-7, Septicemia, atraumatic surgery, preserve Urinary fistulas ureter vasculature, no traction on anastomosis Metabolic acidosis N a -bicarbonate Complications of cystectomy Mortality 1 – 2% in major centers

39. 100 60 80 40 0 20 time from operation (years) % continent < 65 years (n=161) > 65 years (n=170) p=0.005 Nighttime continence according to age at the time of operation 1 2 5 3 4 Kessler et al., J Urol, 172, 1323, 2004

40. 100 60 80 40 0 20 0 1 2 5 time from operation (years) % continent Nighttime continence according to attempted neurovascular bundle preservation 3 4 with attempted nerve sparing (n=256) without attempted nerve sparing (n=75) p=0.036 Kessler et al., J Urol, 172, 1323, 2004

41. 100 60 80 40 0 20 0 1 2 time from operation (years) % recovery rate of erectile function Kessler et al., J Urol, 172, 1323, 2004 with attempted bilateral nerve sparing (n=38) with attempted unilateral nerve sparing (n=218) p<0.0001 Reported recovery of erectile function (no versus reduced or normal erections) according to attempted sparing of one, both or neither neurovascular bundles without attempted nerve sparing (n=75)

42. Simone G et al., UROLOGY 72: 162–166, 2008. Prostatic Capsule and Seminal Vesicle-Sparing Cystectomy: Improved Functional Results, Inferior Oncologic Outcome All disease progressions occurred in patients with Stage T2G3 tumor at TURB. Patient age 57 y (range 39 - 66) Local recurrence rate 20% at 2 y FU Distant failure rate 30% at 2 y FU 1-year cancer-specific mortality rate 10% 2-year 20%

43. Ong CH et al., J Urol 183, 1337–1342, 2010 Individualized Seminal Vesicle Sparing Cystoprostatectomy Combined With Ileal Orthotopic Bladder Substitution Achieves Good Functional Results N = 31 100% continent 74% potent preoperatively 17(55%) Unilateral SVS RC 14(45%) Bilateral SVS RC pTa/pT1 15 (48%) pT2 9 (29%) pT3 2 (7%) pT2-3 pN1 5 (16%) No pos. SM Median Follow up 18 months (range 3 – 63)

44. Ong CH et al., J Urol 183, 1337–1342, 2010 Individualized Seminal Vesicle Sparing Cystoprostatectomy Combined With Ileal Orthotopic Bladder Substitution Achieves Good Functional Results N = 31 100% continent 74% potent preoperatively 17(55%) Unilateral SVS RC 14(45%) Bilateral SVS RC Daytime continence 27/29 (93%) Nighttime continence 19/29 (66%) Remained potent 5/19 (79%) Pelvic recurrence 1 (3%) Distant recurrence 4 (13%) Median Follow up 18 months (range 3 – 63) The preliminary results on continence and oncological outcomes are at least as good as those of conventional RC.

45. Laparoscopic Cystectomy? „ We believe that nerve-sparing LRC may be the treatment of choice in well- selected younger patients with low-volume, organ-confined disease in whom preservation of sexual function is a high priority. Nerve-sparing LRC is a technique in evolution that is an option at centers competent in advanced urologic laparoscopy .“ UROLOGY 68: 778–783, 2006. N = 5

46. Robotic-assisted Cystectomy? „ Robot-assisted laparoscopic radical cystoprostatectomy with intracorporeal ileal neobladder construction is technically feasible . However, its role in the management of invasive bladder cancer remains to be defined .“ Sala LG et al. J Endourol 20: 233–5, 2006.

47. Conclusions Extended pelvic lymph node dissection provides a clear survival advantage Open radical cystectomy is the gold standard in the treatment of localized muscle invasive bladder cancer

48. ?

50. Staging Surface Frequency

51. EAU Guidelines 4 Treatment options : Ileal conduit Bladder reconstruction Continent pouch Ureterosigmoidostomy („Minimal“ urinary diversion) Diversion?