1. Management of Invasive Bladder Cancer
JONATHAN WU, MD
STANFORD UNIVERSITY MEDICAL CENTER

2. Staging
T2a: superficial m. propria T2b: deep m. propria T3a: micro extension into fat T3b: macro extension into fat T4a: invades pelvic viscera T4b: extends to abd/pelvic walls

3. Presentation 75% Superficial 20% Invasive 5% Distant disease Ta 70%
CIS 10%
20% Invasive
5% Distant disease

4. Staging TUR – local staging CT abd/pelvis – regional/distant staging
Relatively inaccurate for local invasion
Fails to detect nodal mets in 20-60%
MRI no better
CXR (or CT chest)
CBC, complete metabolic panel
Bone scan if elevated alk phos or symptoms
From NCCN 2012 guidelines

5. Management Intravesical therapy is not effective for stages T2 – T4
Gold Standard: Radical cystectomy, urinary diversion, pelvic lymphadenectomy +/- urethrectomy
Conservative: only dietary mgmt; empiric: everyone got K-Cit and dietary advice. Simple: hr urine collection, identified abnormality in 70% opf patients, of whom 35% have hypercalciuria. Hypercalc pts get thiazide with K cit, others get K-cit alone. Comprehensive: 2, 24 hr collections as well as fast and oral calcium load test.

6. Overall Survival After Cystectomy
Pathologic Stage N
5-year (%)
10-year (%)
T0, Ta, Tis N0
208 85 67
T1N0
194 76 52
T2N0 94 77 57
T3N0 98 64 44
T4N0 79 23 N+
246 31
*24% with LN invovlement
-Experience at USC btw with 1054 pts (843 men), median age 66 yrs with median FU 10.2 yrs.
-2.5% periop deaths, 28% early complication rate
Stein 2001 JCO

7. Lymph Node Involvement
Stage
Lymph node positive
T0, Ta, Tis, T1 5%
T2a
18%
T2b
27% T3
45% T4
*24% with LN invovlement
-Experience at USC btw with 1054 pts (843 men), median age 66 yrs with median FU 10.2 yrs.
-2.5% periop deaths, 28% early complication rate
Stein 2001 JCO

8. Recurrence-free Survival
*Overall median time to recurrence was 1 year
Stein 2001 JCO

9. Perioperative Complications
64% had complication within 90 days of surgery
GI complications (29%) were most common, followed by infections (25%) and wound-related complications (15%)
30 day mortality rate was 1.5%
MSKCC experience btw of 1142 consecutive RCs

10. Perioperative Complications
MSKCC experience btw of 1142 consecutive RCs
Highest was Grade 0 in 26%, Grade 1-2 in 51%, and Grade 3-5 in 13%

11. Outcomes Dependent on Clinical Volume
UHC clinical database: Alliance of 100 US academic health centers
421 patients underwent radical cystectomy at Vanderbilt between compared to 6,728 in the UHC system

12. Outcomes Dependent on Clinical Volume

13. Surgical Factors Affecting Outcomes

14. Surgical Factors Affecting Outcomes
1) Surgical Margins

15. Surgical Factors Affecting Outcomes
1) Surgical Margins
2) Lymph Node dissection

16. Surgical Margins MSKCC: 67/1589 (4.2%) positive margins
21% with local recurrence at 5 yrs (vs. 6%)
Median time to recurrence: 16 mo
HR 1.98 ( ) for disease-specific death
MSKCC experience from , 1589 patients

17. Surgical Margins
MSKCC experience from , 1589 patients

18. Lymph Node Dissection Node Positive Herr 2003 J Urol
**Disease specific survival curves
Take home point, #nodes removed matters, not just positive nodes
MSKCC 637 pts, 489 node neg and 148 node pos with minimal FU time of 5 yrs. All pts tx’d with primary cystectomy (no neoadj)
Herr 2003 J Urol

19. Lymph Node Dissection Node Negative Herr 2003 J Urol
MSKCC 322 pts with 10 yr followup. This graph shows 68 node-positive patients
Herr 2003 J Urol

20. Why Lymph Node Dissection Matters
More positive nodes removed equates to a better chance for cure
Node +/-
More lymph nodes removed/examined means more accurate staging
Marker of “better” surgery
Node -
Removal of lymph nodes with undetectable micrometastases

21. Other Treatment Options
Chemotherapy
Neoadjuvantvs Adjuvant
Bladder Preservation Strategies
Chemotherapy and radiation
Transurethral resection with chemotherapy

22. Chemotherapy Neoadjuvant treatment
Largest trial by EORTC with 976 patients with T2-4, N0-x, M0 planned for definitive treatment randomized to 3 cycles of MVAC vs no chemotherapy
Median survival was 44 mths vs 37.5 mths in favor of the chemotherapy group but this was non-significant
SWOG trial published in 2003 involved 137 patients with T2-4a bladder cancer randomized to 3 cycles of MVAC prior to cystectomy vs cystectomy alone

23. Chemoradiation Solitary tumor < 5 cm Clinical stage T2-3a No CIS
No hydronephrosis
No evidence of lymph node or distant metastases
Normally functioning bladder

24. Efficacy of Chemoradiation
415 patients treated with radiotherapy +/- chemotherapy (89 T1, 326 T2-T4)
Re-resected 6 weeks after treatment
Cystectomy recommended if incomplete response
Median followup of 60 months (6-199 months)
126 pts with RT alone
Chemo given during 1st and 5th wk of XRT, usually cisplat in 145 pts and carbo in 95 pts. Since 1993, combo of 5FU and cisplat given to patients
RT started 4-8 wks after TUR, daily fxn of Gy on 5 consec days. Median total dose of 54 Gy to bladder and 45 to pelvis. 79 with G3 tumors, macroscopically incomplete TUR, or evidence of pelvic nodes received additional dose of 45 Gy to para aortic nodes up to level of 3rd lumbar vert.

25. Efficacy of Chemoradiation
Complete response: 72% (288 patients at time of re-staging TUR)
Local control after CR (no muscle invasion) maintained in 64% at 10 yrs
10-year disease specific survival 42%
> 80% of survivors preserved their bladder
Tumor stage and TUR most important predictors of outcome

26. Efficacy of Resection and Chemotherapy
63 patients with muscle invasive disease with complete response to neoadjuvant chemotherapy who then refused cystectomy
All underwent re-staging TUR
64% survived, 54% with intact bladder
8/14 patients who underwent salvage cystectomy died of bladder cancer
Median FU 84 mths with min FU of 5 yrs
All pts had at least 4 cycles of cisplatinbased regimen
Multivariate analysis showed that multiple invasive tumors, large (>5cm) tumor size, and less than complete TUR predicted systemic relapse and worse survival.

27. Efficacy of Resection and Chemotherapy
JCO 2002
Goal is bladder preservation
Radiosensitizers: 5FU, cisplatin, gemcitabine, paclitaxel
**No randomized trials of chemoradiationvs surgery**

28. Efficacy of Resection and Chemotherapy
JCO 2002
Goal is bladder preservation
Radiosensitizers: 5FU, cisplatin, gemcitabine, paclitaxel
**No randomized trials of chemoradiationvs surgery**

29. Summary Surgical Management Margins Lymph node dissection Chemotherapy
Adjuvant vsneoadjuvant
Modest benefit
Best regimen?
Bladder Preservation
Chemoradiation
Chemotherapy and TUR