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

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

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

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

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: 1 24 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.

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 1971-1997 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

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 1971-1997 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

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

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 1995-2005 of 1142 consecutive RCs

Perioperative Complications MSKCC experience btw 1995-2005 of 1142 consecutive RCs Highest was Grade 0 in 26%, Grade 1-2 in 51%, and Grade 3-5 in 13%

Outcomes Dependent on Clinical Volume UHC clinical database: Alliance of 100 US academic health centers 421 patients underwent radical cystectomy at Vanderbilt between 2001-2005 compared to 6,728 in the UHC system

Outcomes Dependent on Clinical Volume

Surgical Factors Affecting Outcomes

Surgical Factors Affecting Outcomes 1) Surgical Margins

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

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 (1.2-2.43) for disease-specific death MSKCC experience from 1985-2005, 1589 patients

Surgical Margins MSKCC experience from 1985-2005, 1589 patients

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

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

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

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

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

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

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 1.8-2.0Gy 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.

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

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.

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

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

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