Intravesical Therapy 2010-When, with What, When to Stop Friday, April 9, 2010 Ralph de VereWhite, MD Director, UC Davis Cancer Center Associate Dean for Cancer Programs Professor, Department of Urolgoy Codman-Radke Chair in Cancer Research Non Muscle Invasive Bladder Cancer Two major consequences: Recurrence & Progression Strategies: Treatment of Primary Tumor Complete visualization Complete resection Decrease Recurrences (intravesical therapy) Minimize Progression (maintenance therapy) Primary and Recurrent TCC Stage %TCC Deaths Treatment to: TA 71% stop recurrence } >15% T1 22% stop progression T2 7% 85% High-Risk NMI TCC High grade: CIS: TI Multifocal: >3cm After intravescal therapy Recurrence 50% in first year Progression 50% 1
Non Muscle Invasive Cancer-Risk of Recurrence Study Stage Grade Recurrence (%) Follow-up Fitzpatricket all (1986) Ta G1 & 2 46 Avg.59 mos Herr (1997 Ta G1-3 56 20 yrs or until death Proutet.al (1992) Gilbert etal. (1978) Heneyet. al (1983) Jakseet al (1997) Ta G1 61 Median 58 mos Ta G3 44 >60 mos T1 G1-3 79 36 mos T1 G3 80 60 mos Abel et. al T1 G1-3 79 36 mos Reasons for Recurrence Post-TURBT Implantation Incomplete Resection Missed CIS New Tumor Transurethral Resection Is it completely resected? Especially large volume tumors Up to 30% have residual tumors Is it accurately staged? Must have muscularis propria 30% T1G3 are actually T2 High-Risk NMI TCC High grade or T1 at 1 st resection Repeat TUR @ 4 weeks 37% positive 2
Fluorescence Cystoscopy Agent Sensitivity Specificity ALA 97% 65% HAL 75-90% 80-95% Hypericin (CIS) 94% 95% Seeing Is Believing Rationale: Intravesical Chemotherapy: Single Instillation Post TUR Decreases tumor cell reimplantaion Reduces recurrence rate at 3 months Contraindications: Bladder perforation Significant bleeding Can use Mitomycin-C or Thiotepa, never BCG Thiotepa has low MW and higher absorption rate Tolley DA, J Urol 1996; 155: 1233-8 Intravesical Chemotherapy: Single Instillation Post TUR (Mitomycin C) at conclusion of TUR decreases tumor recurrence rate by 50% 502 pts. Randomized post TUR No further treatment Or: 1 instillation of Mitomycin-C post TUR Or: above plus instillations q3mo. for one year No conclusive benefit to long term over single instillation Tolley DA, J Urol 1996; 155: 1233-8 Single Post-op Chemotherapy Reduces Tumor Recurrence Meta Analysis of Randomized Trials 7 trials, 1476 patients, median follow 3.4 years (max 14.5) Recurrence: reduce from 362/748 (48.4%) with TUR to 267/728 (36.7%) with one postop dose of chemo 39% reduction in the odds of recurrence with chemotherapy (OR = 0.61, P<0.0001) 65.2% with multiple tumors recurred vs 35.8% with single tumors Sylvester R. J Urol. 2004; 270 3
Utilization of Post TUR Instillation 16, 748 patients with bladder cancer (1997-2004) MEDSTAT claims data 14,677 underwent TUR or biopsy 49 (0.33%) received same day post TUR instillation Little change in rate of use from 1997-2004 Authors propose annual savings of $24.8 million if chemo used in all eligible patients SWOG Trial (0337)of Gemcitibine Single dose of intravesical Gemcitibine following TURBT for Low risk disease Madleb, Cancer 2009 Single Dose Perioperative Gemcitibine (Germany) Double-blind, randomised, placebo controlled trial in NMIBC 355 patients at 24 urologic centres Arms were equally balanced pta: 75.0% vs 71.0%, G1-G2: 85.5% vs 87.9%; relapsed tumors 24.2% vs 21.0% Median f/u of 24 mo Gem 77.7% RFS vs placebo 75.3% RFS (HR): 0.946 p=0.777) Bohle J Eur Urol 2009 Low Risk If not given Post TUR Resection Single Post-op MMC wait for 3mo cysto MMC x 6 (Thiotepa 10-20% myelosuppression) Intermediate risk MMC x 6 High risk BCG + maintenance 4
Non Muscle Invasive Cancer-Risk of Progression Group Tumor Types Risk of Progression at 5 years (%) Low-Risk Intermediate- Risk High-Risk Single ptag1 ptag1-g2 (not recurring in <3 mo) Multifocal ptag2 ptamultiple recurrences ptag3 Single pt1g2 pt1g3 Diffuse ptis Multifocal pt1 pt1 recurring in <6 mo Risk of Cancer- RelatedDeath at 10 years (%) 7.1 4.3 17.4 12.8 41.6 36.1 High Risk NMI TCC Making MMC more effective Fluid restriction: alkalinize the urine Did best in low risk group Au. JNCI 93.597 (2008) Chopin DK, et al. Eur Urol 2002; 42: 533-41 Intravesical BCG Attenuated bacillus causing bovine tuberculosis Best agent for CIS Elicits immune response (IL-2,8, IFN & TNF) following intravesical instillation Urinary IL-8/IL-18 expression (6 & 12 hrs., respectively) following instillation predicts freedom from disease Thalmann GN, J Urol 2000 Dec; 164(6): 2129-33 Intravesical BCG BCG superior to TUR alone with regard to tumor recurrence 1,2 31% net benefit Most effective for post-tur residual papillary tumors (61% complete response rate) 3 Increases progression-free survival at 10 yrs 4 TUR + BCG = 62% TUR + delayed or no BCG = 37% 1. Brake M, Urology 2000; 55: 673-678. 2. Hurle R, Urology 1999; 54: 258-263. 3. Mack K, J Urol 2001; 165: 401-403. 4. Herr H, J Clin Oncol 1995; 13; 1404 5
Intravesical BCG Optimization of Outcome Maintenance BCG for Recurrent TIS & select Ta, T1 (3 weekly instillations at 3,6,12,18,24,30 & 36 mos) Outcome No maintenance Maintenance Meidan disease-free survival: 35.7 mos 76.8 mos (p<0.0001) Progression-Free Survival: 70 mos 76 mos (p=0.04), too early Overall Survival: 78 mos 80 mos (p=0.08), too early Toxic (only 16% completed the regimen) Decrease toxicity by using 1/3 strength BCG for maintenance. Lamm DL, J Urol 2000; 163: 1124-9 Making MMC More Effective Intravesical electromotive drug administration (EMDA) 40mg/mml in 100cc of water 212 Pt s PT1. 39% G3 BCG Only Sequential/BCG:MMC Pt s 105 107 Recurrence 61 45 DF Interval 21 mo 69 mo Progression T2 16 37 Death Due to TCC 17 6 DI. STASI SM WJU 27.325(2009) High-Risk NMI TCC After BCG 40% fail. When this occurs consider early cystectomy NMI Bladder Cancer Therapies After BCG Failure Cystectomy 15-year survival 92% if performed within 2 years of first intravesical therapy 56% if performed after 2 years (Herr & Sogani, J Urol, 2001) Risk of Invasive/Metastatic Progression 2 using additional BCG After: 1 Course 2 Courses 3 Courses Au. JNCI 93.597(2008) Invasive 7% 11% 30% Metastatic 5% 14% 50% Catalona, J. Urol. 137:1573-83, 1987 6
SWOG 8795 244 Patients BCG vs. MMC 122 Have recurred 29 Progressed (40% if high S-phase) 14 TCC deaths High Grade T1 TCC BCG 126 Pts with primary pt1: grade 1=6 grade 2=74 grade 3=46 Methods: All had repeat TUR with random biopsies If residual tumor, then 3 rd TUR If positive, then radical cystectomy BCG x 6 instillations Rebiopsied after BCG, medial F/U =53mo Brake M, Urol. 2000; 55:673-78 High Grade T1 TCC BCG Results: % Remained tumor free, bladder intact 86 Recurrent superficial disease 19 Progression to > pt2 13 Radical cystectomy 5 Tumor free survival rate (53mo. Median f/u) 89 Brake M, Urol. 2000; 55:673-78 Their therapeutic approach in patients with T1G3TCC was TUR then cystectomywithin 90 days. 114 pt s followed this approach, 260 pt s long term F/U prior to cystectomy. Reported Group 124 Early cystectomy99 delayed Retrospective: selective 7
Early Delayed Combination BCG and IFN Immunotherapy Patient numbers 124 99 Upstaged 29% 63.6% Non O.C 8.6% 14.1% LN + 9.1% 20.2% CCS 5 years 83.9% 74.8% 10 years 78.9% 64.5% First Line Therapy 670 pts BCG ±IFN no difference in outcome For BCG failures Induction 1/3 BCG + 50mu IFN x6 Maintenance 1/3, 1/10, 1/10 BCG + IFN 3,9,12mo 497 pt s. 45% DF @ 24 mos Can not be advocated for true BCG refractory disease O DonnelWJU 22 343 2009 BCG Refractory NMI TCC Intravescial Docetaxel 75mg/100ml ns 33 pts induction and maintenance DFS 45% 12mo 32% 24mo Benson M. WJU 27 331 (2009) 8
Non Muscle Invasive TCC Conclusions Enhance visulaization Complete initial resection Post-TUR instillation of Mitomycin-C Intravesical therapy based upon risk Optimize therapies Backup therapies Maintenance therapies Don not hold on too long Do not start the clock when you first see patient 9