Superficial Bladder Cancer PowerPoint Presentation

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Bladder Cancer: What’s New? Douglas S. Scherr, M.D. Assistant Professor of Urology Clinical Director, Urologic Oncology Weill Medical College-Cornell University

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Epidemiology 5th most common cancer in men with 55,000 new cases in 2002 12,000 cancer related deaths/year Approximately 11,000 are T1 Men>Women

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

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

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Pathology of Superficial Bladder Cancer 90% Transitional Cell Carcinoma (TCC) 5% squamous cell - more common in middle east – schistosomiasis -also seen in chronic catheterization 0.5%-2% Adenocarcinoma - urachal

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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

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Risk Factors for Superficial TCC Cigarette smoking: 2-4 fold increase risk 4-Aminobiphenyl O-toluidine Arylamine exposure 2-Naphthylamine Benzidine 4-Aminobiphenyl Chemotherapy – cyclophosphamide Pelvic radiation therapy

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Bladder Cancer WHO, International Society of Urological Pathology Consensus Classification of Urothelial Neoplasms

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Urinary Cytology Voided or urine washing 40-60% sensitivity (as high as 90% in G3 Lesions) Dependent on grade of tumor Incidence of + urine cytology according to grade Heney et al. J Urol, 130: 1083, 1983

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Natural History Ta Tumor Recurrence and Progression Overall 60-70% recurrence rate Progression based on Grade: Low grade – 4-5% progression High grade – 39% progression (26% died of TCC) Bostwick, DG J Cell Biochem, 161:31, 1992 Herr et al. J Urol, 163: 60, 2000

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Natural History Tis 54% progress to muscle invasive disease If diffuse and associated with symptoms – progression rate higher Worse prognosis if associated with papillary tumor Lamm et al, Urol Clin NA, 19:499, 1992 Herr et al, J Urol, 147: 1020, 1992

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Long term survival of patients with CIS Cheng L., et al. Cancer 1999

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Natural History T1 Tumor Most often high grade 30-50% progression rate Depth of lamina propria prognostic 70% associated with Cis Size of tumor predictive of recurrence

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Natural History T1, GIII TCC Natural history of T1, G3: -69-80% recurrence rate -53% progression rate -21% develop upper tract TCC “Rule of 30%” a.) 30% never recur b.) 30% die of metastatic TCC c.) 30% require deferred cystectomy Cookson et al. J Urol, 158(1): 62-7, 1997

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Diagnosis and Staging of T1 Disease Aggressive TURB important Adequacy of Biopsy – must contain muscularis propria Pathological Re-review: 11% of T1 recategorized as T2 (Van der Miejden et al. J Urol, 164:1533, 2000) Random Biopsies: 50-70% of T1 tumors have coexisting CiS - pan-urothelial defect Prostatic urethral biopsy

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Diagnosis and Staging “Utility of Micro-classification” T1a: up to muscularis mucosa (6% progression) T1b: into muscularis mucosa (33% progression) T1c: beyond muscularis mucosa (55% prog.) Smits et al. Urology, 52: 1009, 1998 Using 1.5mm depth of invasion as cutoff Good correlation of depth on TURB and final P stage 95% of pts with >1.5mm had >T2 83% of pts with >4mm had extravesical extension Cheng et al. Cancer, 86(6): 1035, 1999

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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

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Treatment of High Grade T1 TUR alone TUR + Intravesical Therapy TUR + Radical Cystectomy TUR +chemo/XRT

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TUR Alone Survival Rates at 10 years for High Grade T1 tumors are 55% These improve to 75% at 10 years with BCG Herr et al. J Clin Oncol, 13: 1404-8, 1995

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TUR vs. TUR + BCG T1, GIII 153 patients (92 TUR+BCG, 61 TUR alone) 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

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

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TUR + BCG BCG given as an “induction” course Must define BCG failure adequately 20-30% of pts with + cytology at 3 mos will convert spontaneously by 6 mos Shahin et al. J Urol 169: 96-100, 2003

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2nd Course of BCG Salvage up to 50% on non-responders Risk of progression and Mets increases as the # courses of BCG increases Catalona et al., J Urol, 137: 220-4, 1987

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Maintenance BCG SWOG: Lamm et al. J Urol, 163: 1124-9, 2000 Compared induction vs. induction + 3 weekly BCG at 3,6,12,18,24, 30,36 mos No difference in overall survival (5 years) Improvement in: Recurrence free survival (60% vs. 41%) Progression free survival (76% vs 70%) Only 16% completed the maintenance protocol

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BCG + Interferon O’Donnel et al. - effect in BCG-refractory patients 5/99-1/01 – 1100 patients 460 failed BCG 2 or more times 50%Ta, 22%T1, 21%CIS, 7% mixed 1/3 dose BCG+50 million U Interferon-alpha2B (Intron A)

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BCG + Interferon Single agent Interferon ineffective with recurrence rates of 21-60% Belldegrun et al. J Urol, 159: 1793-1801, 1998 Using 1/3 does BCG + Interferon –alpha2B at 50MU for 6-8 weeks At 30 mos. Recurrence free survival=55% O’Donnell et al., J Urol, 166: 1300-04, 2001

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BCG and Interferon 45% NED at 24 months 28% NED if re-induction necessary

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BCG + Interferon Factors that Influence Outcome Papillary vs. Flat CIS - -no difference Ta and T1 had same results (even if G3) # BCG failures not significant Low grade tumors did worse Small tumors (<2.5cm) do better >5 TURB do worse Residual disease do worse Multifocal tumors do worse Longer duration of cancer do worse Failure of 3 or more courses of chemo do worse Those who fail initial BCG<6 mos do worse

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BCG vs. Mitomycin Meta analysis – 11 trials (1421 patients-BCG and 1328 – Mitomycin) 26 mos median follow-up BCG: 38.6% recurrence Mitomycin: 46.4% recurrence BCG superior to Mitomycin in preventing recurrence Superiority of BCG over Mitomycin in preventing recurrence mostly seen in maintenance BCG trials Bock et al. J Urol 169: 90-95, 2003

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BCG Large studies by Lamm and Herr have demonstrated decrease in recurrence and delay in progression Does not prevent progression Theracys – live attenuated Mycobacterium Bovis from Connaught strain of Bacillus Calmette and Guerin

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High grade, cT1 treated with BCG At 15 years 52% progression (35% within 5 years) 31% DOD (25% within 5 years) 35% alive with intact bladder Herr et al. J. Urol 1992, JCO 1995, BJU 1997

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BCG Two Methods for Therapy Second induction course Maintenance Therapy

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BCG Second Induction Course Second course of BCG warranted in patients with initial prolonged response to induction therapy Also indicated in a select group of patients who fail a single course of BCG BCG Failure= + cytology or biopsy after 6 months 32% of patients with a + biopsy at 3 months were NED at 6 months Herr et al. J Urol, 141: 22-29, 1989. Dalbagni and Herr Urol Clin NA, Feb. 2000

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Maintenance BCG

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Maintenance BCG Lamm et al. J Urol, 163: 1124-29, 2000 Recurrence free survival Worsening free Survival Survival P<0.0001 P=0.04 P=0.08 SWOG 8507 BCG given weekly for 3 Weeks at 3,6,12,18,24,30,36 months

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

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Muscle Invasive TCC Timing of Cystectomy Role of Neoadjuvant Chemotherapy

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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): 92% survival Late cystectomy (>2 years): 56% survival Herr and Sogani, J Urol, 166: 1296-9, 2001

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

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

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

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

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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

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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

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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)

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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

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Potential Diagnostic Markers S phase (Ki67) P53 P21 – downstream of p53 – if + favorable outcome Rb

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Androgen Receptor Expression in Bladder Cancer

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Conclusion 92% of all bladder cancer is Ta/T1 – 15% deaths 8% of all TCC is T2 – 85% deaths BCG effect in delaying progression BCG + Interferon may have role Timing of Cystectomy is critical Neo-adjuvant Chemotherapy has a clear role Molecular biology will further define bladder cancer

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