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

2. 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

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

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

5. 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

6. 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

7. 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

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

9. 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
Grade
# patients
Negative (%)
Positive (%) I 68
62(91)
6(9) II 60
41(68)
19(32)
III 20
6(30)
14(70)
Heney et al. J Urol, 130: 1083, 1983

10. 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

11. 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

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

13. 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

14. Natural History T1, GIII TCC
Natural history of T1, G3: % 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

15. 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: % of T1 tumors have coexisting CiS - pan-urothelial defect
Prostatic urethral biopsy

16. 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

17. 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: , 1999
Brauer et al. J Urol, 165: , 2001
Dalbagni et al, Urology, 10: 19-24, 2003
Dutta et al. J Urol, 166:

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

19. 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: , 1995

20. TUR vs. TUR + BCG T1, GIII Shahin et al. J Urol 169: 96-100, 2003
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: , 2003

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

22. 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: , 2003

23. 2nd Course of BCG
Salvage up to 50% on non-responders
Risk of progression and Mets increases as the # courses of BCG increases
# courses
Progression Rate
% Developing Mets 1 7% 5% 2
11%
14% 3
30%
50%
Catalona et al., J Urol, 137: , 1987

24. 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

25. 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)

26. BCG + Interferon
Single agent Interferon ineffective with recurrence rates of 21-60% Belldegrun et al. J Urol, 159: , 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: , 2001

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

28. 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

29. 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

30. 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

31. 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

32. BCG Two Methods for Therapy
Second induction course
Maintenance Therapy

33. 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

34. Maintenance BCG Bedalament et al. 93 22 mos. Monthly x 2 years yes
Author
# Patients
Follow-up
Maintenance protocol
Randomized
Toxicity
Recurrence
Progression
Bedalament et al. 93
22 mos.
Monthly x 2 years
yes
increased
No change
Hudson et al. 80
14 vs. 17
Quarterly BCG x 2 years
Witjes et al. 49
43 mos.
6 biw + 8 monthly
Yes
16 pts. Did not complet maintence
Lamm et al.
SWOG
Tiw mos.
Decreased
384
91 vs. 87 mos
Weekly at 3,6,12,18,24,30,36 mos.

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

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

37. Muscle Invasive TCC Timing of Cystectomy
Role of Neoadjuvant Chemotherapy

38. 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: , 2001

40. N Engl J Med 349; August 28, 2003

41. Patient Characteristics
N Engl J Med 349; August 28, 2003

42. MVAC Toxicities  Grade 3 (n = 150)
N Engl J Med 349; August 28, 2003

43. N Engl J Med 349; August 28, 2003

44. 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
Grossman, H. B. et. al. N Engl J Med 2003;349:

45. Survival According to Treatment Group and Whether Patients Were Pathologically Free of Cancer (pT0) or Had Residual Disease (RD) at the Time of Cystectomy
Grossman, H. B. et. al. N Engl J Med 2003;349:

46. Survival According to Treatment Group and Whether Patients Had Superficial Muscle Involvement (Stage T2 Disease) or More Advanced Disease (Stage T3 or T4a)
Grossman, H. B. et. al. N Engl J Med 2003;349:

47. 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; August 28, 2003

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

52. Androgen Receptor Expression in Bladder CancerF
NON-TUMOR A
pTa C NT
TUMOR B D
pT1

53. 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