Bladder Cancer: What

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Bladder Cancer Whats 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 menwith 55,000 new
  cases in 2002
• 12,000 cancer related deaths/year
• Approximately 11,000 are T1
• MengtWomen

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Estimated new cancer cases.10 leading sites by
gender, US, 2000
38 300
14 900
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Estimated cancer deaths.10 leading sites by
gender, US, 2000
8 100
4 100
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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 men0.9 lifetime
  risk in African American men
• 1 risk in caucasian women0.6 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 HistoryTa 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, 16131, 1992 Herr
et al. J Urol, 163 60, 2000
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Natural HistoryTis

• 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, 19499, 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 HistoryT1 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 HistoryT1, 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 Stagingof 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, 1641533,
  2000)
• Random Biopsies 50-70 of T1 tumors have
  coexisting CiS - pan-urothelial defect
• Prostatic urethral biopsy

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Diagnosis and StagingUtility 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 gt1.5mm had gtT2 83 of pts
  with gt4mm had extravesical extension
• Cheng et al. Cancer, 86(6) 1035, 1999

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Diagnosis and StagingThe 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 BCGT1, GIII

• 153 patients (92 TURBCG, 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

• ODonnel et al. - effect in BCG-refractory
  patients
• 5/99-1/01 1100 patients460 failed BCG 2 or
  more times50Ta, 22T1, 21CIS, 7 mixed
• 1/3 dose BCG50 million U Interferon-alpha2B
  (Intron A)

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BCG Interferon

• Single agent Interferon ineffectivewith
  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
  survival55

ODonnell 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 InterferonFactors 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 (lt2.5cm) do better
• gt5 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 BCGlt6 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 recurrenceMitomycin 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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BCGTwo Methods for Therapy

• Second induction course
• Maintenance Therapy

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BCGSecond 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
SWOG 8507 BCG given weekly for 3
Weeks at 3,6,12,18,24,30,36 months
Worsening free Survival
Survival
Recurrence free survival
P0.04
Plt0.0001
P0.08
Lamm et al. J Urol, 163 1124-29, 2000
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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 (lt2
  years) 92 survival Late cystectomy (gt2 years)
  56 survival

Herr and Sogani, J Urol, 166 1296-9, 2001
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N Engl J Med 3499 859-66 August 28, 2003
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Patient Characteristics
N Engl J Med 3499 859-66 August 28, 2003
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MVAC Toxicities ? Grade 3 (n 150)
N Engl J Med 3499 859-66 August 28, 2003
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N Engl J Med 3499 859-66 August 28, 2003
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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
2003349859-866
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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
2003349859-866
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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
2003349859-866
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Conclusions

• Median survival of cystectomy alone was 46 mo c/w
  77 mo for combination therapy (p0.06 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, plt0.001)

N Engl J Med 3499 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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