Non-Muscle Invasive Bladder Cancer

Non-Muscle Invasive Bladder Cancer
Trinity J. Bivalacqua M.D. Ph.D.
Assistant Professor of Urology and Oncology
The James Buchanan Brady Urological Institute
Johns Hopkins Medical Institutions
Baltimore, MD USA
Disclosures
• Principal Investigator – Bladder Cancer Clinical
Trial (Tengion)
• National Institute of Health (NIH) K08 and R01
Grants.
• Patrick C. Walsh Prostate Cancer Fund Grant.
• Canadian Institutes of Health Research
Pathology of Bladder Cancer
• 90% Transitional Cell Carcinoma (Urothelial
Carcinoma; TCC)
• 5% squamous cell - more common in middle
east – schistosomiasis
-also seen in chronic catheterization
• 0.5%-2% Adenocarcinoma - urachal
Bladder Cancer: Stage
Non-Muscle Invasive Bladder
Cancer: Management
• Low Grade Lesions
– Typically, patients are followed with serial
cystoscopy and, in the absence of recurrence, no
further therapy is indicated
• High Grade Lesions
– High grade lesions have a far greater propensity
for recurrence and progression into muscle
invasion
– Typically, the use of intravesical
chemotherapy/immunotherapy is indicated
Urothelial Carcinoma (UrCa)
Two Phenotypes?
Superficial non-muscle invasive UrCa (NMIBC) : 70-80%
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Majority of UrCa (60-70%) present as non-invasive tumors at time of
first Dx
50% will recur as non-Invasive tumors
Mainstay of Rx: TURB +/- Intravesical Chemotherapy and Immune
therapy BCG
Muscle Invasive UrCa (MIBC): 20-30%
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15 % of MI UrCa have history of prior Superficial UrCa
80-90% are “primary” Muscle invasive UrCa
Practically all are high grade
Non-Invasive Urothelial Carcinoma
Recurrence/Progression
WHO/ISUP Grade:
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Urothelial Papilloma: lowest risk of recurrence & no progression
PUNLMP: 35% (25-47%) risk of recurrence, 4% risk of progression,
1% DOD
LG UrCa: 50% (30-76%) recurrence rate, 10% progress, 5% DOD
HG UrCa: most frequent recurrence rate ( 50-69%), 25-65%
progress
Flat CIS is an aggressive disease
Ledbret et al J Urol 2000
Lopez-Beltran et al Eur Urol 2004
Non-Muscle Invasive UrCa
Clinico-Pathologic PGx
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Urothelial Dysplasia
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Urothelial CIS
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O’Donnell et al Sem Oncol 2007
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The Importance of Proper Staging
• Re-staging TURBT often performed 2-6 weeks
after diagnosis for high grade (T1) non-muscle
invasive disease or if no detrusor muscle
present in speciment
• 20-30% risk of upstaging
• Prognostic value of residual disease
• Important prior to intravesical therapy
NCCN Guidelines
NCCN guidelines principles of
intravesical therapy
Mitomycin C single instillation after TURBT
Management of NMIBC
• Surveillance with endoscopic evaluation for
low grade Ta lesions
• Intravesical therapy for CIS, high grade Ta and
T1 lesions
BCG
BCG + Interferon
Mitomycin C
Valstar
Intravesical agents
Intravesical Immunotherapy: BCG
• BCG is an attenuated mycobacterium
developed as a vaccine for TB
• Has demonstrated anti-tumor activity in
several different cancers including urothelial
carcinoma
• Following transurethral resection, patients are
administered intravesical BCG weekly for ~
6wks
Bacillus Calmette-Guérin
• The original regimen described by Morales
included a percutaneous dose, which was
discontinued after success using a similar
intravesical regimen by Brosman
• One of the enduring urban myths in urology is
the story of Dr. Alvaro Morales’ initial work with
BCG. Although the rumor is usually stated that he
chose the dosing regimen based on the fact the
drug is shipped in a “6-pack,”.
BCG Preparation
• BCG is reconstituted from a lyophilized powder.
• Connaught, Tice, Armand Frappier, Pasteur,
Tokyo, and RIVM strains all arise from a common
original strain developed at the Pasteur Institute.
• The vaccine is reconstituted with 50 mL of saline
and should be administered through a urethral
catheter under gravity drainage soon thereafter
to avoid aggregation
BCG Administration
• Treatments are generally begun 2 to 4 weeks
after tumor resection, allowing time for
reepithelialization, which minimizes the potential
for intravasation of live bacteria.
• UA is usually performed immediately before
instillation to further ensure a diminished
probability of systemic uptake of BCG.
• In the event of a traumatic catheterization, the
treatment should be delayed for several days to 1
week, depending on the extent of injury.
• After instillation, the patient should retain the
solution for 2 hours
Contraindications to BCG
Administration
BCG treatment of CIS
• Before the adoption of BCG intravesical therapy, CIS reportedly
progressed at an average rate of 7% per year
• Approximately 50% of patients experience a durable response for a
median period of 4 years.
• Over a 10-year period, approximately 30% of patients remain free
of tumor progression or recurrence, so close follow-up is
mandatory.
• The majority of these occur within the first 5 years.
• Herr and coworkers (1989) reported progression in 19% of initial
responders at 5 years but found the rate to be 95% in
nonresponders—findings confirmed by other investigators
• American Urological Association (AUA) Guidelines Panel supported
BCG as the preferred initial treatment option for CIS (Hall et al,
2007).
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
2nd Course of BCG
• Salvage up to 50% on
non-responders
# courses
• Risk of progression and
Mets increases as the #
courses of BCG
increases
Catalona et al., J Urol, 137: 220-4, 1987
Progressio
n Rate
%
Developing
Mets
1
7%
5%
2
11%
14%
3
30%
50%
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
Typical Post-Rx Monitoring
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Cystoscopy q 3 months X 2 years
Cystoscopy q 6 months X 2 years
Cystoscopy q 1 year …..
Annual imaging?
Cytology with each cysto
“Molecular” cytology now available
Mitomycin C
• Alkylating agent, inhibits DNA synthesis
• Instilled Qwk for 6 to 8 wks (dose 20 to 60 mg)
• Optimization: (1) Eliminate residual urine (2) overnight
fasting (3) sodium bicarbonate to reduce drug
degradation (4) concentration of 40 mg in 20 mL
• Often used in patients with recurrent multifocal low
grade lesions (Ta)
• Bohle & Bock 2004
– Meta-analysis of 9 clinical trials compared MMC with BCG
– Median follow-up 26 months
– Tumor progression in 7.67% of BCG pts and 9.44% of MMC
pts
NCCN guidelines for post-treatment or
recurrent disease
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
BCG + Interferon
Factors that Influence Outcome
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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
Valrubicin
• Semisynthetic analog of doxorubicin
• Approved by FDA for treatment of BCG
refractory CIS; became available in US in 2009
• Regimen: 6 weekly instillations of 800 mg
intravesical valrubicin
• Main side effects: Urinary frequency, urgency,
dysuria
Efficacy and safety of valrubicin for the treatment of BCG
refractory CIS of the bladder. The Valrubicin Study Group.
Steinberg et al. J Urol 2000
• 90 pts with recurrent cis after failed intravesical BCG
therapy
• Evaluations: cysto w/ bx & cytology
• No evidence of recurrence for >6m considered
complete response
• 21% complete response, including 7 who remained
disease-free at last eval, w/ median f/u 30m
• 14 pts who did not meet definition of complete
response had superficial Ta disease only
• Median time to failure and/or last f/u for complete
responders >18m
Take-home points
• Intravesical BCG has higher efficacy than
intravesical chemotherapy.
• BCG is the only agent shown to delay or reduce
high-grade tumor progression.
• Maintenance BCG reduces recurrence rates
• Interferon-α has not been shown to have benefit
compared with BCG for primary treatment but
appears to work well in combination with lowdose BCG, especially for salvage.