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A part of the Virtual Edition on Intravesical therapy on www.bjui.org. Go to www.bjui.org to read the open access article.
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Miss Jo CresswellMiss Jo Cresswell
Consultant UrologistConsultant Urologist
James Cook University Hospital, Middlesbrough James Cook University Hospital, Middlesbrough
Overview of Intravesical Therapy: Current Overview of Intravesical Therapy: Current ControversiesControversies
Overview
Intravesical, Oct 2010
Intravesical Therapy
Single Immediate Instillation
Maintenance Chemotherapy
BCG Failure T1G3
Single instillation of intravesical chemotherapy
Single instillation of MMC: Always appropriate?
Intravesical, Oct 2010
Single instillation of intravesical chemotherapy
“One immediate post-operative instillation of chemotherapy should be given in all patients after TUR of presumably non-muscle invasive bladder cancer.”(EAU Guidelines, 2009, Level 1a evidence)
↓ risk of recurrence by 50% at 2 years
OR 39% reduction in recurrence with single instillation
48.4% versus 36.7%, median FU 3.5 yrs
(Metanalysis Sylvester et al, J Urol 2004)
However, 50% of European urologists, and 4% in USA routinely..
Intravesical, Oct 2010
MMC in UK – timing.....MMC in UK – timing.....
Within 24 hours - evidence from literature
Within 6 hours – recommended by EAU
Immediate intra-op instillation(Mostafid et al, 2006)
Benefits:Tolerability=dwell timeImmediateShorter hospital stay
Single instillation of intravesical chemotherapy
NMIBC, May 2010
Single instillation for all new tumours.....Single instillation for all new tumours.....
Appears solid/high gradeVisual assessment85% specific, 90% sensitive(Cresswell et al, 2007)
Pros:Why not?Potential benefit even if high grade
Cons:Solid tumours?MMC unnecessary, more treatment reqdCost of MMCOften large tumours, perforation/bleeding more common
Single instillation of intravesical chemotherapy
NMIBC, May 2010
A prospective study of the accuracy of flexible cystoscopy:
Haematuria clinic
89 new tumours (10 MI, 79 NMIBC)
Prospective study
Cystoscopists asked to indicate if NMIBC or muscle-invasive
Cp to TURBT histology
Sensitivity 90%,Specificity 85%
Those incorrectly assessed as MI – T1
Prev studies Herr et al, 93% accurate for low grade recurrence
NMIBC, May 2010
Prediction of stage and grade
Single instillation for all new tumours.....Single instillation for all new tumours.....
An accepted standard of care
Surely not controversial .........
RCT cp single instillation of epirubicin vs no instillation
219 patients. ↓Risk of recurrence by 15%
BUT no benefit for intermediate/high risk tumours(Gudjonsson et al, 2009)
Overall 8.5 pts receive instillations to prevent 1 recurrence
often small, low risk
Adds time, expense, side effects for small gain(Herr, 2009)
NMIBC, May 2010
Single instillation of intravesical chemotherapy
A new EAU recommendation.....A new EAU recommendation.....
‘‘A single instillation of a chemotherapeutic agent after TUR should be administered only in primary, solitary, low-grade NMIBC.”(Brausi, 2010)
Intermediate risk tumours should be given course of maintenance BCG, chemotherapy if not tolerated (and no immediate instillation is required)
NMIBC, May 2010
Single instillation of intravesical chemotherapy
Immediate instillation after TURBT for recurrence....
Mechanism of action of MMC:
Destruction of circulating cancer cells
Prevention of seeding into disrupted urothelium
Surely this is effective after TURBT for recurrence.....
(Grey et al, BJMSU, 2009 – small study, no difference)
(Gudjonsson et al, 2009 -no benefit for recurrent tumours)
?Intra-operative instillation followed by course of MMC
NMIBC, May 2010
Single instillation of intravesical chemotherapy
Re-resection of high grade disease
Re-resection of high-grade disease: a question of quality?
•Accurate staging/Grading•Removal of macroscopic disease
NMIBC, May 2010
Which cases warrant early re-resection?
T1 -Yes
Ta - ??
Muscle present - ?No
EAU Guidelines:
“A second TUR should be considered when the initial resection was incomplete, or when the pathologist has reported that the specimen contained no muscle tissue. Furthermore, a second TUR should be performed when a high-grade, non-muscle invasive tumour or aT1 tumour has been detected at the initial TUR.”
Re-resection of high grade disease
NMIBC, May 2010
What is the evidence to support this recommendation?What is the evidence to support this recommendation?
• Residual disease on re-resection
Ta/cis 31%, T1 51.7%
(Herr et al, 1999)
Ta 27-72%, T1 33-78%
(Babjuk, 2009)
• Understaging
T1: up to 40% upstaged to T2 on cystectomy
(Dutta et al, 2001)
TaG3 (5%), T1G3 (30%)
(Herr et al, 2008)
NMIBC, May 2010
Re-resection of high grade disease
•↓effectiveness of adjuvant treatment
•Understaging of disease→ inappropriate treatment
•Poorer prognosis
Re-resection of high grade disease
Effect on prognosisEffect on prognosis
• RCT cp routine re-resection to initial TUR only in T1 disease
Progression in 6.5% cp to 23.5%
(Divrik et al, 2010)
• Can re-resection compensate for initial incomplete resection?
Progression may be worse even after re-resection
NMIBC, May 2010
Re-resection of high grade disease
Most important risk factor for understaging was absence of muscle
• Muscle absent in 30-50% specimens
• M’Boro data
Muscle present in 45.8-67.3% of G3
↑with seniority of surgeon
(Jesuraj et al, 2008)
• Understaging:
If muscle present 30%
If muscle absent 64%
(Dutta et al, 2001)
NMIBC, May 2010
Even if muscle present, high-grade disease warrants re-resection
Re-resection of high grade disease
Decisions for re-resection?
• No muscle present – Tx
• TaG3/T1G3
• Review of path slides, discuss at MDT
• Presence of lymphovascular invasion, micropapillary variants
• Conflicts with imaging
• Patient characteristics
Young patients, fit for radical treatment
Older, unfit patients – risk vs benefit
NMIBC, May 2010
Quality of TURBT
NMIBC, May 2010
• Variation in recurrence rates between institutions
7.4-45.8%
(Brausi et al, 2002)
Persistant disease
due to variability in quality of TUR
• Presence of detrusor muscle a measure of quality of TUR?
Very popular concept
Possible standard for audit/competence?
Presence of detrusor muscle:
Reduces risk of recurrenceDM – 21% RR FFCNo DM – 44.4%Even for small, low grade tumours(Mariappan et al, 2010)
Dependent on operator experienceJunior – 56.8%Senior – 72.6%
Effect of training:
RR 28% for juniors
8% for seniors
With training ↑DM, and ↓Rec(Brausi et al, 2008)
Reasons for inadequate TUR?
Lack of experience
Fear of perforation
Perforation 1.3-3.5% (Nieder et al, 2005)
On cystography 58.3% (Balbay, 2005)
NMIBC, May 2010
Quality of TURBT
Quality of TUR
What is a successful TURBT?What is a successful TURBT?
No lesions missed (PDD)
Staging assessed correctly
Without complications
“Larger, high grade lesions should be resected by seniors”(Mariappan et al, 2010)
BUT what of training...
SpR resects, consultant takes deeper resection separately
Emphasis on quality of resection
Re-resection with patient paralysed
Recent innovations may be making us reflect more carefully on technique
NMIBC, May 2010
Failure of intravesical treatment
BCG FailuresBCG Failures
•When has BCG failed?
•What treatment is available?
NMIBC, May 2010
Definition of failure of BCG:Definition of failure of BCG:
Intolerance – patient intolerant of side-effects
BCG resistance- recurrence/persistance of lesser disease, resolves with further BCG
BCG Relapsing-recurrence after initial resolution
BCG Refractory-not improving or worsening with BCG
Failure of intravesical treatment
NMIBC, May 2010
“Treatment with BCG is considered to have failed if high-grade, non-muscle invasive tumour is present at 3 and 6 months”(EAU Guidelines)
Current recommendation:
Offer radical cystectomy
BUT is it reasonable or safe to wait for 6 months?
Patient Factors:
Patient Choice
Patient Age
Patient Fitness
NMIBC, 2010
Failure of intravesical treatment
Tumour Charactistics:SizeMultiplicityCisStage T1 vs Ta*Must be sure of staging
Second induction course of BCG can improve response rate (57-80%)(Herr et al, 2003)
What is the risk of progression for high risk NMIBC?17% progression at 1 year
45% progression at 5 years
Persistant disease at 3/12 check cysto → poor prognosis(Solsona et al, 2000)
If recurs <1 yr poorer prognosis
If recurs >1 yr re-challenge with BCG(Gallagher et al, 2008)
NMIBC, May 2010
Failure of intravesical treatment
Failure of intravesical treatment
When to offer radical cystectomy?When to offer radical cystectomy?
As primary therapy, but morbidity favours BCG initiallyAs primary therapy, but morbidity favours BCG initially
If worsening of disease at 3/12 CC, progressionIf worsening of disease at 3/12 CC, progression
Dysfunctional bladderDysfunctional bladder
Impossible to control disease cystoscopicallyImpossible to control disease cystoscopically
Failure of second induction course Failure of second induction course
In other cases discuss with patient...In other cases discuss with patient...
From the outset – “50:50 chance of surviving with bladder to 5 years”From the outset – “50:50 chance of surviving with bladder to 5 years”
NMIBC, May 2010
Failure of intravesical treatment
What if the patient is unfit/unwilling.....What if the patient is unfit/unwilling.....
Currently offer 2Currently offer 2ndnd course of BCG, endoscopic management course of BCG, endoscopic management
Other options: Other options:
Device assisted – Thermotherapy, EMDADevice assisted – Thermotherapy, EMDA
Chemotherapy – Gemcitabine, DocetaxolChemotherapy – Gemcitabine, Docetaxol
Immunotherapy – IFNImmunotherapy – IFNαα
NMIBC, May 2010
Failure of intravesical treatment
Thermotherapy:Thermotherapy:
Synergo systemSynergo system
Bladder heated to approx 42ºC
MMC circulated into bladder for 2 x 30 minute treatments
Initial 6 weekly treatmentsInitial 6 weekly treatments
Maintenance single treatment Maintenance single treatment at 4-6 week intervalsat 4-6 week intervals
HYMN trial due to openHYMN trial due to open
TC cp to standard of careTC cp to standard of care
BCG failure, high gradeBCG failure, high grade
NMIBC, May 2010
Failure of intravesical treatment
Results of thermotherapy:Results of thermotherapy:
Retrospective study showed 56% DFS at 2 years for BCG refractory (111 pts)
a) High vs int risk
b) 6x vs Maintenance
(Nativ et al, 2009)
European Synergo group
34 BCG refractory cis
approx 50% DFS at 2 yrs, 92% at 1year
(Witjes et al, 2009)
NMIBC, May 2010
a)
b)
Failure of intravesical treatment
Other options:Other options:
EMDA MMC vs BCG in high EMDA MMC vs BCG in high risk (not BCG failures)risk (not BCG failures)
Equivalent recurrence ratesEquivalent recurrence rates
at 6/12 – 58 vs 64%at 6/12 – 58 vs 64%
(Di Stasi et al, 2003)(Di Stasi et al, 2003)
Immunotherapy:Immunotherapy:
BCG failures – BCG + IFNBCG failures – BCG + IFN
45% DFS at 2 yrs45% DFS at 2 yrs
(Joudi et al, 2006)(Joudi et al, 2006)
Intravesical Gemcitabine
BCG failures
1yr DFS – 21%
(Dalbagni et al, 2006)
Overall, results are variable and given 80-90% cure with RC, ?only acceptable if unfit/unwilling
Effects of thermotherapy/EMDA on bladder symptoms ↑ .....
Long-term bladder symptoms?
NMIBC, May 2010
Thank you!