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!