Management of T1G3 Management of T1G3 Bladder cancerBladder cancer

Dr Charles ChabertDr Charles Chabert

T1G3T1G3

High grade lesion with invasion between High grade lesion with invasion between epithelium & muscularis propriaepithelium & muscularis propria

Gene alterations similar to T2 TCCGene alterations similar to T2 TCC

Dilemma is to identify which will be cured Dilemma is to identify which will be cured by TUR & which will progressby TUR & which will progress

Turner E Urol 45 (2004) 401-405Turner E Urol 45 (2004) 401-405

Natural History T1G3Natural History T1G3

Paucity of data on natural history of Paucity of data on natural history of untreated T1G3untreated T1G3

Recurrence rates 50-70%Recurrence rates 50-70%

Progression rate 25-50%Progression rate 25-50%

Heney et al J Urol 1983; 130:1083-6Heney et al J Urol 1983; 130:1083-6

Diagnosis & Initial Diagnosis & Initial ManagementManagement

Is it really T1G3?Is it really T1G3?

Ensure muscle presentEnsure muscle present

Cold cut biopsiesCold cut biopsies

Flourescence endoscopic resectionFlourescence endoscopic resection

Second TURSecond TUR

Retrospective review of concordance of Retrospective review of concordance of 22ndnd TURBT TURBT

2nd TURBT changed management in 2nd TURBT changed management in 33%33%

If no muscle 49% upstaged to T2If no muscle 49% upstaged to T2

J Urol 1999; 146: 316-8J Urol 1999; 146: 316-8

Second TURSecond TUR

Residual tumour present in 33-37%Residual tumour present in 33-37%

Grade & stage predictive of residual Grade & stage predictive of residual tumourtumour

Biopsy abnormal urotheliumBiopsy abnormal urothelium

Soloway et al Urol Clin N Am (2005) 133-145Soloway et al Urol Clin N Am (2005) 133-145

Staging SystemStaging System

Recommendation to substage T1Recommendation to substage T1

121 T1 G3121 T1 G3

T1a : above muscularis mucosaeT1a : above muscularis mucosae

T1b: below muscularis mucosaeT1b: below muscularis mucosae

Only 6% not substaged Only 6% not substaged

5yr survival 54% vs 42%5yr survival 54% vs 42%

Holmang et al J Urol 1997: 157; 800-3Holmang et al J Urol 1997: 157; 800-3

Staging SystemStaging System

Categorised to Categorised to T1a, T1b & T1cT1a, T1b & T1c

No difference in 3 yr risk of recurrenceNo difference in 3 yr risk of recurrence

Risk of progessionRisk of progession

6%, 33% & 55%6%, 33% & 55%

ROP x27 if T1c & CISROP x27 if T1c & CIS

Smits et al Urol 1998;86:1035-43Smits et al Urol 1998;86:1035-43

Staging SystemStaging System

Measured the depth of invasionMeasured the depth of invasion

55 patients55 patients

Measured from the BM to the deepest tumour Measured from the BM to the deepest tumour cellcell

Cutoff 1.5mmCutoff 1.5mm

PPV >T2 95%PPV >T2 95%

Cheng et al. Cancer 1999:86:1035Cheng et al. Cancer 1999:86:1035

Prognostic FeaturesPrognostic Features

Early recurrence after TUR & BCGEarly recurrence after TUR & BCG

SizeSize

MultifocalityMultifocality

CISCIS

Prostatic UrethraProstatic Urethra

LVILVI

Depth of Lamina Propria InvasionDepth of Lamina Propria InvasionRodriguez J urol 2000;163:73-8Rodriguez J urol 2000;163:73-8

Perioperative Cytotoxic Perioperative Cytotoxic ChemotherapyChemotherapy

60-80% recurrence at 5 years60-80% recurrence at 5 years

If high grade, there is risk of progressionIf high grade, there is risk of progression

Perioperative Cytotoxic Perioperative Cytotoxic ChemotherapyChemotherapy

Meta-analysis:Meta-analysis:

One-dose immediate postop cytotoxic One-dose immediate postop cytotoxic chemotherapychemotherapy

Sylvester et al J Urol2004: 171;2186-90Sylvester et al J Urol2004: 171;2186-90

Materials & methodsMaterials & methods

Randomised trials with primary or Randomised trials with primary or recurrent Ta/T1recurrent Ta/T1

Exclusion of CISExclusion of CIS

Sylvester et al J Urol 171, June 2004Sylvester et al J Urol 171, June 2004

Materials & MethodsMaterials & Methods

Primary end pointPrimary end point: :

% of patients with a recurrence in the 2 % of patients with a recurrence in the 2 treatment armstreatment arms

Decrease in Odds of recurrence Decrease in Odds of recurrence calculated without time to recurrencecalculated without time to recurrence

Sylvester et al J Urol 171, June 2004Sylvester et al J Urol 171, June 2004

ResultsResults

12 trials considered12 trials considered

5 exclusions;5 exclusions;

4 inadequate randomisation4 inadequate randomisation1 included CIS1 included CIS

7 trials entered into Meta-analysis7 trials entered into Meta-analysis

Sylvester et al J Urol 171, June 2004Sylvester et al J Urol 171, June 2004

Trial CharacteristicsTrial Characteristics

Accural between 1981-1994Accural between 1981-1994

Median F/U: Median F/U: 3.4 years3.4 years (2-10.7 yrs) (2-10.7 yrs)

3 trials included only primary patients3 trials included only primary patients

2 trials only single tumours2 trials only single tumours

Sylvester et al J Urol 171, June 2004Sylvester et al J Urol 171, June 2004

Trial CharacteristicsTrial Characteristics

4 different drugs used4 different drugs used

EpirubicinEpirubicin 3 trials 3 trials

MitomycinMitomycin C 2 trials C 2 trials

Thiotepa Thiotepa 1 trial1 trial

PirarubicinPirarubicin 1 trial 1 trial

Sylvester et al J Urol 171, June 2004Sylvester et al J Urol 171, June 2004

Patient CharacteristicsPatient Characteristics

1517 eligible patients from 7 trials1517 eligible patients from 7 trials

1476 had F/U1476 had F/U

748 (50.7%) TUR only & 728 (49.3%) 748 (50.7%) TUR only & 728 (49.3%) TUR + instillationTUR + instillation

Sylvester et al J Urol 171, June 2004Sylvester et al J Urol 171, June 2004

Tumour CharacteristicsTumour Characteristics

Predominantly low riskPredominantly low risk

89.2% primary tumours 89.2% primary tumours

84.3% single tumours84.3% single tumours

67.9% Ta67.9% Ta

9.5% G39.5% G3

Sylvester et al J Urol 171, June 2004Sylvester et al J Urol 171, June 2004

RecurrenceRecurrence

629 (42.6%)629 (42.6%) of 1476 patients of 1476 patients

362 (48.4%) TUR & 267 (36.7%) 362 (48.4%) TUR & 267 (36.7%) TUR + ChemoTUR + Chemo

Decrease of 39% in odds of recurrenceDecrease of 39% in odds of recurrence

Sylvester et al J Urol 171, June 2004Sylvester et al J Urol 171, June 2004

ToxicityToxicity

Mild irritative bladder symptoms in 10%Mild irritative bladder symptoms in 10%

Systemic toxicity extremely rareSystemic toxicity extremely rare

Allergic skin reactions 1-3%Allergic skin reactions 1-3%

Sylvester et al J Urol 171, June 2004Sylvester et al J Urol 171, June 2004

SummarySummary

NNT to prevent 1 recurrence:NNT to prevent 1 recurrence:

8.58.5

One instillation cost effectiveOne instillation cost effective

Significantly reduces recurrence with Significantly reduces recurrence with minimal morbidityminimal morbidity

Sylvester et al J Urol 171, June 2004Sylvester et al J Urol 171, June 2004

ImmunotherapyImmunotherapy

BCG results in local immunological BCG results in local immunological responseresponse

Helper T-cellsHelper T-cells

Cytotoxic t-cell activationCytotoxic t-cell activation

Soloway et al Urol Clin N Am (2005) 133-145Soloway et al Urol Clin N Am (2005) 133-145

T1G3T1G3

BCG era “Rule of threes”BCG era “Rule of threes”

1/3 survive with bladder1/3 survive with bladder

1/3 survive without bladder1/3 survive without bladder

1/3 die of their disease1/3 die of their disease

Studer et al J Urol 2003; 169:96-100Studer et al J Urol 2003; 169:96-100

Merits of BCGMerits of BCG

Davis et alDavis et al

59% of 98 patients bladder retention at 10 59% of 98 patients bladder retention at 10 yearsyears

Herr HWHerr HW

50% preservation with 15 year F/U50% preservation with 15 year F/U

Turner E Urol 45 (2004) 401-405Turner E Urol 45 (2004) 401-405

Merits of BCGMerits of BCG

Maintenance BCGMaintenance BCG

SWOG dataSWOG data: reduced recurrence: reduced recurrence

Poor tolerance with regimen 17% Poor tolerance with regimen 17% completion ratecompletion rate

Lamm et al J Urol 2000;163:1124Lamm et al J Urol 2000;163:1124

Role of Cystectomy: Early Role of Cystectomy: Early vs Latevs Late

Conservative management associated Conservative management associated with lifelong risk of recurrence, with lifelong risk of recurrence,

progression & metastasisprogression & metastasis

Studer et al J Urol 2003; 169:96-100Studer et al J Urol 2003; 169:96-100

Role of Cystectomy: Early Role of Cystectomy: Early vs Latevs Late

Series of 153 patientsSeries of 153 patients

Recurrence rate 75% at 10 yearsRecurrence rate 75% at 10 years

30% dead at 10 years30% dead at 10 years

Studer et al J Urol 2003; 169:96-100Studer et al J Urol 2003; 169:96-100

Role of Cystectomy: Early Role of Cystectomy: Early vs Latevs Late

Delay in treatment affects survival:Delay in treatment affects survival:

Cystectomy within or greater 3 monthsCystectomy within or greater 3 months

55% vs 34% 5 year survival55% vs 34% 5 year survival

May et al scand J Urol Neph 2004May et al scand J Urol Neph 2004

Role of Cystectomy: Early Role of Cystectomy: Early vs Latevs Late

Improved 15 year survival with early Improved 15 year survival with early cystectomycystectomy

Review of 90 patientsReview of 90 patients

Cut off 2 yearsCut off 2 years

Herr et al J Urol 2001,166:1296-9Herr et al J Urol 2001,166:1296-9

Role of Cystectomy: Early Role of Cystectomy: Early vs Latevs Late

Immediate cystectomy if :Immediate cystectomy if :

YoungYoung

Deep T1Deep T1

One additional poor prognostic featureOne additional poor prognostic feature

SummarySummary

Highly malignant tumour Highly malignant tumour

Variable & unpredictable behaviourVariable & unpredictable behaviour

Accurate staging & re –TURAccurate staging & re –TUR

Intravesicle immunotherapyIntravesicle immunotherapy

Early cystectomyEarly cystectomy