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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
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