High-Grade T1 Bladder Cancer: A High-Grade T1 Bladder Cancer: A Clinical QuandaryClinical Quandary

Daniel Canter, M.D.Daniel Canter, M.D.Assistant Professor of UrologyAssistant Professor of UrologyEmory UniversityEmory University

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BackgroundBackground Incidence of High-grade T1 DiseaseIncidence of High-grade T1 Disease Importance of Re-resectionImportance of Re-resection Recurrence and ProgressionRecurrence and Progression Clinical UnderstagingClinical Understaging Patient SelectionPatient Selection Morbidity/Mortality of SurgeryMorbidity/Mortality of Surgery Risk StratificationRisk Stratification

BackgroundBackground

Jemal et al. Ca Cancer J Clin 60: 277, 2010

BackgroundBackground

Jemal et al. Ca Cancer J Clin 60: 277, 2010

BackgroundBackground

70,520 new cases of bladder cancer in 201070,520 new cases of bladder cancer in 2010 14,680 deaths attributable bladder cancer in 201014,680 deaths attributable bladder cancer in 2010

Jemal et al. Ca Cancer J Clin 60: 277, 2010

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BackgroundBackground Incidence of High-grade T1 DiseaseIncidence of High-grade T1 Disease Importance of Re-resectionImportance of Re-resection Recurrence and ProgressionRecurrence and Progression Clinical UnderstagingClinical Understaging Patient SelectionPatient Selection Morbidity of SurgeryMorbidity of Surgery Risk StratificationRisk Stratification

Incidence of High-Grade T1 DiseaseIncidence of High-Grade T1 Disease

25% of bladder cancer presents as muscle-invasive disease or 25% of bladder cancer presents as muscle-invasive disease or greatergreater11

17,630 patients (expected)17,630 patients (expected)

Approximately 25% of non-muscle-invasive bladder cancer Approximately 25% of non-muscle-invasive bladder cancer presents as high-grade T1 diseasepresents as high-grade T1 disease22

13,222 patients (expected)13,222 patients (expected)

1Fedeli et al. , J. Urol, 185: 72, 20112 Strope et al., Cancer, 116: 2604, 2010

High-Grade T1 DiseaseHigh-Grade T1 Disease

Rule of 30%sRule of 30%s11

30% never recur30% never recur

30% require deferred cystectomy30% require deferred cystectomy

30% die of metastatic TCC30% die of metastatic TCC

1Cookson et al., J Urol, 158: 1, 1997

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BackgroundBackground Incidence of High-grade T1 DiseaseIncidence of High-grade T1 Disease Importance of Re-resectionImportance of Re-resection Recurrence and ProgressionRecurrence and Progression Clinical UnderstagingClinical Understaging Patient SelectionPatient Selection Morbidity of SurgeryMorbidity of Surgery Risk StratificationRisk Stratification

Importance of re-resectionImportance of re-resection11

1Nieder et al., Urology, 66: 6, 2005

Risk of Understaging for Patients with High-Grade Risk of Understaging for Patients with High-Grade T1 diseaseT1 disease

Study Year % Understaged

Freeman 1995 34%

Pagano 1991 35%

Soloway 1994 36%

Amling 1994 37%

Herr 1999 49%

Ghoneim 1997 62%

Dutta 2001 64%

Prognostic Importance of Re-Prognostic Importance of Re-resectionresection

14% progression rate with less than T1 disease14% progression rate with less than T1 disease

76% progression rate with residual T1 disease76% progression rate with residual T1 disease

1Nepple et al., Can J Urol, 3: 4, 2009

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BackgroundBackground Incidence of High-grade T1 DiseaseIncidence of High-grade T1 Disease Importance of Re-resectionImportance of Re-resection Recurrence and ProgressionRecurrence and Progression Clinical UnderstagingClinical Understaging Patient SelectionPatient Selection Morbidity of SurgeryMorbidity of Surgery Risk StratificationRisk Stratification

Recurrence and ProgressionRecurrence and Progression11

Probability of recurrence at 5 years:Probability of recurrence at 5 years: 50-70%50-70%

Probability of progression to muscle invasion:Probability of progression to muscle invasion: moderate to moderate to highhigh

1NCCN Guidelines Version 2.2011

Recurrence and ProgressionRecurrence and Progression11

Predictive score based onPredictive score based on– Number of tumorsNumber of tumors– Tumor sizeTumor size– Prior recurrence ratePrior recurrence rate– T categoryT category– CISCIS– GradeGrade

1Sylvester et al., Eur Urol, 49: 3, 2006

ProgressionProgression11

Predictive score > 9 or presence of CISPredictive score > 9 or presence of CIS– 2-year progression rate approximately 30%2-year progression rate approximately 30%

1Sylvester et al., Eur Urol, 49: 3, 2006

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BackgroundBackground Incidence of High-grade T1 DiseaseIncidence of High-grade T1 Disease Importance of Re-resectionImportance of Re-resection Recurrence and ProgressionRecurrence and Progression Clinical UnderstagingClinical Understaging Patient SelectionPatient Selection Morbidity of SurgeryMorbidity of Surgery Risk StratificationRisk Stratification

Patient with clinical high-grade T1 disease with metastases to the head of pancreas (Canter et al., Urology, in press)

Pathological Up-Staging at Time of Radical Pathological Up-Staging at Time of Radical CystectomyCystectomy11

51.4% had pT2 disease or greater51.4% had pT2 disease or greater

33.4% had pT3 disease or greater33.4% had pT3 disease or greater

16.2% of patients had lymph node metastasis (range=9-18%16.2% of patients had lymph node metastasis (range=9-18%22))

6.3% of patients had positive surgical margins6.3% of patients had positive surgical margins

1Fritsche et al., Eur Urol, 57: 2, 20102Kulkarni et al., Eur Urol, 57: 1, 2010

Series No. of patients

% Upstaging

LN + Bladder-cancer survival

Overall survival

Herr and Sogani

35 NR NR 92% NR

Dutta et al 78 40 12 78% 64

Thalmann et al 29 41 14 69% 54

Masood et al 30 27 NR 88% NR

Bianco et al 66 27 9 78% NR

Lambert et al 104 40 NR 93% 87

Gupta et al 167 50 18 82% 69

Denzinger et al 54 26 NR 78% NR

Total 563 26-50% 9-18% 69-93% 54-87%

Outcomes of Radical Cystectomy in Patients Outcomes of Radical Cystectomy in Patients with High-Grade T1 Diseasewith High-Grade T1 Disease

Risk StratificationRisk Stratification11

Low-risk T1Low-risk T1– Unifocal diseaseUnifocal disease– No associated CISNo associated CIS– Tumor accessible/resectable in fullTumor accessible/resectable in full– Residual disease <T1 on restaging TURBtResidual disease <T1 on restaging TURBt

High-risk T1High-risk T1– Multifocal diseaseMultifocal disease– Associated CISAssociated CIS– Tumor hard to access/not resectable in fullTumor hard to access/not resectable in full– Residual disease Residual disease >>T1 on restaging TURBTT1 on restaging TURBT

1Nieder et al., Urology, 66: 6, 2005

Indications for Early CystectomyIndications for Early Cystectomy11

Morphologic featuresMorphologic features

– solidsolid

– large tumor sizelarge tumor size

– multifocalitymultifocality Pathologic characteristicsPathologic characteristics

– depth of tumor invasiondepth of tumor invasion

– associated CISassociated CIS

– presence of lymphovascular invasionpresence of lymphovascular invasion Response to prior intravesical therapyResponse to prior intravesical therapy Status of p53, Ki67, Cox-2, NMP-22Status of p53, Ki67, Cox-2, NMP-22

1 Bochner, Urol Oncol, 27, 2009

Indications for Early CystectomyIndications for Early Cystectomy11

YouthYouth Extensive diseaseExtensive disease Incomplete resectionIncomplete resection Multiple, early recurrencesMultiple, early recurrences T1 with CIST1 with CIS High-risk histology (micropapillary, small cell, High-risk histology (micropapillary, small cell,

etc.)etc.)

1Montgomery et al., Urol Oncol, 28, 2010

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BackgroundBackground Incidence of High-grade T1 DiseaseIncidence of High-grade T1 Disease Importance of Re-resectionImportance of Re-resection Recurrence and ProgressionRecurrence and Progression Clinical UnderstagingClinical Understaging Patient SelectionPatient Selection Morbidity of SurgeryMorbidity of Surgery Risk StratificationRisk Stratification

Hollingsworth et al. Journal of NCI, 2006

Source: National Cancer Institute

Prostate Cancer-Specific Mortality for Localized Prostate Cancer-Specific Mortality for Localized Prostate CancerProstate Cancer

Eggener et al. J Urol 185: 2011

High-grade T1 DiseaseHigh-grade T1 Disease

Why are more radical cystectomies not being done Why are more radical cystectomies not being done for high-grade T1 disease?for high-grade T1 disease?

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BackgroundBackground Incidence of High-grade T1 DiseaseIncidence of High-grade T1 Disease Importance of Re-resectionImportance of Re-resection Recurrence and ProgressionRecurrence and Progression Clinical UnderstagingClinical Understaging Patient SelectionPatient Selection Morbidity of SurgeryMorbidity of Surgery Risk StratificationRisk Stratification

Risk Factors for Bladder CancerRisk Factors for Bladder Cancer

AgeAge– Incidence increases with ageIncidence increases with age

– Median age=73 yearsMedian age=73 years

GenderGender– M:F=3:1M:F=3:1

History of cigarette smokingHistory of cigarette smoking History of external beam radiationHistory of external beam radiation

Miller et al. J Urol 169: 2003

Impact of Co-MorbidityImpact of Co-Morbidity

CSS OSp=0.01

24% of patients had a CCI > 2

Aghazadeh et al. J Urol 185: 1, 2011

90-day Mortality Rate after Radical 90-day Mortality Rate after Radical Cystectomy based on Hospital Discharge StatusCystectomy based on Hospital Discharge Status

Home without services = 4%Home without services = 4%

Home with services = 4.8%Home with services = 4.8%

Transferred to facility = 20.5%Transferred to facility = 20.5%

Early ComplicationsEarly Complications

Examination of 1142 consecutive patients who underwent Examination of 1142 consecutive patients who underwent cystectomy at MSKCCcystectomy at MSKCC

Complications occurred in 64% of patients (735/1142) within Complications occurred in 64% of patients (735/1142) within 90 days of surgery90 days of surgery

Major complications (Clavien grade III-V) occurred in 13% of Major complications (Clavien grade III-V) occurred in 13% of patientspatients

Shabsigh et al. Eur Urol, 55: 1, 2009

Early ComplicationsEarly Complications

6,577 patients from NIS from 1998 to 20026,577 patients from NIS from 1998 to 2002

2.57% in-hospital mortality rate2.57% in-hospital mortality rate

28.1% complication rate, digestive system most common 28.1% complication rate, digestive system most common (16.1%)(16.1%)

Age and co-morbid conditions predictors of complications; Age and co-morbid conditions predictors of complications; high-volume centers and women were associated were lower high-volume centers and women were associated were lower risk of complicationsrisk of complications

Konety et al. Urol, 68(1), 2006

Long-term Complications after Radical Long-term Complications after Radical CystectomyCystectomy

1,057 patients1,057 patients

1,453 conduit-related complications in 643 1,453 conduit-related complications in 643 (61%) patients(61%) patients

2.3 complications/patient2.3 complications/patient

Shimko et al. J Urol, 185: 2, 2011

High-grade T1 DiseaseHigh-grade T1 Disease

How can we choose better?How can we choose better?

OutlineOutline

BackgroundBackground Incidence of High-grade T1 DiseaseIncidence of High-grade T1 Disease Importance of Re-resectionImportance of Re-resection Recurrence and ProgressionRecurrence and Progression Clinical UnderstagingClinical Understaging Patient SelectionPatient Selection Morbidity of SurgeryMorbidity of Surgery Risk StratificationRisk Stratification

Charlson Co-Morbidity Index (CCI)Charlson Co-Morbidity Index (CCI)

http://www.medal.org/OnlineCalculators/ch1/ch1.13/http://www.medal.org/OnlineCalculators/ch1/ch1.13/ch1.13.01.phpch1.13.01.php

www.urologymatch.com

or

Competing Risks NomogramsCompeting Risks Nomograms

www.cancernomograms.comwww.cancernomograms.com

www.cancernomograms.comwww.cancernomograms.com

www.cancernomograms.comwww.cancernomograms.com

www.cancernomograms.comwww.cancernomograms.com

ConclusionsConclusions

High-grade T1 bladder is a heterogeneous disease with an aggressive High-grade T1 bladder is a heterogeneous disease with an aggressive biologic behavior in the majority of patientsbiologic behavior in the majority of patients

Radical cystectomy is not without risk, carrying a high amount of Radical cystectomy is not without risk, carrying a high amount of morbidity and mortalitymorbidity and mortality

Risk stratification is imperativeRisk stratification is imperative

These tools exist and can help to objectify treatment decision-making These tools exist and can help to objectify treatment decision-making (i.e, early cystectomy versus delayed cystectomy) (i.e, early cystectomy versus delayed cystectomy)

ConclusionsConclusions

Considering the aggressive phenotype of high-Considering the aggressive phenotype of high-grade T1 bladder cancer and the fact that many grade T1 bladder cancer and the fact that many patients will have extravesical/nodal disease at the patients will have extravesical/nodal disease at the time of time of ““early cystectomyearly cystectomy””, is it justified to defer , is it justified to defer early definitive treatment in this group of patients early definitive treatment in this group of patients when medically fit?when medically fit?