Radical Cystectomy As Early Radical Cystectomy As Early Primary Therapy for T1G3 Primary Therapy for T1G3

Bladder CancerBladder Cancer

Karim Touijer and Bernard H. Bochner.Karim Touijer and Bernard H. Bochner.

Memorial Sloan-Kettering Cancer Center Memorial Sloan-Kettering Cancer Center

T1G3 Bladder CancerT1G3 Bladder Cancer“THE FACTS”“THE FACTS”

• Is a potentially lethal tumorIs a potentially lethal tumor• This is NOT a superficial tumorThis is NOT a superficial tumor• Understaging occurs frequentlyUnderstaging occurs frequently• High recurrence rate and progression despite High recurrence rate and progression despite

intravesical therapyintravesical therapy• Poor markers available to accurately identify Poor markers available to accurately identify

high risk lesions high risk lesions • Can be effectively CURED by early definitive Can be effectively CURED by early definitive

surgery (radical cystectomy)surgery (radical cystectomy)

BLADDER CANCER:TWO PATHWAYS OF PROGRESSION

NORMALUROTHELIUM

Ta

Ta9qDel

RAS

T1 T2-4 N+/M+9pDel

(INK4A)

(Presti et al, Ca Res 91; Cordon-Cardo et al, JNCI 92; Dalbagni et al, Lancet 93; Sarkis et al, JNCI 93; Cairns et al, Science 94; Orlow et al, JNCI 95; Li et al, Am J Path 96; Rabbani et al, JNCI 99; McShane et al, Ca Res 2000; Hernando et al, Int J Ca 2001; Sanchez et al, Ca Res, 2002; Veltman et al Ca Res, 2003 )

Tis

T1 T2-4 N+/M+

TP53RB

5qDel, 3pDel

10qDel, 11pDel, 18qDel

14qDel

T1G3 Bladder CancerT1G3 Bladder Cancer

Can we accurately detect this Can we accurately detect this disease?disease?

Are we at risk for Are we at risk for understaging?understaging?

T1G3 And TIS Bladder CancerT1G3 And TIS Bladder CancerClinical UnderstagingClinical Understaging

AuthorAuthor P stage > T1P stage > T1

Amling (Duke), 1994Amling (Duke), 1994 37%37%

Soloway (Florida) 1994Soloway (Florida) 1994 36% (60% for Tis)36% (60% for Tis)

Stein (USC) 2001Stein (USC) 2001 39%39%

10 - 15% have positive nodes at cystectomy

Risk Of Understaging Is Influenced Risk Of Understaging Is Influenced By Presence Of Muscle In TUR By Presence Of Muscle In TUR

SpecimenSpecimen

Dutta, J Urol 166:490, 2001

N=78

Herr, HW J Urol 162:74, 1999

A second TURBT required to identify extent of disease.

T1G3 Bladder CancerT1G3 Bladder CancerOutcome Of Understaged PatientsOutcome Of Understaged Patients

Disease Specific OutcomesDisease Specific Outcomes

Freeman et al, Cancer, 1995

•179 patients (71% with T1 tumors)•53% failed intravesical therapy•Understaged lesions do significantly worse•Understaged lesions WILL NOT respond to bladder sparing approaches

Repeat TURBT May Help Reduce Repeat TURBT May Help Reduce UnderstagingUnderstaging

Dalbagni et al, UROLOGY 2002

T1G3 Bladder CancerT1G3 Bladder CancerNatural HistoryNatural History

Recurrence and Progression RiskRecurrence and Progression Risk

• Recurrence RiskRecurrence Risk– Following TURBT, 69-80% risk of recurrenceFollowing TURBT, 69-80% risk of recurrence– Intravesical immunotherapy can delay Intravesical immunotherapy can delay

recurrence and progression, but long-term will recurrence and progression, but long-term will not alter natural historynot alter natural history

• Progression RiskProgression Risk– 33-50% will progress to muscle invasion33-50% will progress to muscle invasion

Can BCG Impact Can BCG Impact Ultimate Cancer-Ultimate Cancer-Specific SurvivalSpecific Survival

BCG Can Delay Recurrence But BCG Can Delay Recurrence But May Not Impact Ultimate Cancer-May Not Impact Ultimate Cancer-

specific Survivalspecific Survival

Recurrence-free survival Cancer-specific survival

Orsola et al Eur Urol 48:231, 2005

T1G3 Bladder CancerT1G3 Bladder CancerLong-term Results With BCGLong-term Results With BCG

Cookson, J Urol 158:62, 1997

Pansodoro, Urology 59:227, 2002

Shahin, J Urol 169:96, 2003

StudyStudy # pts# pts Med. F/uMed. F/u ProgressionProgression CystectomyCystectomy DODDOD

CooksonCookson 8686 15.3 yrs15.3 yrs 53%53% 36%36% 34%34%

PansodoroPansodoro 8181 6.3 yrs6.3 yrs 15%15% 8.6%8.6% 6%6%

ShahinShahin 9292 5.3 yrs5.3 yrs 30 %30 % 29%29% 23%23%

T1G3 Bladder CancerT1G3 Bladder CancerLong-Term Outcome ConservativeLong-Term Outcome Conservative

BCG and Progression of DiseaseBCG and Progression of Disease

• 1978-1981 86 patients with high risk non-muscle 1978-1981 86 patients with high risk non-muscle invasive disease (36 patients T1)invasive disease (36 patients T1)

• Randomized to TURBT +/- BCGRandomized to TURBT +/- BCG• Followed q3-6 months for 3 years then annuallyFollowed q3-6 months for 3 years then annually• Evaluated progression and disease specific survivalEvaluated progression and disease specific survival

T1G3 Bladder CancerT1G3 Bladder CancerLong-Term Outcome ConservativeLong-Term Outcome Conservative

BCG and Progression of DiseaseBCG and Progression of Disease

T1G3 Bladder CancerT1G3 Bladder CancerLong-Term Outcome ConservativeLong-Term Outcome Conservative

Disease Specific SurvivalDisease Specific Survival

Cookson J Urol 158:62, 1997

People not treated by cystectomy continue to die of bladder cancer!

T1G3 Bladder CancerT1G3 Bladder CancerLong-Term Outcome ConservativeLong-Term Outcome Conservative

Disease Specific OutcomesDisease Specific Outcomes

T1 Bladder CancerT1 Bladder CancerCharacteristics Associated with Recurrence Characteristics Associated with Recurrence

and Progressionand Progression

• PathologicPathologic– High grade, multifocality, associated CIS, prostatic High grade, multifocality, associated CIS, prostatic

urethral involvement, size, sessile growth pattern, urethral involvement, size, sessile growth pattern, (Others unreliable and controversial: aneuplody, p53 (Others unreliable and controversial: aneuplody, p53 alteration, lymphovascular invasion)alteration, lymphovascular invasion)

• ClinicalClinical– Failure of intravesical therapy (80% with disease at 3 Failure of intravesical therapy (80% with disease at 3

months progress), endoscopically uncontrollable months progress), endoscopically uncontrollable disease, disease within diverticuli disease, disease within diverticuli MAJORITY