BLADDER CANCER

1. What proportion of deaths from bladder cancer could be improved if we could do a cystectomy earlier in the right people?

2. Do we allow the natural history of CIS to become evident with extravesical (prostate, upper tract) extension by delaying cystectomy with conservative treatment?

3. What is the importance of divergent histology on bladder cancer management?

4. What is the optimal integration of systemic chemotherapy along with cystectomy?

5. Partial cystectomy

BLADDER CANCER

The patient and urologist must

walk a tightrope to not remove the

bladder too early but not remove it

too late.

Study ObjectiveStudy Objective• To determine the proportion of patients To determine the proportion of patients

dying of bladder cancer with potentially dying of bladder cancer with potentially avoidable deathsavoidable deaths

– If large—suggests aggressive therapy may save livesIf large—suggests aggressive therapy may save lives– If small—suggests tumor biology has already If small—suggests tumor biology has already

determined ultimate outcomedetermined ultimate outcome

David S Morris Alon Weizer, James Montie, David S Morris Alon Weizer, James Montie, Rodney Dunn, Zaojun Ye, Brent HollenbeckRodney Dunn, Zaojun Ye, Brent HollenbeckCancer: March 2009Cancer: March 2009

Study PopulationStudy Population• Patients with deaths directly caused by bladder Patients with deaths directly caused by bladder

cancercancer

• Institutional dataInstitutional data– 126 patients from 2001-2005126 patients from 2001-2005

– 4 independent expert reviewers 4 independent expert reviewers

• Administrative data (SEER-Medicare)Administrative data (SEER-Medicare)– 6,326 patients from 1992-20036,326 patients from 1992-2003

– Algorithms follow clinical courseAlgorithms follow clinical course

– i.e. look at those who died and make assumptions on those who could have i.e. look at those who died and make assumptions on those who could have livedlived

UM Institutional DataUM Institutional Data

• 40 of 126 bladder cancer deaths 40 of 126 bladder cancer deaths potentially avoidable = 32%potentially avoidable = 32%

• Substantial agreement between Substantial agreement between reviewersreviewers– Kappa range 0.74 to 0.96Kappa range 0.74 to 0.96– All reviewers agreed on 30 of 40 patients, 3 of 4 All reviewers agreed on 30 of 40 patients, 3 of 4

agreed on additional 8 patientsagreed on additional 8 patients

Administrative DataAdministrative Data

• 3293/6326 (52%) of deaths occurred 3293/6326 (52%) of deaths occurred within 1 year of diagnosiswithin 1 year of diagnosis

• Estimated between 21% and 39% Estimated between 21% and 39% potentially avoidablepotentially avoidable– Based on delays in treatment Based on delays in treatment – Majority were healthy patients who did not receive Majority were healthy patients who did not receive

any form of definitive therapyany form of definitive therapy

ConclusionsConclusions• A significant proportion of bladder A significant proportion of bladder

cancer deaths may be avoidable with cancer deaths may be avoidable with “ideal” therapy“ideal” therapy–Estimated as 1/3Estimated as 1/3rdrd by clinical and by clinical and

administrative dataadministrative data–““ideal” therapy requires better decision-ideal” therapy requires better decision-

making by the doctor and patient to predict the making by the doctor and patient to predict the futurefuture

–We can do a lot better with just clinical data We can do a lot better with just clinical data now available to usnow available to us

–The delay in these patients is long, almost 5 The delay in these patients is long, almost 5 yearsyears

Institutional Data:Institutional Data:Survival CurvesSurvival Curves

5810

Potentially curable patients:Lived longer with disease (58 vs. 10 months) Longer delay between diagnosis and cystectomy (23 vs. 2 months)

Diagnosis to Death Diagnosis to Treatment

CurableNon-Curable

Conclusions

• The majority of deaths from bladder cancer occur within 1 year of diagnosis and thus the greatest benefit will likely come from other factors– Earlier detection/screening– Improved systemic therapy

• Improving physician/patient decision-making with clinical data and understanding progression risk better may avoid 30-40% of bladder cancer deaths

BLADDER CANCER GOALS OF TREATMENT

• LOW GRADE

• HIGH GRADE CHANGE IN

• RECURRENCE RATE

• WORTHLESS !

• MUST ELIMINATE HIGH GRADE CANCER

RECURRENCE RATE

INTRAVESICAL THERAPY

• Change in paradigm:

– Surveillance works for HG Ta or T1 or CIS ONLY if there is no progression. Once progression occurs, we have lost 20-30% survival.

BLADDER CANCER SURGERY

Which are the most dangerous cancers?

• CIS• Papillary Ca and CIS• T1• High grade T1 with CIS:

Answer: High grade T1 and CIS: knows how to invade and mucosa abnormal

CIS

• CIS must be viewed as a potentially pan-urothelial disease. The longer the disease is allowed to persist, the greater the chance for:

1. Extravesical spread

2. Invasion

CIS: HOW DOES IT GET THERE?

Cystectomy specimens• Intramural ureter: 35%• Prostatic ducts: 43%

Late recurrences with CIS treated with BCG• Upper tracts: 25% (5 yrs)• Prostate: 24% (1 yr)• Seminal vesicles: 8 cases

Pagetoid spread MUST be a mechanism

T1 BLADDER CAHOW DO WE DO ?

• How many patients have residual tumor at second resection? Answer: 20-40%

(Jakse et al, 2004)

• Well, that’s when other people do the resection, not me.

OK, what if it is only 10% ? That’s still 10% who will get insufficient treatment.

HG T1 with focal micro-papillary

T1 BLADDER CA:OUR CONCEPTS

1.If TURBT & BCG works, everyone happy

2.If TURBT & BCG doesn’t’ work, I’ll find out before muscle invasion

3.Even if muscle invasion does occur, I can take out the bladder and results will not be as bad as usual T2

T1 BLADDER CAHOW DO WE DO IN A PINCH ?

• “I’ll find the recurrence before it invades the muscle”

Wrong !

Progression to T2 or greater occurs in 10-50% of cases.

Jakse, 2004

Peyromaure, 2004

Thalmann, 2004

Serretta, 2003

Divrik, 2006

Herr, 2005

T1 BLADDER CANCERHOW DO WE DO ?

• “Since I found the muscle-invading recurrence early, the patient will still do well”.

Wrong ! • The literature doesn’t support this notion and

patients do just as badly or worse.Herr and Sogani, J Urol 166:1296, 2001

Yiou et al, BJU 89:374,2002

Schrier et al, Eur Urol 45: 292-296, 2004

p = 0.05

Lee et al, UM, 2005

T1 BLADDER CANCER

• “Well, it’s crazy to take the bladder out in everyone with a T1 cancer”

• I agree !!! Let’s pick out the BAD T1 cancers

Montie

EVILT1 BLADDER CANCER

1.Bad location (inaccessible to good TUR)

2.Multifocal T1

3.Lymphovascular invasion (LVI)

4. Recurrent T1 on reresection

5. T1 after BCG6. T1 without muscle

in specimen 7. ? Abnormal

markers8. ? T1b

Re-resect all T1 cancers, no matter who does the initial one

HIGH GRADE T1 AND CIS

• Change in paradigm:

– Surveillance works ONLY if there is no progression. Once progression occurs, we have lost 20-30% survival.

IF NO CR, TAKE OUT BLADDER

Urothelial Divergent Histology

• Definition: Bladder cancer with both urothelial and non-urothelial components, such as:

1. Squamous2. Glandular (adeno)3. Nested4. Micropapillary5. Plasmacytoid6. Signet cell7. Lymphoepithlioma8. Small cell9. Sarcomatoid

Pathological spectrum of mixed histology component: Rajal Shah MD

Squamous39%

Glandular18%

Sarcomatoid11%

Micropapillary10%

Small cell9%

Lymphoepithelial1%

Multiple12%

Squamous and Glandular most common followed bySarcomatoid, Micropapillary and Small cell

112 of 448 (25%) of TURBTs contained Mixed Histology

Results

• UC with mixed histology were uniformly (100%) high grade

• Only one tumor with mixed histology was non-invasive (99% demonstrated invasion of at least lamina propria –T1 disease)

Extra vesicular disease at cystectomy Independent Variable Hazard Ratio (95% CI) P-value Mixed versus Pure Histology 2.6 (1.3,5.2) 0.0072 Clinical stage 0.0001 T2 versus <T2 2.9 (1.3,6.3) T3/T4 versus <T2 7.7 (3.0,19.6) Age 0.0085 55-64 versus <55 1.2 (0.4,3.7) 65-74 versus <55 3.1 (1.0,9.6) 75+ versus <55 3.9 (1.3,12.0) Male versus Female 1.2 (0.5,2.8) 0.7462

TURBT CYSTECTOMY

(295 patients underwent cystectomy: 90 in mixed histology group and 205 in pure UC group)

Conclusions

• Divergent differentiation common in TURBT~30%• Micropapillary as well other types of divergent

differentiation present at TURBT is associated with high pathologic stage at cystectomy and usually with a poor prognosis

• Response to BCG or systemic treatment uncertain but patients with T1 disease should be offered aggressively early radical cystectomy (currently well accepted with micropapillary variant)

• Just in the last month, I have had 3 cases initially called urothelial but reclassified as divergent with micropapillary, small cell, or plasmacytoid/signet ring components on review at UM

Neoadjuvant Chemotherapy

INT 0080 Figure 1: Unadjusted Survival Curves

by Treatment Arm

0

0 %

20 %

40 %

60 %

80 %

100 %

24 48 72 96 120 144 168

Number of Patients at Riskat 2 Years at 5 Years

Cystectomy 88 60MVAC/Cystectomy 112 84

MedianAt Risk Death in Months

Cystectomy 154 100 46MVAC/Cystectomy 153 90 77

Months from Registration

INT 0080 Figure 3: Unadjusted Survival CurvesStratified by Treatment and T-Stage Classification

0

0 %

20 %

40 %

60 %

80 %

100 %

24 48 72 96 120 144 168

MedianAt Risk Death in Months

MVAC/Cyst T2 61 32 105Cyst T2 61 33 75MVAC/Cyst T3-4a 92 58 65Cyst T3-4a 93 67 24

Months from RegistrationThis secondary analysis underpowered and thus can’t be used to say only treat T3 with neoadjuvant

CONFIRMATORY DATA FOR INT 0080

The Three Largest Studies

• INT 0080 (MVAC) .74 (.55-.99)*• MRC/EORTC (CMV) .85 (.71-1.02)**• Nordic 1&2 (AC or CM) .80 (.64-.99)***

*p= 0.088 (2 sided), thus called non-sig; greatest benefit T3/T4

**p= 0.075 (2-sided), thus called non-sig; now significant at 7 years FU for both survival and locoregional control

*** 11% survival advantage for T3/T4a, marginal for T1 and T2

UM philosphy: neoadjuvant chemo for all T2 unless reason not to

What about Partial Cystectomy?

• Candidates: single tumor in space and time, no CIS, good location

• With these criteria, only 2-3 % of patients qualify

• Age is NOT an indication: a bad cancer operation in a 60 y/o does not become a good cancer operation in an 80 y/o

UNIVERSITY OF MICHIGAN UROLOGY CENTERUNIVERSITY OF MICHIGAN UROLOGY CENTER

Partial Cystectomy Use is Decreasing

0

5

10

15

20

25

1988-91 1992-94 1995-97 1998-00

Treatment Year

SEERNIS

% S

ubje

cts

Und

ergo

ing

Par

tial

UNIVERSITY OF MICHIGAN UROLOGY CENTERUNIVERSITY OF MICHIGAN UROLOGY CENTER

Partial Utilization by Patient Age

0

5

10

15

20

25

30

35

40

< 60 60 to < 70 70 to < 80 80 years+

Patient Age

SEERNIS

% S

ubje

cts

Und

ergo

ing

Par

tial

Bladder Cancer Outcomes

• What proportion of deaths from bladder cancer could be improved if we could do a cystectomy earlier in the right people? 30%

• Do we allow the natural history of CIS to become evident with extravesical (prostate, upper tract) extension by delaying cystectomy with conservative treatment? Yes, I bet

Bladder Cancer Outcomes

• What is the importance of divergent histology on bladder cancer management? Very

• What is the optimal integration of systemic chemotherapy along with cystectomy? All muscle invasive get neoadjuvant

• Isn’t partial cystectomy safer in an older person? Not if it doesn’t get rid of all the cancer

BLADDER CANCER

The patient and urologist must

walk a tightrope to not remove the

bladder too early but not remove it

too late ---and do it right