Transcript Sample Talk

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 Objective
•
To determine the proportion of patients
dying of bladder cancer with potentially
avoidable deaths
– If large—suggests aggressive therapy may save lives
– If small—suggests tumor biology has already
determined ultimate outcome
David S Morris Alon Weizer, James Montie,
Rodney Dunn, Zaojun Ye, Brent Hollenbeck
Cancer: March 2009
Study Population
•
Patients with deaths directly caused by
bladder cancer
•
Institutional data
– 126 patients from 2001-2005
– 4 independent expert reviewers
•
Administrative data (SEER-Medicare)
– 6,326 patients from 1992-2003
– Algorithms follow clinical course
– i.e. look at those who died and make assumptions on those who
could have lived
UM Institutional Data
•
40 of 126 bladder cancer deaths
potentially avoidable = 32%
•
Substantial agreement between
reviewers
– Kappa range 0.74 to 0.96
– All reviewers agreed on 30 of 40 patients, 3 of 4
agreed on additional 8 patients
Administrative Data
•
3293/6326 (52%) of deaths occurred
within 1 year of diagnosis
•
Estimated between 21% and 39%
potentially avoidable
– Based on delays in treatment
– Majority were healthy patients who did not receive
any form of definitive therapy
Conclusions
•
A significant proportion of bladder
cancer deaths may be avoidable with
“ideal” therapy
–Estimated as 1/3rd by clinical and
administrative data
–“ideal” therapy requires better decisionmaking by the doctor and patient to predict the
future
–We can do a lot better with just clinical data
now available to us
–The delay in these patients is long, almost 5
years
Institutional Data:
Survival Curves
Diagnosis to Death
Diagnosis to Treatment
Curable
Non-Curable
10
58
Potentially curable patients:
Lived longer with disease (58 vs. 10 months)
Longer delay between diagnosis and cystectomy (23 vs. 2 months)
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
•
•
RECURRENCE RATE
CHANGE IN
RECURRENCE RATE
WORTHLESS !
• MUST ELIMINATE HIGH GRADE CANCER
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 CA
HOW DO WE DO ?
• How many patients have
residual tumor at second
resection? Answer: 2040%
(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 foca
micropapillary
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 CA
HOW 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 CANCER
HOW 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
EVIL
T1 BLADDER CANCER
1.Bad location
(inaccessible to good
TUR)
2.Multifocal T1
3.Lymphovascular
invasion (LVI)
4. Recurrent T1 on
reresection
5. T1 after BCG
6. T1 without muscle
in specimen
7. ? Abnormal
markers
8. ? 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 2030% survival.
IF NO CR, TAKE OUT BLADDER
Urothelial Divergent Histology
•
1.
2.
3.
4.
5.
6.
7.
8.
9.
Definition: Bladder cancer with both urothelial and nonurothelial components, such as:
Squamous
Glandular (adeno)
Nested
Micropapillary
Plasmacytoid
Signet cell
Lymphoepithlioma
Small cell
Sarcomatoid
Pathological spectrum of mixed
histology component: Rajal Shah MD
112 of 448 (25%) of TURBTs contained Mixed Histology
Multiple
12%
Lymphoepithelial
1%
Small cell
9%
Squamous
39%
Micropapillary
10%
Sarcomatoid
11%
Glandular
18%
Squamous and Glandular most common followed by
Sarcomatoid, Micropapillary and Small cell
Results
TURBT
• UC with mixed histology
were uniformly (100%)
high grade
• Only one tumor with
mixed histology was noninvasive (99%
demonstrated invasion of
at least lamina propria –
T1 disease)
(295 patients underwent
cystectomy: 90 in mixed histology
group and 205 in pure UC group)
CYSTECTOMY
Extra vesicular disease at cystectomy
Independent Variable
Mixed versus Pure Histology
Clinical stage
T2 versus <T2
T3/T4 versus <T2
Age
55-64 versus <55
65-74 versus <55
75+ versus <55
Male versus Female
Hazard Ratio (95% CI)
2.6 (1.3,5.2)
P-value
0.0072
0.0001
2.9 (1.3,6.3)
7.7 (3.0,19.6)
0.0085
1.2 (0.4,3.7)
3.1 (1.0,9.6)
3.9 (1.3,12.0)
1.2 (0.5,2.8)
0.7462
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
100 %
Cystectomy
MVAC/Cystectomy
80 %
At Risk
154
153
Death
100
90
Median
in Months
46
77
60 %
40 %
20 %
Cystectomy
MVAC/Cystectomy
Number of Patients at Risk
at 2 Years
at 5 Years
88
60
112
84
0%
0
24
48
72
96
Months from Registration
120
144
168
INT 0080 Figure 3: Unadjusted Survival Curves
Stratified by Treatment and T-Stage Classification
100 %
MVAC/Cyst T2
Cyst T2
MVAC/Cyst T3-4a
Cyst T3-4a
80 %
At Risk
61
61
92
93
Median
Death in Months
32
105
33
75
58
65
67
24
60 %
40 %
20 %
0%
0
24
48
72
96
120
144
Months from Registration
This secondary analysis underpowered and thus can’t
be used to say only treat T3 with neoadjuvant
168
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
Partial Cystectomy Use is
Decreasing
% Subjects Undergoing Partial
UNIVERSITY OF MICHIGAN
UROLOGY CENTER
25
20
15
SEER
NIS
10
5
0
1988-91
1992-94
1995-97
Treatment Year
1998-00
Partial Utilization by Patient Age
% Subjects Undergoing Partial
UNIVERSITY OF MICHIGAN
UROLOGY CENTER
40
35
30
25
20
SEER
NIS
15
10
5
0
< 60
60 to < 70
70 to < 80
Patient Age
80 years+
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