Transcript AUA panel 2005

Management of Difficult
Cases of Non-Muscle
Invasive Bladder Cancer
1
Bladder Cancer
• Recurrence is common
• Progression is uncommon
• Progression is more important
than recurrence
• There are indicators of
recurrence and progression
2
Clinical Prognostic Markers
Risk of recurrence of Ta/T1 TCC by tumor characteristics
ATC = 0
ATC = 1
ATC = 2
ATC = 3
Allard et al, Br J Urol 81:692, 1998
3
Progression at 3 years after TUR
30%
30%
25%
20%
15%
10%
4%
5%
0%
Ta
N = 207
p < 0.001
T1
Heney et al, J Urol 130:1083, 1983
4
T1 Progression by Stage and Grade
58%
60%
50%
36%
40%
30%
40%
Grade 2
Grade 3
26%
20%
10%
0%
T1a
T1b
Holmang J Urol 157:800, 1997
5
Risk of Death from Bladder Cancer
by Presenting Stage
30%
30%
25%
20%
15%
11%
Ta (N = 77)
T1 (N = 99)
10%
5%
0%
20 year follow-up, Rx with cystoscopy ± thiotepa
Holmang et al, J Urol 153:1823, 1995
6
Adjuvant Therapy 2005
•
•
•
•
Cystoscopic surveillance
Repeat TUR
Perioperative chemotherapy
Intravesical therapy
– BCG
– BCG + Interferon
– Chemotherapy
• Cystectomy
7
Multiple Recurrences
• Jan 2004 -63 y/o man with multifocal Ta G2 TCC
– Perioperative treatment with mitomycin
• April 2004 – 5 small Ta G2 TCC
– BCG x 6 weeks
• July 2004 – 4 small Ta G2 TCC
– BCG + interferon x 3 weeks
• Oct 2004 – 8 small, Ta G2 TCC
– Mitomycin 40 mg/20 ml x 6
• Jan 2005 – 6 small, Ta G2 TCC
– Doxorubicin 50 mg/50 ml x 6
• April 2005 – 4 small, Ta G2 TCC
Dr. Lamm?
8
Refractory G2, Ta TCC
• We desperately need more drugs!
• Cystectomy may otherwise be required
• Look for and remove carcinogens
• Diet and life style changes
• Oncovite 2 tabs BID (Mission Pharm)
• New options: immediate gemcitabine
1000mg/25cc
• Improved BCG immunotherapy
9
Prevention: Smoking cessation,
carcinogen avoidance, nutrition
• 2-fold risk for bladder cancer associated with
increased DNA adducts in smokers
– Mutagenesis. 18:445, 2003
• Intake of fruit and vegetables in smokers
decreased DNA adducts
– Carcinogenesis. 23:861, 2002
• 286 Ta, T1 patients: Quitting  recurrence-free
(P<.003) and progression-free (P<.001) survival
– J Urol 161:172, 1999
10
Bladder Cancer Chemoprevention
• Vitamins: A, B6, C, D, E, folic acid, C+K3
– A: Sporn’79, Moon’83; B6: Byar’77, C: Schlegel’75, D: Konety’01;
E: Michaud’00; C+K3: Gilloteaux’98; A,B6,C, E: Lamm, ‘94
• Allium sativum (Garlic)
– Lau’86, Riggs’97, Lamm’01
• NSAIDS, Cox 2 inhibitors
– Goodwin’81, Waddell’83, Earnest’92, Moon’92
• DMFO
– Messing’88, Boone’90, Kellog’92, Loprinzi’96
• Oltipraz
– Wattenberg & Buening’86, Moon’94, Kensler’95
• Selenium
– Helzlsouer’89
• Soy protein, Green Tea
– Mokhtar’88, Kemberling ‘03
11
Kaplan Meier Estimate of 5 Year
Tumor Free Rate
100
Lamm DL, J Urol 151: 21-26, 1994
Percent Tumor Free
90
80
40,000u Vitamin A, 100mg B6,
2gm C, 400mg E: "Oncovite"
70
60
p=0.0014
50
40
30
Multi Vitamin (N=30)
Mega Vitamin (N=35)
20
10
RDA Vitamins
0
0
5
10
15
20
25
30
35
40
45
50
55
60
Months After Registration
12
Improved BCG Administration
• Low grade tumors respond less favorably
• Minimize tumor burden with complete
resection and immediate chemotherapy
• Immune status: check the PPD; add
percutaneous BCG if negative
• Weekly BCG x3 every 6 months, reducing
dose 1/3, 1/10, 1/30, 1/100th
13
T1 TCC
• 56 y/o man with T1, G3 TCC and CIS
• BCG x 6 weeks
• Biopsy 6 weeks later demonstrates
T1 G3 TCC
Dr. Theodorescu?
14
What are this man’s chances of progressing?
...or for harboring invasive disease already?
• After BCG failure each additional course of
BCG carries a 7% actuarial risk of
progression
– Catalona, 1987
• In patients with T1G3 cancers, multiple
tumors and/or presence of CIS are major
determinants of upstaging at radical
cystectomy
– Masood, 2004
– N=17 (single tumor, no CIS): upstaging in 1 (6%)
– N=13 (mult. Tumor +/- CIS): upstaging in 7 (55%)
15
There is a Survival Advantage in patients
with sTCC treated with “early” cystectomy
N=307 high risk sTCC
treated with TURBT+BCG
90 underwent cystectomy for
recurrent tumor: 35 superficial
and 55 invasive recurrence
Of 35 with sTCC, 92% and 56%
survived who underwent
cystectomy <2 yrs after initial
BCG therapy vs. >2 yrs
Multivariate analysis:  survival
in patients who underwent earlier
cystectomy for sTCC relapse
Months Follow Up
Herr, 2001
16
Defining BCG refractory sTCC
• 93 patients received a 6-week induction
course of BCG
• Evaluated for response after 3 and 6 months
• 57% were negative for tumor at 3 months
• 80% of the patients were tumor-free at 6 mo
• Tumor-free interval during 24 mo followup
best predicted by response to BCG at 6 mo
Herr, 2003
17
Excellent Prognosis of sTCC with
cystectomy for sTCC
• 5 and 10 year cancer-specific survival rates
as a function of pathological tumor stage:
• Amling 1994
–
–
–
–
pT0 (43) 80% and 66%
pTa (11) 88% and 75%
pTis (19) 100% and 92%
pT1 (91) 76% and 62%
• Stein 2001
– pT0, pTa, pTis (N0): (208) 89% and 85%
– pT1 (N0): (194) 83% and 78 %
18
Practical approach to T1G3
after 1st BCG failure
Initial Treatment
T1G3
BCG
1st Evaluation
Multiple tumors or CIS (original or rec)
Yes
Cystectomy
No
Second Line Intravesical Tx
2nd Evaluation
(>6 mo)
Cystectomy
19
Positive Cytology
• 71 y/o man with T1 G3 TCC with CIS
• BCG x 6 weeks
• After last dose had severe irritative
sx and fever to 102 x 24 hours
• 6 weeks later – cysto negative and
cytology positive
Dr. Ratliff?
20
Issues Highlighted by Case
• What defines BCG intolerance &
contra-indication for further BCG
therapy
• Approach to patients with positive
cytology post-BCG
21
Issue 1: Fever & Irritative
Symptoms after BCG
• Irritative symptoms occur in 35-90% of
patients (median, 75%)
– AUA Bladder Cancer Guidelines
• Transient fever > 102 in 1-2% at each
instillation
– Lamm, DL and Torti, FM, Cancer Journal
for Clinicians, 1996
• Fever longer than 24 hrs considered
infection and treated accordingly
22
Issue 1: Fever & Irritative
Symptoms after BCG
• Reduction of transient symptoms
(30-50%) by either:
– BCG dose reduction (1/2 to 1/3)
• Martinez-Pineiro, BJU International 2002
– Slow dosing BCG on an every other
week schedule
• Bassi, Eur. Urol. 2002
• Current patient not considered
BCG intolerant
23
Issue 2: Positive Cytology Post-BCG
• Positive cytology strong indicator of
presence of TCC (>95%)
• BCG induced antitumor activity can be
delayed
– CIS without maintenance: 57% to 68% CR
• Lamm J Urol 2002
• Additional treatment increases response
– maintenance 55% to 84% CR
• Lamm, J Urol 2002
Tim, you could consider quoting the Herr paper from
my section to tie these 2 sections together
24
Issue 2: Positive Cytology Post-BCG
• Determine source of positive cytology
– >80% in bladder while ≈ 20% outside
bladder (ureter, kidney, prostatic ducts)
• At U. Iowa routinely restage patients
with post-treatment positive cytology
– Bladder barbotage, random bladder bx,
prostatic urethra bx, upper tract washings,
bilateral retrograde pyelograms
25
Treatment
• If disease localized to bladder, 3
reduced doses BCG (1/3, 1/10, 1/10)
with IFN (50 MU followed 1 mo later
with another 3 treatment cycle
• Evaluate at 6 mo.
26
Positive Cytology
• 53 y/o non-smoker
• History of Ta, G2 TCC 2 years ago
• Positive cytology
• IVP negative
• Bladder and prostatic urethral biopsies negative
• 3 months later – positive cytology
Dr. Lamm?
27
Positive Cytology, Negative Bx
• 0.2% Methylene blue vital staining will
increase yield of biopsy
• UroVysion should be positive, but can
be checked if there are doubts
• Differential wash: bladder and each
ureter for cytology
• Ureteroscopy with biopsy of any
suspicious urothelium
28
Unusual Histology
• 58 y/o man with T1
micropapillary bladder cancer
Dr. Theodorescu?
29
Clinical demographics of
“Micropapillary” bladder cancer
Literature review 1966 to 3/2005
N
Country
% of All
BC
Mean Age
M:F
Author
Year
18
USA
n/a
67
5:1
Amin
1994
20
Sweden
0.7%
69
2:1
Johansson
1999
20
Australia
n/a
69
4:1
Samaratunga
2004
38
Mexico
6%
68
37:1
Alvarado
2005
7
Several
n/a
60-70
n/a
Case reports
19952001
Search Terms: “micropapillary bladder cancer (carcinoma)”
30
What is micropapillary (MPC)
bladder cancer?
Clinical Features
• Variant of carcinoma in various anatomic sites
(breast, urinary bladder, lung, and salivary glands)
• High propensity for lymphovascular invasion and
lymph node metastases
• Often high-stage disease at presentation
• Tumors with <10% MPC have a high chance of
detection at an early stage
• Poor clinical outcome compared with that of
patients with urothelial carcinoma (N=38, 40% DFS
at 3yrs)
• Radiation and chemotherapy do not seem to be
effective
31
What is micropapillary (MPC)
bladder cancer?
Pathology
• immunohistochemical staining pattern supports that
MPC is a variant of adenocarcinoma
• small tight clusters of neoplastic cells floating in clear
spaces resembling lymphatic channels
• pattern is mixed with a variable component of
conventional urothelial carcinoma or other variants
Low Power
High Power
32
Figures from: webpathology.com
58 y/o man with T1 MPC
• Very lucky to have detected it at an early stage
• Staging workup (CT chest, CT-IVP and BS)
• Given aggressive clinical behavior and lack of
evidence intravesical therapy, radiation
therapy or systemic chemotherapy of benefit
patient
CYSTECTOMY ASAP!
33
Carcinoma in Situ
• 68 y/o woman former smoker with CIS
• BCG x 6 weeks
• Biopsy 6 weeks later demonstrates CIS
Dr. Ratliff?
34
Issues Highlighted by Case
• Conservative vs radical therapy
• Conservative treatment options
35
Issue 1
Conservative vs Radical Therapy
• Natural history CIS progression  7%
annually and 3.3% at 6 mo
– Cheng, Cancer, 1999
– Millan-Rodriquez, J Urol, 2000
• Cystectomy mortality  2%
• Thus another 3 mo for additional
conservative therapy is acceptable risk
36
Issue 2: Treatment Options
• BCG induced antitumor activity can be
delayed
CIS without maintenance: 57% to 68% CR
Lamm J Urol 2002
• Additional treatment increases response
 maintenance 55% to 84% CR
Lamm, J Urol 2002
37
Issue 2: Treatment Options
• Chemotherapy for BCG failures
provides poor response rates
 19% for MMC post BCG
Malmstrom, J Urol, 2001
• Low Dose BCG after one cycle BCG
failure provides 60% durable CR
(same as BCG naive)
38
39
Maymi et al, AUA Abstract 918
Treatment
• Low dose BCG + IFN (50 MU)
• Evaluate at 3 and 6 mo.
• If fail at 6 mo., cystectomy
40
Recurrent High Grade TCC
• 65 y/o woman with a history of
Ta G2-3 TCC
• Intravesical BCG for 6 weeks
• Regular surveillance cystoscopy
• 2 years after her initial tumor
has a 2 cm, Ta G3 TCC
Dr. Lamm?
41
High Grade Recurrence
after BCG Induction
• Meta analysis shows BCG reduces
progression, but only with maintenance
• Repeated 6 week treatments is historically
suboptimal, suppresses cytokines, risks
immunosuppression, and is ineffective in
a controlled trial
• 3 weekly BCG (extending if there are no
symptoms), repeating at 3 months, then q.
6 months would be my choice for her
42
3 Week Maintenance BCG
550 pts. 6 wk vs. 3 wk maintenance at
3, 6, 12, 18, 24, 30, & 36 months
Recurrence -free
Survival
p < 0.0001
Worsening -free
Survival
p = 0.04
Survival
p = 0.08
Lamm DL et al, J Urol 163, 1124, 2000
43
BCG Maintenance: Not Created Equal
% Tumor Free
100
M BCG
I BCG
50
100
N=42 pts. 1q
3mo.
90
0
% Disease Free
Months
100
90
80
70
60
50
40
30
20
10
0
M BCG
I BCG
N=93 pts. 1q
1mo.
0
9
18
27
36
Global recurrence
Months
1.
.9
0
.8
.7
.6
.5
.4
.3
.2
.1
0.
00
Percent Tumor Recurrence
80
3 6 9 1 1 1 2 2 2 3 3
2 5 8 1 4 7 0 3
M. Ta, T1
M. CIS
70
60
I. CIS
50
I. Ta, T1
40
N=385, 3q 3-6mo.
30
M, TaT1, 3wk maintenance BCG
M, CIS, 3wk maintenance BCG
I, CIS, 6wk induction BCG
I, TaT1, 6wk induction BCG
20
10
0
N=126, 6q 6mo.
0
Maintenance
Control
12
24
36
48
Time in months
60
72
1
2
3*
4 **
5
6
7
8
9
Years
* Completion of Therapy
* Apparent Increase in Rate of Recurrence
* One Year After Completion of Maintenance
44
Meta Analysis: BCG vs Control
24 trials with 4863 patients were eligible:
Start of Patient Entry:
Date of Publication:
Duration of Follow Up:
1978 to 1993
1982 to 2001
Median: 2.5 years
Maximum: 15 years
Five BCG strains:
TICE, Connaught,
Pasteur, RIVM,
A. Frappier
Sylvester, R: J Urol, 2002
45
Progression:
Maintenance BCG
Patients
No BCG
BCG
OR
No Maint
1049
10.3%
10.8%
1.28
Maintenance
3814
14.7%
9.5%
0.63
Test for heterogeneity: P = 0.008
BCG was only effective in trials with maintenance,
where it reduced the risk of progression by 37%
p = 0.00004.
46
Progression
Progression
Studies With Maintenance
AllAll
Studies
With Maintenance
Study Publ Year
Author and Group
Events / Patients
No BCG
BCG
1991 Pagano (Padova)
11 / 63
1987 Badalament (MSKCC) 6 / 46
2000 Lamm (SW8507)
2001
1996
1995
1995
1999
2001
1991
2001
2001
1982
1990
1999
1997
1994
1991
1993
1988
102 / 192
Palou
Rintala (Finnbl 2)
Rintala (Finnbl 2)
Lamm (SW8795)
Malmstrom (Sw-N)
Nogueira (CUETO)
Rintala (Finnbl 1)
de Reijke (EORTC)
vd Meijden (EORTC)
Brosman (UCLA)
Martinez-Pineiro
Witjes (Eur Bropir)
Jimenez-Cruz
Kalbe
Kalbe
Melekos (Patras)
Ibrahiem (Egypt)
Total
2
3
4
24
22
8
2
18
19
0
4
2
7
2
2
7
12
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
61
90
40
186
125
127
58
84
279
22
109
25
61
35
17
99
30
Statistics
(O-E)
Var.
3 / 70
6 / 47
-4.4
-0.1
3.1
2.6
87 / 192
-7.5
24.1
3
3
2
15
15
10
3
10
24
0
1
1
6
0
0
2
5
0.4
0
-0.5
-4.8
-3.5
-1.9
0.7
-4
-4.7
0
-0.9
-0.6
-0.5
-1
-1.1
-1.5
-1.1
1.2
1.5
1.3
8.8
7.9
3.9
1.2
5.9
9.1
0
1.2
0.7
2.9
0.5
0.5
2
2.6
-36.8
80.9
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
65
92
28
191
125
247
51
84
558
27
67
28
61
32
21
62
17
257 / 1749 196 / 2065
(14.7 %)
(9.5 %)
(BCG
|1-OR|
% ± SD
No BCG)
37% ±9
reduction
0.0
Test for heterogeneity
c2=9.73, df=18: p=0.9
OR & CI
:
0.5
1.0
1.5
BCG
No BCG
better
better
Treatment effect: p=0.00004
2.0
Survival
Death
All
Bladder
Patients
No BCG
BCG
Total OR
2930
2370
26.7%
7.7%
23.2%
5.6%
24.8% 0.89
6.5% 0.81
The reductions in the odds of death, 11% overall
and 19% bladder cancer, are not statistically
significant, as might be expected with 2.5 year
mean follow up
48
•
•
•
•
Use perioperative therapy for low-risk TCC
Use maintenance BCG for high-risk TCC
Lower the dose for BCG toxicity
Don’t abandon BCG therapy for CIS at 3
months
• Recurrent T1 disease is dangerous
• Be more aggressive with micropapillary &
small cell histology
• Don’t follow your patient to the grave –
consider cystectomy when local Rx fails
49