Transcript Bladder Cancer - Biotech Due Diligence

Bladder Cancer
R. Zenhäusern
Bladder cancer:
• Incidence:
• Mortality:
Epidemiology
20/100000/year (Europe)
8-9/100000/year
• Fourth most common cancer in men
– Incidence: 31.1
mortality: 12.1
• Seventh most common cancer in women
– Incidence: 9.5
mortality: 4.5
• At diagnosis >70%: > 65 y of age
Bladder cancer:
Histology
• 90-95%
transitional-cell carcinoma
• 3%
• 2%
• <1%
squamos-cell carcinoma
adenocarcinoma
small-cell carcinoma
Bladder cancer:
Entities
• 75-85% superficial bladder cancer
pTa, pTis, pT1
• 10-15% muscle-invasive bladder cancer
pT2, pT3, pT4
• 5%
metastatic bladder cancer
N+, M+
Bladder cancer:
Stage and Prognosis
Stage
TNM
5-y. Survival
0
Ta/Tis
NoMo
>85%
I
II
T1
T2a-b
NoMo
NoMo
65-75%
57%
III
T3a-4a
NoMo
31%
IV
T4b
NoMo
24%
each T
each T
N+Mo
M+
14%
med. 6-9 Mo
Superficial Bladder Cancer
pTa, pT1, Tis
• Standard of care=intravesical Therapy
 transurethral resection
• Relapse rate:
70%
 adjuvant therapy
Superficial Bladder Cancer
• Histological grading is important
G1
G2
G3
Relapse rate
42% 50% 80%
Progression rate
2%
11% 45%
Superficial Bladder Cancer
Adjuvant Therapy
• Reduces relpase rate by 30-80%
– Doxorubicin
weekly 6-8 w. / monthly 6-12
– Mitomycin C
weekly 6-8 w. / monthly 6-12
– BCG
weekly 6-8 w. /Mo 3 and 6
Invasive bladder cancer
• Standard of care =
Radical cystectomy with pelvic
lymphadenectomy
Only about 50% of patients with highgrade invasive disease are cured
Results of radical cystectomy
Stage
T2
T3a
T3b
T4a
NN+
NN+
NN+
NN+
Recurrence-Free
5 y.
10y.
Overall Survival
5 y.
10y.
89
50
78
41
62
29
50
33
77
52
64
40
49
24
44
26
87
50
76
37
61
29
45
33
57
52
44
26
29
12
23
20
Stein et al JCO 2001;19:666
Results of radical cystectomy
Stage
Recurrence-Free /Overall Survival
5 years
Organ-confined (<pT2pNo)
73%
62%
non-organ-confined (>pT2pNo)
56%
49%
Positiv lymph nodes (pT1-4, pN+)
33%
24%
Madersbacher et al JCO 2003;21:690
Chemotherapy for bladder cancer
• Bladder cancer is a chemosensitive disease
• Active single agents.
–
–
–
–
Cisplatin
Carboplatin
Gemcitabine
Ifosfamide
RR
30%
20%
20-30%
20%
Chemotherapy for bladder cancer
Combination chemotherapy.
–
–
–
–
MVAC
Gemzar / Cisplatin
Gemzar / Carboplatin
Taxol / Carboplatin
RR
CR
40-75%
40-70%
65%
20-40%
<20%
5-15%
5%
Adjuvant chemotherapy
• Six randomised trials have compared CT
with observation after cystectomy or RT
• 4x no survival benefit
• 2x benefit from adjuvant CT
 no standard of care
– node positive disease, lymphovascular
invasion, positive margins
Neoadjuvant chemotherapy
• Meta-analysis of ten randomised trials
(2688 patients)
13% reduction in risk of death
5% absolute benefit at 5 years
OS increased from 45% to 50%
ABC Meta-analysis Collaboration. Lancet 2003;361:1927
Combined Radio- and Chemotherapy
CR
5y.OS
• Radiotherapy
57%
47%
• RT and cisplatin
85%
69%
• RT and carboplatin
70%
57%
Birkenhake et al. Strahlenther Onkol 1998;174:121
Bladder-sparing therapy for
invasive bladder cancer
• High probability of subsequent distant
metastasis after cystectomy or radiotherapy
alone (50% within 2 years)
• Radiotherapy im comparison with cystectomy
has inferior results (local control 40%)
• muscle-invasive bladder cancer is often a
systemic disease
 combined modality therapy
Bladder-sparing protocol
Transurthral resection
Induction Therapy: Radiation + chemotherapy
(cisplatin, paclitacel)
Cystoscopy after 1 month
no tumor
Consolidation: RT + CT
tumor
cystectomy
Bladder-sparing protocol
T2: 5y / 10y OS: 74% / 66%
T3-T4a: 5y / 10y OS: 53% / 52%
Shiply et al. Urology 2002;60:62
Results of bladder-sparing therapy
and cystectomy
Bladder-sparing
n Pat.
therapy
5y. OS
%
5y. Survival
with Bladder %
Houssett 1997
120
63
NA
Sauer 1998
Shipley 1998
Shipley 2002
Rodel 2002
162
123
190
415
55
49
54
50
44
38
45
42
Dalbagni 2001
181
36
NA
Stein 2001
633
48
NA
Cystectomy
Combined-modality treatment and organ
preservation in invasive bladder cancer
Rödel et al. JCO 2002;20:3061
415 patients with T1 high-risk, T1-4, No-1
Treatment: 1. Transurethral resection
2. RT (n=126), RCT (n=289)
RT median 54 Gy, CT cisplatin week 1, 5
3. Restaging-TUR
Combined-modality treatment and organ
preservation in invasive bladder cancer
• Rödel et al. JCO 2002;20:3061
•
•
•
•
•
Complete remission
Local control after CR
distant metastasis
Disease-specific survival
Preservation of bladder
72%
64% (10 y.)
35% (10 y.)
42% (10 y.)
>80%
Local control
Distant metastasis
Rödel et al. JCO 2002;20:3061
Disease-specific survival for patients after salvage
cystectomy
50%
21%
45%
18%
Rödel et al. JCO 2002;20:3061
TUR and adjuvant
Radio-Chemotherapy
• 5 year Survival
50-65%
• Preservation of Bladder
38-43%