Transcript EORTC 22911 (Prostate) Study Coordinator: M. Bolla

POSTOPERATIVE RADIOTHERAPY IMPROVES
CLINICAL AND BIOCHEMICAL PROGRESSION FREE
SURVIVAL AFTER RADICAL PROSTATECTOMY :
FIRST RESULTS OF EORTC TRIAL 22911
M. Bolla (Grenoble, France), H. van Poppel, L. Collette
,P.J. van Cangh, K. Vekemans, L. Da Pozzo, R. Van
Velthoven, JM Maréchal , P. Scalliet, , Th.M. de Reijke, A.
Verbaeys, J.-F. Bosset, K. Haustermans, M. Piérart
On behalf of the EORTC Radiotherapy and Genito-Urinary
Groups
EORTC
For pT3 patients (cancer extending beyond the
capsule) the risk of local failure varies from 10 to
50%.
PSA level, Gleason score and positive surgical
margins are independant predictors of biochemical
relapse.
Post operative radiotherapy reduces significantly
the local relapse and PSA failure rates without any
impact on disease-free survival.
EORTC
Trial Design
S
U
R
G
E
R
Y
RANDOMIZATION and
Stratification for
Institution
Capsule invasion
Positive margins
Invasion of seminal vesicles
Wait and see until
local failure
Post-op radiotherapy
(60 Gy/6wks)
1005 patients recruited between end 1992 and end 2001
Median follow-up: 5 years
EORTC
Selection Criteria

Age 75 years,

WHO performance status (PS) 0-1

T0-3 N0 M0 Prostate Cancer preoperatively

1 pathological risk factor of:




capsule invasion
positive surgical margins
invasion of seminal vesicles
Informed consent
EORTC
Trial objectives

The trial is planned to demonstrate an increase of 7.5%
of the 5-year biochemical progression free survival with
post-operative radiotherapy with 80% power (2-sided
Logrank test, =0.05)

Secondary endpoints
 Clinical progression-free survival
 Local control
 Overall survival
 Acute toxicity (WHO) and late Morbidity
EORTC
Yearly accrual
160
145
140
128
120
143
123
131
108
94
100
82
80
60
50
40
20
0
1
1992 1993 1994 1995 1996 1997 1998 1999 2000 2001
EORTC
Accrual by Country
The Netherlands: 146
United Kingdom: 5
Switzerland: 31
Belgium: 597
Italy: 115
France: 84
Spain: 19
Israel: 8
Patient characteristics

The characteristics were well balanced between the
groups

Median age 65 y (47 – 75)

WHO PS 0 : 93.8% - PS1: 5.5% - PS2: 0.3%

T0-1: 17.6% - T2: 65.1% - T3: 17.2% - Tx: 0.1%

WHO G1: 12.5% - G2: 62.7% - G3: 23.6% - Gx: 1.2%

Median PSA before surgery: 12.3 ng/ml (0.3-159.4)

Median PSA after surgery: 0.2 ng/ml (0.0 - 48.7)
EORTC
Pathological Risk factors
Treatment Arm
No RT
(N=503)
High Risk factors
Not pT3
N
(%)
RT
(N=502)
N
(%)
Total
(N=1005)
N
(%)
0 ( 0.0)
2 ( 0.4)
2 ( 0.2)
127 (25.2)
139 (27.7)
266 (26.5)
40 ( 8.0)
26 ( 5.2)
66 ( 6.6)
169 (33.6)
149 (29.7)
318 (31.6)
19 ( 3.8)
23 ( 4.6)
42 ( 4.2)
8 ( 1.6)
16 ( 3.2)
24 ( 2.4)
Margin only
79 (15.7)
84 (16.7)
163 (16.2)
Capsule + S.V. + margin
61 (12.1)
63 (12.5)
124 (12.3)
Capsule only
Capsule + S.V.
Capsule + Margin
S.V. only
S.V. + Margin
EORTC
Treatment actually received
No Further Trt
(N=503)
Treatment actually received
No Further Trt
N
(%)
Post-op RT
(N=502)
N
(%)
497 (98.8)
41* ( 8.2)
Post-op RT
5 ( 1.0)
457 (91.0)
Unknown
1 ( 0.2)
4 ( 0.8)
* Reasons were: ineligibility (10), post-operative complications (8),
refusal (21), unspecified (2)
EORTC
Radiotherapy Treatment
N=457
Time from Surgery to d1 of RT (days)
90 (14-156)
Duration of RT (days)
44 (18-106)
Total Dose (Gy)
<57 Gy
57-63Gy
>63 Gy
Total Number of Fractions
Interruptions for toxicity
60.0 (50 – 74)
3 ( 0.7%)
420 (91.9%)
34 ( 7.4%)
30 (26 – 39)
14 (3.1%)
EORTC
Radiation treatment
Field size
(square field-equivalent)
Post-op RT
(N=457)
Large*-Large
247 (54.0)
Large-Small**
175 (38.3)
Small-Small
Missing
28 ( 6.1)
7 ( 1.5)
* > 9 cm² square-field equivalent
**  9 cm² square-field equivalent
EORTC
Data Maturity

The median follow-up is 5 years for both arms

A total of 351 of the 478 events of biochemical/
clinical progression-free survival needed per
protocol were observed (73.4%)

The EORTC Independent Data Monitoring
Committee recommended the early release of the
results in December 2003

It is too early to assess the impact on time to
distant metastases or survival (only 89 patients
have died)
EORTC
Late toxicity
Time to first Grade >=3
Time to first Grade >=1
100
90
80
70
60
50
40
30
20
10
0
RT
68.0%
No RT
54.3%
0
1 2
3
4 5 6
years
7
8
9 10 11
100
90
80
70
60
50
40
30
20
10
0
At 5 years:
RT: 4.2%
No RT: 2.6%
0
1 2
3
4
5 6
years
7
8
9 10 11
More gastro-intestinal toxicity grade 1 and genito-urinary toxicity
grade 1-2 are observed with RT, few grade 3 are reported
EORTC
Cumulative incidence of
loco-regional failure
100
90
80
70
Post-operative RT: 5.4% at 5 years (98% CI: 2.7 – 8.0)
No further treatment: 15.4% at 5 years (98% CI: 11.2 – 19.6)
60
50
Gray test P<0.0001
40
30
20
10
0
(years)
0
O N
74 503
25 502
1
2
3
4
5
Number of patients at risk :
468 404 330 268 194
465 426 362 298 228
6
128
154
7
82
107
8
44
55
9
16
14
10
Treatment
Wait-and-See
Irradiation
Clinical progression-free survival
100
86.3%
(82.2 – 90.4)
90
Post-operative RT
80
70
77.1%
(72.1 – 82.0 )
60
%
No further
treatment
50
40
30
HR=0.61 98% CI: (0.43, 0.87)
Logrank P=0.0009
20
10
0
(years)
0
O N
113 503
75 502
1
2
3
4
5
Number of patients at risk :
467 401 324 259 188
464 424 357 291 221
6
7
8
9
124
150
79
101
42
53
16
14
10
Biochemical progression-free survival
100
74.0%
(68.7 – 79.3)
90
80
70
Post-operative RT
60
%
50
52.6%
(46.6 - 58.5 )
40
No further
treatment
30
HR=0. 48 98% CI: (0.37, 0.62)
Logrank P<0.0001
20
10
0
(years)
0
O N
220 503
131 502
1
2
3
4
5
Number of patients at risk :
425 337 243 182 126
456 407 330 262 193
6
7
8
9
84
125
52
85
27
41
10
11
10
Biochemical PFS by pT
Code and name
Events / Patients
Post-op RT
Wawa
Statistics
(O-E) Var.
SM+, ECESM-, ECE+
13/ 84
34/ 139
27/ 79
40/ 127
-9.7
-6.2
9.8
18.3
SM+, ECE-
33/ 149
74/ 169
-24.1
26.5
SV+
51/ 128
79/ 128
-22.9
30.9
131/ 500
(26.2 %)
220/ 503
(43.7 %)
Total
HR & CI
(Post-op RT :
Wawa)
-63 85.5
0.25
Test for heterogeneity
Chi-square=4.41, df=3: p=0.2
Test for trend
Chi-square=0.06, df=1: p=0.8
|1-HR|
% ± SD
52% ±8
reduction
0.5
1.0
2.0
4.0
Post-op RT
Wawa
better
better
Treatment effect: p=0.00000
EORTC
B-PFS
76
22
65.60 (50.89, 76.86)
Local - / Review +
33
22
45.27 (25.84, 62.88)
Local + / Review -
40
11
69.75 (50.34, 82.78)
Local + / Review +
119
57
49.44 (39.38, 58.72)
% at 5 Year(s)
(95% CI)
Overall Wald test: p=0.0007 (df=3)
(years)
0
O
22
22
11
57
Local - / Review -
Margin status
Wait and See
100
90
80
70
60
50
40
30
20
10
0
Patients
(N)
Observed
Events
(O)
N
76
33
40
119
2
4
6
Number of patients at risk :
65
34
12
21
10
4
30
19
13
86
48
23
8
6
2
5
6
10
Margin status
Loc - / Rev Loc - / Rev +
Loc + / Rev Loc + / Rev +
EORTC
Other randomized studies
ARO 96-02 : 385 patients
Southwest Oncology Group Trial : 431 patients
EORTC
ARO 96-02
385 patients with pT3 N0 M0
4-year biochemical progression free survival
1
0,75
RT 81%
0,5
WW 60%
0,25
p = 0,0010 HR : 0,49 (IC 95 0,3-0,75)
0
0
Wiegler T et al et al ASCO 2005, abstract 4513
EORTC
SWOG 8794
1988-1995 - 473 pts
pT3 prostate cancer randomized to RT - 60-64Gy or observation
only
Thompson et al. AUA 2005 Abstract #1665
EORTC
Conclusion
Post-operative radiotherapy results in improved
biochemical and clinical progression-free survival.
Today, T1c stages are most common and the rate of
SM(+) is far lower as well as the median PSA before
surgery.
The results of RP and immediate RT for pT3 R0-1 N0
might be improved by : i) accruing patients with a
negative
post-operative
PSA,
ii)
replacing
conventional RT by 3D-CRT, iii) promoting dose
escalation.
EORTC