Transcript adjuvant RT - Europa Uomo Slovensko

Adjuvant or Salvage
Radiotherapy after Radical
Prostatectomy
M. Wirth
Department of Urology, Technical University of Dresden
Adjuvant or Salvage Radiotherapy
after Radical Prostatectomy:
Background
PSA-relapse after RPE in locally
advanced PCa (n=2091)
% PSA-relapse (0.2 ng/ml) after 10 years
100
80
60
preop. PSA
40
20+ ng/ml
10.1-20 ng/ml
4.1-10 ng/ml
0-4 ng/ml
20
0
6-
3+4
4+3
8-10
Gleason-Score
Han, Partin et al., J Urol 2003
cT3: MSKCC-Nomogramm: pT Stage
Exampel: cT3, PSA 10 ng/ml, Gleason 4+4=8
extracapsular: 82 %
organconfined: 18 %
Ohori, Kattan et al., J Urol 2004
cT3: MSKCC-Nomogramm:pT-Stage
Exampel: cT3, PSA 10 ng/ml, Gleason 3+3=6
organconfined: 50 %
extracapsular: 50 %
Ohori, Kattan et al., J Urol 2004
Adjuvant or Salvage Radiotherapy after
Margin Positive Radical Prostatectomy
• Patients with R1 after RPE are at an
increased risk of biochemical, local and
distant failure [1].
• With R1, the risk of biochemical
recurrence may supersede 50 % after 10years [2].
• The associated 10-year local recurrence
rate accounts for narrowly 30 % [2].
1 EAU guidelines 2008; 2 Pfitzenmaier et al., BJU Int 2008
Adjuvant Radiotherapy vs.
Wait-and-see
after Radical Prostatectomy
Wait-and-see vs. immediate postoperative
radiotherapy - EORTC trial 22911 (n=1005)

randomised controlled trial
 pT3 or positive margins, pN0
 age < 76 years, WHO perf. status 0-1

wait-and-see (n=503) vs.
irradition (60 Gy) within 16 w. after RPE
(n=502)
Bolla et al., Lancet 2005
wait-and-see vs. immediate postoperative
radiotherapy - EORTC trial 22911 (n=1005)






age 65 y. (61-69)
PSA: 12.4 ng/ml (7.2-20.3)
PSA: 3 weeks after RPE, before RTX
0.2 (0.0-0.3)
median FU 5 y.
biochemical and clinical progression free
survival significantly improved after ART
overall survival with trend towards
improvement after ART,
but not (yet?) significant
Bolla et al., Lancet 2005
EORTC trial 22911 (n=1005)
clinical progression free survival
Clinical progression-free survival
Bolla et al., Lancet 2005
EORTC trial 22911 (n=1005)
biochemical progression free survival
PSA progression-free survival
Bolla et al., Lancet 2005
EORTC trial 22911 (n=1005)
cumulative incidence of locoreg. failure
local progression-free survival
Bolla et al., Lancet 2005
Patients who benefit from immediate
postoperative RT – EORTC trial 22911 (n=1005)
Van der Kwast, JCO 2007
Patients who benefit from immediate
postoperative RT – EORTC trial 22911 (n=1005)
Margins
ECE
SV
Gleason
Postop.
PSA
Van der Kwast, JCO 2007
Patients who benefit from immediate
postoperative RT – EORTC trial 22911 (n=1005)
Van der Kwast, JCO 2007
Patients who benefit from immediate
postoperative RT – EORTC trial 22911 (n=1005)
control arm
Van der Kwast, JCO 2007
Patients who benefit from immediate
postoperative RT – EORTC trial 22911 (n=1005)
immediate
postoperative radiation
Van der Kwast, JCO 2007
EORTC trial 22911 (n=1005)
cumulative incidence of late complications
Late complications
Bolla et al., Lancet 2005
Adjuvant RTX for T3N0M0 PCA –
randomised SWOG trial 8794 (n=425)

Randomised controlled trial
 clinical T1/T2 preoperatively
 pT3 or positive margins, N0 M0
 WHO perf. status 0-2

Wait-and-see (n=211) vs.
Irradition (60-64 Gy, n=214)
Thompson et al., J Urol 2009
Adjuvant RT in pT3 PCA
(randomised study SWOG 8794, n=425)
100
Percentage
80
60
40
20
0
Thompson et al., JAMA 2006
Adjuvant RTX for T3N0M0 PCA –
randomised SWOG trial 8794 (n=425)
Overall survival
p=0.023
Thompson et al., J Urol 2009
Adjuvant RTX for T3N0M0 PCA –
randomised SWOG trial 8794 (n=425)
Metastatic-free survival
p=0.016
Thompson et al., J Urol 2009
Adjuvant RTX for T3N0M0 PCA –
randomised SWOG trial 8794 (n=425)
Metastatic-free survival, PSA < / > 0.2
p=0.03
Thompson et al., J Urol 2009
Adjuvant RTX for T3N0M0 PCA –
randomised SWOG trial 8794 (n=425)
Summary
Thompson et al., J Urol 2009
Adjuvant radiotherapy after RPE
(ARO 96-02 / AUO AP 09/95 , pT3R0-1, PSA 0, n=108)
% PSA recurrence after 4 years
100
p<0.0001, hazard ratio 0.4
80
60
40
81 %
60 %
20
0
adjuvant RT (60 Gy)
no adjuvant RT
Wiegel et al., ASCO 2005 [in press as full article: J Clin Oncol 2009]
RPE with and without adjuvant RT
in pT3-PCA
Bottke and Wiegel, Urol Int 2007
Adjuvant radiotherapy following radical prostatectomy
for pathologic T3 or margin-positive prostate cancer
A systematic review and meta-analysis
Survival
Biochemical progression
Morgan et al., Radiother Oncol 2008
Salvage Radiotherapy vs.
Observation
at PSA Failure after Radical
Prostatectomy
PCA specific survival following salvage RTX
vs observation after RPE – survival

no salvage treatment (n=397) vs.
salvage radiotherapy (n=160) vs.
salvage radiotherapy + HT (n=78)
 significant increase of PC-specific survival
for both SRT (HR 0.32, p<0.001)
and SRT+HT (HR 0.34, p=0.003)
 improvement limited to patients with
- PSA-doubling time < 6 month
- SRT within 2 y. after recurrence
Trock et al., JAMA 2009
PCA specific survival following salvage RTX
vs. observation after RPE – survival
PCA specific survival
Trock et al., JAMA 2009
PSA failure following salvage radiotherapy –
CaPSURE data (retrospective study, n=194)
Macdonald et al., Urol Oncol 2008
Radiotherapy at biochemical recurrence
after RPE (retrospective study, n=162)
No biochemical recurrence
1,0
0,8
PSA ≤ 0,5 ng/ml
p bned
0,6
0,4
PSA ≥ 0,5 ng/ml
0,2
p = 0,031 (log rank test)
0,0
0
20
40
60
80
100
time / months
Wiegel et al., IJROBP 2008
Radiotherapy at biochemical recurrence
after RPE (retrospective study, n=162)
No biochemical recurrence
Wiegel et al., IJROBP 2008
Radiotherapy at biochemical recurrence
after RPE (retrospective study, n=162)
No biochemical recurrence
Wiegel et al., IJROBP 2008
Salvage RTX at PSA progression: long-term efficacy
Literature review
35-54 %
Bottke and Wiegel, Urologe 2008
Arguments pro delayed radiotherapy for
positive surgical margins
• Questionable survival advantage for
immediate adjuvant RTX
• Sparing of side effects and costs in
about 50 % of patients
• Improved risk stratification by monitoring of
PSA value and PSA kinetics
• High rate of disease control with timely
applied salvage therapy
Adjuvant vs. Salvage Radiotherapy
after Radical Prostatectomy
Adjuvant vs. Salvage Radiotherapy
Matched-control analysis (n=192)
Five-year freedom from
biochemical failure
from end of RT
Trabulsi et al., Urology 2008
Adjuvant vs. Salvage Radiotherapy
Matched-control analysis (n=192)
Five-year freedom from
biochemical failure
from end of surgery
Trabulsi et al., Urology 2008
Adjuvant and Salvage RTX after RPE
Biochemical failure free survival
Adjuvant RT
Salvage RT
n=410
Jereczek-Fossa, IntJRadOncol 2008
Adjuvant and Salvage RTX after RPE
Grade 2 or greater rectal and urinary toxicity
n=410
Adjuvant RT
Salvage RT
Jereczek-Fossa, IntJRadOncol 2008
Adjuvant and Salvage RTX after RPE
Biochemical failure free survival
Taylor et al., IntJRadOncBiolPhys 2003
Adjuvant and Salvage RTX after RPE
Biochemical failure free survival
Adjuvant RT
Taylor et al., IntJRadOncBiolPhys 2003
Adjuvant and Salvage RTX after RPE
Biochemical failure free survival
Salvage RT +/adj. androgen ablation
Taylor et al., IntJRadOncBiolPhys 2003
Adjuvant RTX for pN+
disease?
Conclusions: This study is the first to report a significant
protective role for adjuvant RT in BCR-free survival and
CSS of node-positive patients.
Da Pozzo et al., Eur Urol 2009
Adjuvant RTX for pN+ disease
(retrospective study, n=250)
No biochemical failure
Da Pozzo et al., Eur Urol 2009
Adjuvant RTX for pN+ disease
(retrospective study, n=250)
PCA-specific survival
Da Pozzo et al., Eur Urol 2009
RT for PSA-Recurrence after RPE:
Dosage?(n=122)
No new PSA-recurrence
p<0.0001
0
3
6y
King et al. IJROBP 2008
RT in prostate cancer induces secondary
malignancies (n=130.375 vs. 375.235)
!
odds-ratio for secondary malignancy
2
1.5
1.89 (1.85-1.95)
1
0.5
0
PCA, no RT
PCA, RT
Chamie et al., AUA 2008 #393
Risk stratification?
Biological heterogeneity of R1 disease:
risk of failure after 2 years, nomogram (n=2911)
Failure risk:
6%
65 %
!
Walz et al., J Urol 2009
Summary
• definite evidence for adjuvant RTX for
margin-positive disease is still pending
• patients should be informed on the
significance of the presently available results
from randomized trial
• stratification by recurrence risk is a plausible
but not yet proven concept to select patients
• with “temporarily delayed” RTX at PSA
relapse, early onset is needed to maintain the
chance of durable remission
Adjuvant hormonal
therapy?
Prospective randomised study: flutamide vs. control
after RPE in pT3-4 pN0 (n=309)
recurrence-free survival [%]
survival [%]
100
100
80
80
60
60
40
40
Flutamide, n=152
20
control,
n=157
20
log-rank-Test, p=0.0041
0
0
100
200
300
400
log-rank-Test, p=0.92
500
600
0
0
100
200
300
400
500
600
weeks after RPE
Wirth et al., Eur Urol 2004
EPC program: objective progression
(prospective randomised trial, n=8116, FU 7.4 y)
McLeod et al., BJU Int 2006
EPC program: overall survival
(prospective randomised trial, n=8116, FU 7.4 y)
McLeod et al., BJU Int 2006
Adjuvant hormonal therapy
after RPE for pN+-PCa (randomised trail, n=98, FU 11.9 y)
Messing et al., Lancet Oncol 2006
Adjuvant hormonal therapy after RPE
author, year
stage
regimen
progression
survival
Messing et al.,
1999, 2003
pN+
orchiectomy
or LHRHanalog
benefit
benefit
stage C
LHRHanalog
benefit
no data
available
pT34pN0
flutamide
benefit
no
difference
T1b-T4
bicalutamide
benefit
no
difference
Prayer-Galetti et al.,
2000
Wirth et al., 2004
Mc Leod et al., 2006
BACKUP
Adjuvant or Salvage
Radiotherapy after Radical
Prostatectomy
M. Wirth
Klinik und Poliklinik für Urologie
PSA-relapse after RPE in locally
advanced PCa (n=2091)
% PSA-relapse (0.2 ng/ml) after 10 years
100
80
60
preop. PSA
40
20+ ng/ml
10.1-20 ng/ml
4.1-10 ng/ml
0-4 ng/ml
20
0
6-
3+4
4+3
8-10
Gleason-Score
Han, Partin et al., J Urol 2003
cT3: MSKCC-Nomogramm: pT Stage
Exampel: cT3, PSA 10 ng/ml, Gleason 4+4=8
extracapsular: 82 %
organconfined: 18 %
Ohori, Kattan et al., J Urol 2004
cT3: MSKCC-Nomogramm:pT-Stage
Exampel: cT3, PSA 10 ng/ml, Gleason 3+3=6
organconfined: 50 %
extracapsular: 50 %
Ohori, Kattan et al., J Urol 2004
RPE with and without adjuvant RT
in pT3-PCA
Bottke and Wiegel, Urol Int 2007
Adjuvant RTX for T3N0M0 PCA –
SWOG 8794

Randomised controlled trial
 clinical T1/T2 preoperatively
 pT3 or positive margins, N0 M0
 WHO perf. status 0-2

Wait-and-see (n=211) vs.
Irradition (60-64 Gy, n=214)
Thompson et al., JUrol 2009
Adjuvant RTX for T3N0M0 PCA –
SWOG 8794
Thompson et al., JUrol 2009
wait-and-see vs. immediate postoperative
radiotherapy - EORTC trial 22911

Randomised controlled trial
 pT3 or positive margins, pN0
 age < 76 years, WHO perf. status 0-1

Wait-and-see (n=503) vs.
Irradiation (60 Gy) within 16 w. after RPE
(n=502)
Bolla et al., Lancet 2005
wait-and-see vs. immediate postoperative
radiotherapy - EORTC trial 22911






Age 65 y. (61-69)
PSA: 12.4 ng/ml (7.2-20.3)
PSA: 3 weeks after RPE, before RTX
0.2 (0.0-0.3)
median FU 5 y.
biochemical and clinical progression free
survival significantly improved after ART
overall survival with trend towards
improvement after ART,
but not (yet?) significant
Bolla et al., Lancet 2005
EORTC trial 22911
clinical progression free survival
Bolla et al., Lancet 2005
EORTC trial 22911
biochemical progression free survival
Bolla et al., Lancet 2005
EORTC trial 22911
cumulative incidence of locoreg. failure
Bolla et al., Lancet 2005
Patients who benefit from
immediate postoperative RT – EORTC trial 22911
Van der Kwast, JCO 2007
Adjuvant Radiotherapy after RPE
(ARO 96-02 / AUO AP 09/95 , pT3R0-1, PSA 0, n=108)
% PSA recurrence after 4 years
100
p<0.0001, hazard ratio 0.4
80
60
40
81 %
60 %
20
0
adjuvant RT (60 Gy)
no adjuvant RT
Wiegel et al., ASCO 2005
PSA Recurrence after RPE:
Salvage Radiotherapy vs.
Observation
Salvage radiotherapy within 2 years of
biochemical recurrence was associated
with a significant increase in CaP–
specific survival among men with a PSA
doubling time <6 months, independent of
pathological stage or Gleason score.
JAMA 2008
PCA specific survival following salvage RTX
vs observation after RPE – survival
Trock et al., JAMA 2009
PCA specific survival following salvage RTX
vs observation after RPE – survival

no salvage treatment (n=397) vs.
salvage radiotherapy (n=160) vs.
salvage radiotherapy + HT (n=78)
 significant increase of PC-specific survival
for both SRT (HR 0.32, p<0.001)
and SRT+HT (HR 0.34, p=0.003)
 improvement limited to patients with
- PSA-doubling time < 6 month
- SRT within 2 y. after recurrence
Trock et al., JAMA 2009
PSA Recurrence after RPE:
Salvage Radiotherapy vs.
Observation:
Timing?
Radiotherapy for PSA-Recurrence (n=1540)
bis 0.5 ng/ml
0.51-1.0 ng/ml
1.01-1.50 ng/ml
1.51+ ng/ml
Stephenson et al., JCO 2007
PSA Failure following Salvage Radiotherapy –
CaPSURE data
Macdonald et al., UrolOncolSemOrigInv 2008
Adjuvant Radiotherapy or after PSARecurrence (n=162)
Wiegel et al., IJROBP 2009
Adjuvant and Salvage RTX after RPE
Biochemical failure free survival
Adjuvant RT
Salvage RT
Jereczek-Fossa, IntJRadOncolBiolPhys 2008
Adjuvant and Salvage RTX after RPE
Biochemical failure free survival
Taylor et al., IntJRadOncBiolPhys 2003
RT for PSA-Recurrence after RPE:
Dosage?(n=122)
No new PSA-recurrence
p<0.0001
0
3
6 Jahre
King et al. IJROBP 2008
Radiotherapy for PSA-Recurrence(n=1540)
Stephenson et al., JCO 2007
Summary (I)
• adjuvant and Salvage-RT after RPE
both improve recurrance free
survival and offer a second chance
of cure
• adjuvant RT should be considered
in patients with positive margins
Summary (II)
• Salvage-RT should be performed at
a low PSA-level << 1.0 ng/ml
• postoperative RT has a limited
effect on patients with pN+
• optimal radiation dose unclear
BACKUP
Summary (I)
• adjuvant and salvage-RT after RPE
both improve recurrance free
survival and offer a second chance
of cure
• adjuvant RT should be considered
in patients with positive margins
Summary (II)
• salvage-RT should be performed at
a low PSA-level << 1.0 ng/ml
• postoperative RT has a limited
effect on patients with pN+
• optimal radiation dose unclear
Radiotherapy + HT vs.
hormonal Therapy alone
Adjuvant RT in pT3 PCA
(randomised study SWOG 8794, n=425)
Thompson et al., JAMA 2006
RT + hormonal therapy* vs. hormonal therapy*
alone in locally advanced PCA (n=875)
PSA recurrence (%)
*flutamide 3x250 mg/d
P<0.0001
Widmark et al., Lancet 2009
RT + Hormonal Therapy* vs. Hormonal Therapy*
alone in lokally advanced PCA (n=875)
P=0.004
Hormonal Therapy alone
Radiotherapy + Hormonal Therapy
*flutamide 3x250 mg/d
Widmark et al., Lancet 2009
Adjuvant HT* after RT in
organ confined high risk tumor *6 mo., n=206
D‘Amico et al., JAMA 2008
Short vs. long* adjuvant ADT after RT
*3 years vs. 6 months
Overall survival
Bolla et al., ASCO 2007
Adjuvant hormonal treatment after RTX for
locally advanced prostate cancer
Authors
Stages
Regimen
Progression
Survival
T1-T4N0-x
LHRH
analogues
advantage
advantage
stage C or D1
LHRH
analogues
advantage
advantage
T1-4N0-1
orchiectomy
advantage
advantage in
N1 subgroup
Hanks et al., 2003
T2b-T4,
PSA<150 ng/ml
LHRH
analogues plus
flutamide
advantage
advantage in
Gleason score
8-10 subgroup
D’Amico et al., 2004
Gleason score
7+, cT3-4 or
PSA>10 ng/ml
LHRH
analogues
advantage
advantage
Wirth et al., 2001,
McLeod et al., 2006
T1b-T4
N0-1M0
bicalutamide
advantage
advantage in
locally
advanced
disease
D’Amico et al., 2006
Localized or locally
advanced, PSA velocity
>2ng/ml/y
Not specified
advantage
advantage
Bolla et al., 1997, 2002
Pilepich et al., 1997,
Lawton et al., 2001,
Pilepich et al., 2003
Granfors et al., 1998, 2006
Increased cardiovascular mortality at
hormonal therapy after RPE (n=3262)
HR: 2.6; 95% CI: 1.4-4.7; p =0.002
<65 Jahre
65+ Jahre
Tsai et al., JNCI 2007
Negative consequences of androgen suppression in men
with comorbidities and RT in high-risk PCA
(randomised trial, n=206)
D‘Amico et al., JAMA 2008
After RPE adjuvant hormonal
therapy is not necessary!
After radiotherapy an
adjuvant hormonal therapy
is recommended(side
effects!) for at least 3
years.
Summary (I)
• good results after RPE
• adjuvant / early RT after RPE
improves recurrance free survival
and offers a second chance of cure
• neoadjuvant hormonal therapy
after RPE not necessary
Summary (II)
• adjuvant hormonal therapy after
RPE is not necessary – no survival
benefit
• radiotherapy + hormonal therapy is
recommended
• best concept of hormonal therapy
adjuvant to radiotherapy is unclear