neadjuvant hormonal therapy
TRANSCRIPT
Neadjuvant Hormonal Therapyin Men Being Treated with
Radiotherapy for Localized Prostate Cancer
Mack Roach III, MDProfessor, Radiation Oncology & Urology
University of California, San FranciscoUCSF/Mt. Zion NCI-Designated Comprehensive Cancer Center
San Francisco, California
Background
Several prospective Phase III randomized trials have demonstrated that the addition of long-term adjuvant HT to EBRT prolongs survival for patients with high-risk Prostate Cancer, including:– EORTC (Bolla)EORTC (Bolla)– Swedish Trial N+ (Granfors)*Swedish Trial N+ (Granfors)*– RTOG 8531 (Pilepich) updatedRTOG 8531 (Pilepich) updated
*Granfors et al. J Urol. Jun 1998;159(6):2030-2034.
All Patients
RT+ Adj LHRH RT+ Adj LHRH (n=477)(n=477)
RT+HT at RT+HT at Relapse Relapse (n=468)(n=468)
5 yr5 yr 10 yr10 yr 5 yr5 yr 10 yr10 yr PP
Local FailureLocal Failure 15%15% 23%23% 30%30% 39%39% <0.0001<0.0001
Distant FailureDistant Failure 15%15% 25%25% 29%29% 39%39% <0.0001<0.0001
NED SurvivalNED Survival 62%62% 36%36% 44%44% 22%22% <0.0001<0.0001
Absolute Absolute SurvivalSurvival
76%76% 47%47% 71%71% 38%38% 0.00430.0043
Prostate Cancer Prostate Cancer DeathDeath
9%9% 17%17% 13%13% 22%22% 0.00530.0053
Pilepich et al. Proc Am Soc Clin Oncol. 2003;22:381(Abs1530).
Years from Randomization
Per
cent
(%
)
0 3 6 9 12
RT+ImmediateHormones
RT+Hormonesat Relapse
P=0.042
Absolute Survival Central Gleason 7
Pilepich et al. Proc Am Soc Clin Oncol. 2003;22:381(Abs1530).
0
25
50
75
100
P=0.0061
Absolute SurvivalCentral Gleason 8-10
Pilepich et al. Proc Am Soc Clin Oncol. 2003;22:381(Abs1530).
Years from Randomization
Per
cent
(%
)
0 3 6 9 12
RT+ImmediateHormones
RT+Hormonesat Relapse
0
25
50
75
100
Purpose
Several prospective randomized trials have demonstrated that men with localized prostate cancer benefit from the use of short-term NHT in combination with EBRT
The optimal timing and total duration of NHT remain controversial
This review critically analyzes the major randomized trials incorporating NHT with EBRT reported to date
1. Is there consistent evidence NHT is beneficial?
2. Is there evidence of a sequence dependent biologic interaction between HT and EBRT?
3. Is there a sub-population of patients treated with EBRT in which NHT is not justified?
4. If justified how long should NHT be used?
5. Should adjuvant HT be added as well?
6. What volume should be irradiated?
7. Should high-risk patients receive NHT?
All major prospective randomized trials published to date were critically reviewed in an
attempt to answer the following questions:
Materials and Methods
Seven randomized trials reported in six papers including patients treated with NHT in combination with EBRT on one or more arms were identified
In total 17 arms compared either EBRT alone (n=3); NHT & concurrent hormonal therapy (N&CHT) (n=12) +/- short-term adjuvant hormonal therapy (SAHT) (n=5) or long term HT (n=1)
The Features of the Major HT Trials
In total >4300 patients were treated on all 17 arms Doses of EBRT used were similar @ 65 to 70 Gy Three trials omitted pelvic EBRT in all patients
(both Quebec series & Harvard series) One study included WPRT in patients with a risk
of + nodes >10 to 15% (Princess Margaret) Two studies used WPRT in all patients (RTOG
8610 & 9202) & in the remaining study half of the patients received WPRT (RTOG 9413)
The Major Features of the Trials
RTOG trials were: – Larger (456-1514 vs 161-378 patients). – Patients on RTOG had more advanced Dz:
Higher Median preTx PSAs– 20 to 26 vs ~10 to 12 ng/mL
Higher T-stages with <T2c– 0 to 30% vs 52 to 100%
Higher grade tumors GS=7-10 in: – 60 to 73% vs 28 to 74%
Phase III RTOG Randomized Trials
RTOG 8610: WP & PO RT +/- NHT RTOG 9202: NHT WP+Prostate RT +/-
Adj LHRH x 2 years RTOG 9413: Four Arm Trial WP vs PO &
N&CHT vs AHT (4 months) RTOG 9408 (analysis pending)
– Prostate RT +/- NHT
First Author (Year)
Total / No. patients with NHT +/- concurrent HT
No HT
Short / Long Term Adjuvant HT (no.)
T-StagesT1-2bT2cT3-4
GS#2-67
8-10
PreTx PSA
(Med)^Comments:
Pilepich (2001) RTOG 8610
456 / 226 230 0 / 00%
30%70%
--
28%26
ng/mL
Survival advantage for
GS <7, Included N+
patients
Hanks (2003) RTOG 9202
1514 / [761 vs753 (+adjuvant)] 0 0 / 753
045%55%
40%35%26%
20 ng/mL
Disease-specific
survival and Overall for GS = 8-10.
Roach (2003) RTOG 9413
1291 / 645 0 646 / 033%NRNR
28%NRNR
23 ng/mL
Progression-free survival advantage with short follow-up
Randomized Trials Using NHT
Phase III RTOG Trial 8610 of Androgen Deprivation Adjuvant to Definitive Radiotherapy in Locally
Advanced Carcinoma of the Prostate
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6 7 8
RT + NHT
RT alone
Sur
viva
l (%
) G
leas
on 2
-6
Years
P=0.015
Pilepich MV et al. Int J Radiat Oncol Biol Phys 2001; 50(5): 1243-52.
Arm 1:Arm 1: goserelin and flutamide goserelin and flutamide2 months before and during 2 months before and during standard RT (STAD)standard RT (STAD)
Arm 2:Arm 2: goserelin and flutamide goserelin and flutamide2 months before and during2 months before and duringstandard RT, followed bystandard RT, followed bygoserelin alone for 24 months (LTAD)goserelin alone for 24 months (LTAD)
T2c-T4T2c-T4PreRx PSA PreRx PSA
<150 <150 ng/mLng/mL
RANDOMIZE
RTOG 92-02
Overall SurvivalAll Patients RTOG 9202
Years since randomization
Sur
viva
l rat
e
STAD+RT
LTAD+RT0.0
0.2
0.4
0.6
0.8
1.0
0 1 2 3 4 5 6 7 8
159 22
169 28P=0.73
9202 Prostate Cancer Survival
0.0
0.2
0.4
0.6
0.8
1.0
0 1 2 3 4 5 6 7 8
Failed/Total
STAD+RT 87/762
LTAD+RT 55/755
Years Since Randomization
Sur
viva
l Rat
e
P=0.006
RTOG 9413 Scheme: Timing
FirstMonth
HTT HT HT HT none none
EBRT EBRT none none
HT HT HT HT
EBRT EBRT
Arms 1 & 2
Arms 3 & 4
2 months different Rx duration
SecondMonth
ThirdMonth
FourthMonth
FifthMonth
SixthMonth
Progression-Free Survival Arm 2 vs Arm 4 (RTOG 9413)
Years since randomizationApproximatelytwo months
N&CHT+PO RT
0 .0
0 .2
0 .4
0 .6
0 .8
1 .0
0 1 2 3 4 5
Non
-fai
lure
rat
e
PO RT+AHT
Progression-Free SurvivalArm 1 vs Arm 2 (RTOG 9413)
Years since randomization
0 .0
0 .2
0 .4
0 .6
0 .8
1 .0
0 1 2 3 4 5
Non
-fai
lure
rat
e
N&CHT+WP RTN&CHT+PO RT
Randomized Trials Using NHT
First Author (Year)
Total / No. patients with NHT +/- concurrent HT
No HT Short / Long Term Adjuvant HT (no.)
T-Stages
T1-2b
T2c
T3-4
GS#
2-6
7
8-10
PreTx PSA
(Med) Comments:
Laverdeire (2004)
Quebec Trials
161 / 63
296 / 148(3 months)
43
0
55 / 0
148 / 0
NA
NA
30%
NA
NA
13.5%
(7-10) = 26%^
(7-10) = 28%
10 ng/mL
12 ng/mL
PSA failure rates higher with EBRT
alone, otherwise no difference s
D’Amico (2004)
Harvard Study
206 / 104 102 0 / 0 100%,
0%
35%
59%
15%11
ng/mL
Overall & disease specific survival
advantage
Crook (2004)
Princess Margaret
378 / 378 (3 vs 8 months)
0 0
~52%
~35%
13%
50%
38%
11%~10
ng/mL
Overall no difference in PSA failure
rates
Laverdiere Scheme:Timing of Hormonal Therapy (HT)
Arm (no.)
Group 1Study 1
EBRT EBRT none none none none
Group 2Study 1
HT HT HT EBRT EBRT none
Group 3Study 1
HT HT HT HT
EBRT
HT
EBRT
HT*
Maximum field size 10 x 10 cm to 64 Gy.
*HT = Combined Androgen Blockade with a LHRH & Flutamide
*10 months. Laverdiere J et al. J Urol 2004; 171(3): 1137-40.
FirstMonth
SecondMonth
ThirdMonth
FourthMonth
FifthMonth
Sixth-Tenth
The Efficacy and Sequencing of Short Course of Androgen Suppression on Freedom from Biochemical Failure When
Administered with Radiation Therapy for T2-T3 Prostate Cancer
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0
Months
bNE
D S
urvi
val (
%)
3 month NHT
N&CHT+Adj (10 months)
EBRT Alone
Laverdiere J et al. J Urol 2004; 171(3): 1137-40.
Laverdiere Scheme: Timing of Hormonal Therapy (HT)
Group 1Study 2 HT HT HT
HT
EBRT
HT
EBRTnone
Group 2Study 2 HT HT HT
HT
EBRT
HT
EBRTHT*
*HT = Combined Androgen Blockade with a LHRH & Flutamide
Maximum field size 10 x 10 cm to 64 Gy.
*10 months. Laverdiere J et al. J Urol 2004; 171(3): 1137-40.
Arm (no.) FirstMonth
SecondMonth
ThirdMonth
FourthMonth
FifthMonth
Sixth-Tenth
6-Month Androgen Suppression Plus Radiation Therapy vs Radiation Therapy Alone for Patients
with Clinically Localized Prostate Cancer
0
10
20
30
40
50
60
70
80
90
100
0.0 1.0 2.0 3.0 4.0 5.0 6.0
3D-CRT + Hormones
3D-RT alone
Sur
viva
l (%
)
Years
P=0.04
D’Amico et al. JAMA. 2004;292:821-827.
The Results
Every study comparing EBRT alone vs EBRT + NHT (n=3) demonstrated a benefit to patients treated with the addition of NHT
One trial demonstrated no advantage to using longer NHT (3 versus 8 months)
Two studies demonstrated no benefit to adding concurrent & short-term adjuvant HT (3 months NHT vs N&C&SAHT (total time, 10 months) &5 months N&CHT vs N&C&SAHT (10 months)
The Results
Considering using prostate only EBRT, N&CHT appears to be equal to SAHT (9413)
Patients with very high-risk disease did better if treated with longer term adjuvant HT (n=1) &a trend to do better with longer NHT (8 months) (n=1) (P >0.05)
Despite variability in study design & definitions of PSA failure there is consistent evidence for a benefit to NHT in patients with intermediate risk disease
RTOG 9413
RTOG 9202RTOG 8610
Princess Margaret
Quebec StudiesHarvard Study
Rel
ativ
e E
x ten
t o f
Dis
ease
-50
-40
-30
-20
-10
0
10
20
30
40
Low Risk Intermediate High Risk Very High Risk Dz
Impact of Short Term NHT on SurvivalImpact of Disease on survivalNet Impact of Dz & HT
Model and Literature on the Impact of Short-TermNHT and EBRT on Outcome in Treatment ofClinically Localized from Prostate Cancer
Based on the data from these studies the following conclusions seem reasonable:
1. NHT is beneficial with EBRT in intermed risk patients (RTOG 8610, Quebec study #1, Harvard study)
2. Biologic interactions between NHT & PO RT may not be sequence dependent (Arms 2 vs 4 of RTOG 9413)
3. Interactions between HT & WPRT are sequence dependent (Arms 1 vs 3 RTOG 9413)
4. NHT without long term adj HT is inadequate for very high-risk patients (RTOG 9202, subset RTOG 9413)
Based on the data from these studies the following conclusions seem reasonable:
5. Two to 3 months of NHT + EBRT appears to be adequate for intermediate risk patients with no additional benefit with concurrent & / or SAHT(Quebec studies, Princess Margaret study)
6. Patients with a risk of + nodes > 15% should undergo prophylactic WP EBRT with NHT(RTOG 9413, RTOG 8610 & RTOG 9202)
7. High-risk patients should probably receiveshort-term NHT & long-term adjuvant HT(RTOG 9413, RTOG 9202, RTOG 8610)
8. The role of NHT in low-risk patients has not been defined (RTOG 9408)
Final Conclusions
The composite findings from these 7 prospective Phase III randomized trials are remarkable because:– There are NO contradictory studiesThere are NO contradictory studies– As a body of evidence they should establish a As a body of evidence they should establish a
standard of carestandard of care– Few comparable examples of evidence-based Few comparable examples of evidence-based
practices can be found elsewhere in GU practices can be found elsewhere in GU OncologyOncology