Neadjuvant Hormonal Therapy

Neadjuvant Hormonal Therapy in Men Being Treated with Radiotherapy for Localized Prostate Cancer Mack Roach III, MD Professor, Radiation Oncology & Urology University of California, San Francisco UCSF/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)
Swedish Trial N+ (Granfors)*
RTOG 8531 (Pilepich) updated
*Granfors et al. J Urol. Jun 1998;159(6):2030-2034.

All Patients Pilepich et al. Proc Am Soc Clin Oncol . 2003;22:381(Abs1530). 0.0053 22% 13% 17% 9% Prostate Cancer Death 0.0043 38% 71% 47% 76% Absolute Survival <0.0001 22% 44% 36% 62% NED Survival <0.0001 39% 29% 25% 15% Distant Failure <0.0001 39% 30% 23% 15% Local Failure P 10 yr 5 yr 10 yr 5 yr RT+HT at Relapse (n=468) RT+ Adj LHRH (n=477)

Absolute Survival Central Gleason 7 Years from Randomization Percent (%) 0 3 6 9 12 RT+Immediate Hormones RT+Hormones at Relapse P =0.042 Pilepich et al. Proc Am Soc Clin Oncol . 2003;22:381(Abs1530). 0 25 50 75 100

Absolute Survival Central Gleason 8-10 P =0.0061 Pilepich et al. Proc Am Soc Clin Oncol . 2003;22:381(Abs1530). Years from Randomization Percent (%) 0 3 6 9 12 RT+Immediate Hormones RT+Hormones at 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

Is there consistent evidence NHT is beneficial?
Is there evidence of a sequence dependent biologic interaction between HT and EBRT?
Is there a sub-population of patients treated with EBRT in which NHT is not justified?
If justified how long should NHT be used?
Should adjuvant HT be added as well?
What volume should be irradiated?
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

Randomized Trials Using NHT Progression-free survival advantage with short follow-up 23 ng/mL 28% NR NR 33% NR NR 646 / 0 0 1291 / 645 Roach (2003) RTOG 9413 Disease-specific survival and Overall for GS = 8-10. 20 ng/mL 40% 35% 26% 0 45% 55% 0 / 753 0 1514 / [761 vs 753 (+adjuvant)] Hanks (2003) RTOG 9202 Survival advantage for GS <7, Included N+ patients 26 ng/mL - - 28% 0% 30% 70% 0 / 0 230 456 / 226 Pilepich (2001) RTOG 8610 Comments: PreTx PSA (Med)^ GS# 2-6 7 8-10 T-Stages T1-2b T2c T3-4 Short / Long Term Adjuvant HT (no.) No HT Total / No. patients with NHT +/- concurrent HT First Author (Year)

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 Survival (%) Gleason 2-6 Years P =0.015 Pilepich MV et al. Int J Radiat Oncol Biol Phys 2001; 50(5): 1243-52.

RTOG 92-02 Arm 1: goserelin and flutamide 2 months before and during standard RT (STAD) Arm 2: goserelin and flutamide 2 months before and during standard RT, followed by goserelin alone for 24 months (LTAD) T2c-T4 PreRx PSA <150 ng/mL R A N D O M I Z E

Overall Survival All Patients RTOG 9202 Years since randomization Survival rate STAD+RT LTAD+RT 0 . 0 0 . 2 0 . 4 0 . 6 0 . 8 1 . 0 0 1 2 3 4 5 6 7 8 159 22 169 28 P =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 Survival Rate P =0.006

RTOG 9413 Scheme: Timing First Month HT T 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 Second Month Third Month Fourth Month Fifth Month Sixth Month

Progression-Free Survival Arm 2 vs Arm 4 (RTOG 9413) Years since randomization Approximately two months N&CHT+PO RT 0 . 0 0 . 2 0 . 4 0 . 6 0 . 8 1 . 0 0 1 2 3 4 5 Non-failure rate PO RT+AHT

Progression-Free Survival Arm 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-failure rate N&CHT+WP RT N&CHT+PO RT

Randomized Trials Using NHT Overall no difference in PSA failure rates ~10 ng/mL 50% 38% 11% ~52% ~35% 13% 0 0 378 / 378 (3 vs 8 months) Crook (2004) Princess Margaret Overall & disease specific survival advantage 11 ng/mL 35% 59% 15% 100%, 0% 0 / 0 102 206 / 104 D’Amico (2004) Harvard Study PSA failure rates higher with EBRT alone, otherwise no difference s 10 ng/mL 12 ng/mL (7-10) = 26%^ (7-10) = 28% NA NA 30% NA NA 13.5% 55 / 0 148 / 0 43 0 161 / 63 296 / 148 (3 months) Laverdeire (2004) Quebec Trials Comments: PreTx PSA (Med) GS# 2-6 7 8-10 T-Stages T1-2b T2c T3-4 Short / Long Term Adjuvant HT (no.) No HT Total / No. patients with NHT +/- concurrent HT First Author (Year)

Laverdiere Scheme: Timing of Hormonal Therapy (HT) Arm (no.) Group 1 Study 1 EBRT EBRT none none none none Group 2 Study 1 HT HT H T EBRT EBRT none Group 3 Study 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. First Month Second Month Third Month Fourth Month Fifth Month 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 bNED Survival (%) 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 1 Study 2 HT HT HT HT EBRT HT EBRT none Group 2 Study 2 HT HT HT HT EBRT HT EBRT HT* *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.) First Month Second Month Third Month Fourth Month Fifth Month 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 Survival (%) 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

Model and Literature on the Impact of Short-Term NHT and EBRT on Outcome in Treatment of Clinically Localized from Prostate Cancer RTOG 9413 RTOG 9202 RTOG 8610 Princess Margaret Quebec Studies Harvard Study Relative Extent of Disease -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 Survival Impact of Disease on survival Net Impact of Dz & HT

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 receive short-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 studies
As a body of evidence they should establish a standard of care
Few comparable examples of evidence-based practices can be found elsewhere in GU Oncology

Neadjuvant Hormonal Therapy

by fondas vak on Mar 10, 2010

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