Neadjuvant Hormonal Therapy in Men Being Treated with Radiotherapy for  Localized Prostate Cancer Mack Roach III, MD Profe...
Background <ul><li>Several prospective Phase III randomized trials have demonstrated that the addition of long-term adjuva...
All Patients Pilepich et al.  Proc Am Soc Clin Oncol . 2003;22:381(Abs1530). 0.0053 22% 13% 17% 9% Prostate Cancer Death 0...
Absolute Survival  Central Gleason 7 Years from Randomization Percent (%) 0 3 6 9 12 RT+Immediate Hormones RT+Hormones at ...
Absolute Survival Central Gleason 8-10 P =0.0061 Pilepich et al.  Proc Am Soc Clin Oncol . 2003;22:381(Abs1530). Years fro...
Purpose <ul><li>Several prospective randomized trials have demonstrated that men with localized prostate cancer benefit fr...
<ul><li>Is there consistent evidence NHT is beneficial? </li></ul><ul><li>Is there evidence of a sequence dependent biolog...
Materials and Methods <ul><li>Seven randomized trials reported in six papers including patients treated with NHT in combin...
The Features of the Major HT Trials <ul><li>In total >4300 patients were treated on all 17 arms  </li></ul><ul><li>Doses o...
The Major Features of the Trials <ul><li>RTOG trials were:  </li></ul><ul><ul><li>Larger (456-1514 vs 161-378 patients).  ...
Phase III RTOG Randomized Trials <ul><li>RTOG 8610: WP & PO RT +/- NHT </li></ul><ul><li>RTOG 9202: NHT WP+Prostate RT +/-...
Randomized Trials Using NHT Progression-free survival advantage with short follow-up 23 ng/mL 28% NR NR 33% NR NR 646 / 0 ...
Phase III RTOG Trial 8610 of Androgen Deprivation Adjuvant to Definitive Radiotherapy in Locally Advanced Carcinoma of the...
RTOG 92-02 Arm 1:  goserelin and flutamide 2 months before and during standard RT (STAD) Arm 2:  goserelin and flutamide 2...
Overall Survival All Patients RTOG 9202 Years since randomization Survival rate STAD+RT LTAD+RT 0 . 0 0 . 2 0 . 4 0 . 6 0 ...
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...
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 &...
Progression-Free Survival  Arm 2 vs Arm 4 (RTOG 9413) Years since randomization Approximately two months N&CHT+PO RT 0 . 0...
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...
Randomized Trials Using NHT Overall no difference in PSA failure rates ~10 ng/mL 50% 38% 11% ~52% ~35% 13% 0 0 378 / 378 (...
Laverdiere Scheme: Timing of Hormonal Therapy (HT) Arm (no.) Group 1 Study 1 EBRT EBRT none none none none Group 2 Study 1...
The Efficacy and Sequencing of Short Course of Androgen Suppression on Freedom from Biochemical Failure When Administered ...
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 ...
6-Month Androgen Suppression Plus Radiation Therapy vs Radiation Therapy Alone for Patients with Clinically Localized Pros...
The Results  <ul><li>Every study comparing EBRT alone vs EBRT + NHT (n=3) demonstrated a benefit to patients treated with ...
The Results <ul><li>Considering using prostate only EBRT, N&CHT appears to be equal to SAHT (9413) </li></ul><ul><li>Patie...
Model and Literature on the Impact of Short-Term NHT and EBRT on Outcome in Treatment of Clinically Localized from Prostat...
Based on the data from these studies the following conclusions seem reasonable: <ul><li>1. NHT is beneficial with EBRT in ...
Based on the data from these studies the following conclusions seem reasonable: <ul><li>5. Two to 3 months of NHT + EBRT a...
Final Conclusions <ul><li>The composite findings from these 7 prospective Phase III randomized trials are remarkable becau...
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Neadjuvant Hormonal Therapy

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  • Neadjuvant Hormonal Therapy

    1. 1. 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
    2. 2. Background <ul><li>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: </li></ul><ul><ul><li>EORTC (Bolla) </li></ul></ul><ul><ul><li>Swedish Trial N+ (Granfors)* </li></ul></ul><ul><ul><li>RTOG 8531 (Pilepich) updated </li></ul></ul>*Granfors et al. J Urol. Jun 1998;159(6):2030-2034.
    3. 3. 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)
    4. 4. 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
    5. 5. 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
    6. 6. Purpose <ul><li>Several prospective randomized trials have demonstrated that men with localized prostate cancer benefit from the use of short-term NHT in combination with EBRT </li></ul><ul><li>The optimal timing and total duration of NHT remain controversial </li></ul><ul><li>This review critically analyzes the major randomized trials incorporating NHT with EBRT reported to date </li></ul>
    7. 7. <ul><li>Is there consistent evidence NHT is beneficial? </li></ul><ul><li>Is there evidence of a sequence dependent biologic interaction between HT and EBRT? </li></ul><ul><li>Is there a sub-population of patients treated with EBRT in which NHT is not justified? </li></ul><ul><li>If justified how long should NHT be used? </li></ul><ul><li>Should adjuvant HT be added as well? </li></ul><ul><li>What volume should be irradiated? </li></ul><ul><li>Should high-risk patients receive NHT? </li></ul>All major prospective randomized trials published to date were critically reviewed in an attempt to answer the following questions:
    8. 8. Materials and Methods <ul><li>Seven randomized trials reported in six papers including patients treated with NHT in combination with EBRT on one or more arms were identified </li></ul><ul><li>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) </li></ul>
    9. 9. The Features of the Major HT Trials <ul><li>In total >4300 patients were treated on all 17 arms </li></ul><ul><li>Doses of EBRT used were similar @ 65 to 70 Gy </li></ul><ul><li>Three trials omitted pelvic EBRT in all patients (both Quebec series & Harvard series) </li></ul><ul><li>One study included WPRT in patients with a risk of + nodes >10 to 15% (Princess Margaret) </li></ul><ul><li>Two studies used WPRT in all patients (RTOG 8610 & 9202) & in the remaining study half of the patients received WPRT (RTOG 9413) </li></ul>
    10. 10. The Major Features of the Trials <ul><li>RTOG trials were: </li></ul><ul><ul><li>Larger (456-1514 vs 161-378 patients). </li></ul></ul><ul><ul><li>Patients on RTOG had more advanced Dz: </li></ul></ul><ul><ul><ul><li>Higher Median preTx PSAs </li></ul></ul></ul><ul><ul><ul><ul><li>20 to 26 vs ~10 to 12 ng/mL </li></ul></ul></ul></ul><ul><ul><ul><li>Higher T-stages with <T2c </li></ul></ul></ul><ul><ul><ul><ul><li>0 to 30% vs 52 to 100% </li></ul></ul></ul></ul><ul><ul><ul><li>Higher grade tumors GS=7-10 in: </li></ul></ul></ul><ul><ul><ul><ul><li>60 to 73% vs 28 to 74% </li></ul></ul></ul></ul>
    11. 11. Phase III RTOG Randomized Trials <ul><li>RTOG 8610: WP & PO RT +/- NHT </li></ul><ul><li>RTOG 9202: NHT WP+Prostate RT +/- Adj LHRH x 2 years </li></ul><ul><li>RTOG 9413: Four Arm Trial WP vs PO & N&CHT vs AHT (4 months) </li></ul><ul><li>RTOG 9408 (analysis pending) </li></ul><ul><ul><li>Prostate RT +/- NHT </li></ul></ul>
    12. 12. 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)
    13. 13. 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.
    14. 14. 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
    15. 15. 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
    16. 16. 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
    17. 17. 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
    18. 18. 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
    19. 19. 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
    20. 20. 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)
    21. 21. 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
    22. 22. 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.
    23. 23. 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
    24. 24. 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.
    25. 25. The Results <ul><li>Every study comparing EBRT alone vs EBRT + NHT (n=3) demonstrated a benefit to patients treated with the addition of NHT </li></ul><ul><li>One trial demonstrated no advantage to using longer NHT (3 versus 8 months) </li></ul><ul><li>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) </li></ul>
    26. 26. The Results <ul><li>Considering using prostate only EBRT, N&CHT appears to be equal to SAHT (9413) </li></ul><ul><li>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) </li></ul><ul><li>Despite variability in study design & definitions of PSA failure there is consistent evidence for a benefit to NHT in patients with intermediate risk disease </li></ul>
    27. 27. 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
    28. 28. Based on the data from these studies the following conclusions seem reasonable: <ul><li>1. NHT is beneficial with EBRT in intermed risk patients (RTOG 8610, Quebec study #1, Harvard study) </li></ul><ul><li>2. Biologic interactions between NHT & PO RT may not be sequence dependent (Arms 2 vs 4 of RTOG 9413) </li></ul><ul><li>3. Interactions between HT & WPRT are sequence dependent (Arms 1 vs 3 RTOG 9413) </li></ul><ul><li>4. NHT without long term adj HT is inadequate for very high-risk patients (RTOG 9202, subset RTOG 9413) </li></ul>
    29. 29. Based on the data from these studies the following conclusions seem reasonable: <ul><li>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) </li></ul><ul><li>6. Patients with a risk of + nodes > 15% should undergo prophylactic WP EBRT with NHT (RTOG 9413, RTOG 8610 & RTOG 9202) </li></ul><ul><li>7. High-risk patients should probably receive short-term NHT & long-term adjuvant HT (RTOG 9413, RTOG 9202, RTOG 8610) </li></ul><ul><li>8. The role of NHT in low-risk patients has not been defined (RTOG 9408) </li></ul>
    30. 30. Final Conclusions <ul><li>The composite findings from these 7 prospective Phase III randomized trials are remarkable because: </li></ul><ul><ul><li>There are NO contradictory studies </li></ul></ul><ul><ul><li>As a body of evidence they should establish a standard of care </li></ul></ul><ul><ul><li>Few comparable examples of evidence-based practices can be found elsewhere in GU Oncology </li></ul></ul>
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