Radiation Oncology/Prostate/Hormones/Adjuvant ADT

Combined Androgen Deprivation Therapy and RT

Summary of hormonal results

 * Combined effect of ADT and RT (both cell kill and re-growth velocity) is largest when ADT is done prior to RT, based on animal studies
 * Based on a Canadian trial, 3 months neoadjuvant ADT has same outcome as 8 months neoadjuvant ADT. Benefit for high-risk patients with 8 months likely due to duration, not the fact it was neoadjuvant (i.e. similar benefit might have been seen with 8 months NACHT-ADJ strategy)
 * For high risk - adjuvant hormonal therapy improves survival (RTOG 85-31, EORTC, RTOG 92-02 for G8-10, EPC for locally advanced). Survival benefit seen for both castration-based therapy (RTOG, EORTC) and non-castration based therapy (EPC)
 * Intermediate risk - neoadjuvant/concurrent hormonal therapy may improve survival (RTOG 86-10 for G2-6, bulky (T2-4), N-/+; Harvard)
 * Low risk - no benefit of hormones; RTOG 94-08 maturing

NCCN Guidelines (v2.2011):
 * Low risk: No ADT
 * Intermediate risk: RT +/- short term neoadjuvant/concomitant/adjuvant ADT (4-6 months)
 * High risk: RT + long-term neoadjuvant/concomitant/adjuvant ADT (2-3 years) (category 1)
 * Locally Advanced: RT + Long-term neoadjuvant/concomitant/adjuvant ADT (2-3yrs) (category 1)

Radiobiology

 * Fox Chase; 2003 PMID 12909211 -- "Effect of sequencing of androgen deprivation and radiotherapy on prostate cancer growth." (Kaminski JM, Int J Radiat Oncol Biol Phys. 2003 Sep 1;57(1):24-8.)
 * Rat prostate tumors. Orchiectomy done for ADT, androgen restoration with testosterone implants on day 14. RT 7/1. Seven groups: Sham (ADT + testosterone day 0), ADT (ADT -> testosterone day 14), RT alone day 7, RT alone day 3, RT during ADT, RT before ADT, RT after ADT. Doubling time evaluated
 * Outcome: Group 1 (sham) shortest Td (5.4 days); Group 7 (RT after ADT) longest Td (32.6 days); Groups 2-6 similar
 * Conclusion: Neoadjuvant ADT prolonged suppresion of tumor growth, even after testosterone replacement


 * Harvard; 1997 PMID 9276373 -- "Androgen deprivation and radiation therapy: sequencing studies using the Shionogi in vivo tumor system." (Zietman AL, Int J Radiat Oncol Biol Phys. 1997 Jul 15;38(5):1067-70.)
 * Shionogi adenocarcinoma, androgen dependent, grown as allograft in SCID mice. Bilateral orchiectomy done for ADT. Orchiectomy done either neoadjuvant (12 days prior to RT) or adjuvant (1-12 days post RT)
 * Outcome: TCD50 significantly lower if ADT prior to RT
 * Conclusion: Sequence/timing of RT and ADT crucial

Neoadjuvant and concurrent androgen deprivation

 * TROG 96.01 (Trans Tasman Radiation Oncology Group; Australia)(1996-2000) -- ADT None vs 3 months vs 6 months
 * Note: possible name confusion with RTOG 96-01, which is a post-prostatectomy salvage RT trial.
 * Randomized. 802 men with locally advanced PCA (T2b-T4N0). Treated with 1) RT alone 66/33 vs. RT + 3 month AST (goserelin+flutamide starting 2 months prior to RT) vs. RT + 6 months AST (starting 5 months prior to RT).
 * 2005 PMID 16257791 -- "Short-term androgen deprivation and radiotherapy for locally advanced prostate cancer: results from the Trans-Tasman Radiation Oncology Group 96.01 randomised controlled trial." (Denham JW, Lancet Oncol. 2005 Nov;6(11):841-50.) Median F/U 5.9 years
 * 5-year outcomes: bF 0 mo 14% vs. 3 mo 20% (SS) vs. 6 mo 21% (SS, NS) Local failure: 10% vs. 6% (SS) vs. 4% (SS, NS); distant failure 7% vs. 8% (NS) vs. 5% (SS, SS); PCA-specific survival: 34% vs. 35% (NS) vs. 35% (NS)
 * Conclusion: 6 months AST before/during improves outlook of patients with locally advanced PCA. 3 months and 6 months comparable with local control, 6 months benefit for distant mets and freedom from salvage
 * Surrogate endpoints; 2008 PMID 18929505 -- "Time to biochemical failure and prostate-specific antigen doubling time as surrogates for prostate cancer-specific mortality: evidence from the TROG 96.01 randomised controlled trial."
 * TTBF and PSADT can be useful as surrogate endpoints for prostate cancer-specific mortality
 * False failures; 2009 PMID 19176272 -- "Recognizing false biochemical failure calls after radiation with or without neo-adjuvant androgen deprivation for prostate cancer" (Denham JW, Int J Radiat Oncol Biol Phys. 2009 Jun 1;74(2):404-11. Epub 2009 Jan 26.)
 * Comparison of ASTRO (61%) vs. Pheoenix (58%) failure. ASTRO 16% false failure, Phoenix 8% false failures. Most associated with "plateuing" in PSA values after nadir. Particularly common in ADT arms
 * Conclusion: Phoenix definition 50% less false failures compared with ASTRO definition. Failures should be confirmed by further PSA rise, since may be part of plateau process
 * PSA Variables; 2010 PMID 20350786 -- "A Comparison of the Prognostic Value of Early PSA Test-Based Variables Following External Beam Radiotherapy, with or without Preceding Androgen Deprivation: Analysis of Data from the TROG 96.01 Randomized Trial." (Lamb DS, Int J Radiat Oncol Biol Phys. 2010 Mar 27. [Epub ahead of print])
 * Retrospective. PSA-related variables evaluated for prognostic impact: initial PSA (iPSA), PSA at 2 months (2PSA), PSA (4PSA) at 4 months, PSA nadir (nPSA). Endpoints bPFS, local progression, DM, CSS
 * Outcome: nPSA powerful predictor of all outcomes; iPSA, 2PSA and 4PSA only predicted for bPFS. nPSA correlated with iPSA, GS, and T-stage, and were significantly higher in men not treated with ADT
 * Conclusion: Post-RT PSA nadir is the strongest prognostic indicator for outcome
 * 10-years; 2011 PMID 21440505 -- "Short-term neoadjuvant androgen deprivation and radiotherapy for locally advanced prostate cancer: 10-year data from the TROG 96.01 randomised trial." (Denham JW, Lancet Oncol. 2011 May;12(5):451-9.) -- Median F/U 10.6 y
 * Both 3-mo and 6-mo NADT lead to a decrease in PSA progression, decreased local progression, and improved EFS compared to RT alone. In the 6-mo arm, there was a greater improvement for these 3 outcomes compared to the 3-mo arm.
 * For the 6-mo arm only, there was improved distant progression (HR 0.49), prostate cancer-specific mortality (0.49), and overall survival (0.63); these were no improvement seen in the 3-mo arm (0.89, 0.86, 0.84).
 * No increase in treatment-related morbidity with NADT.
 * Conclusion: 6 months of neoadjuvant androgen deprivation is an effective treatment option for locally advanced prostate cancer


 * Harvard (DFCI 95096) (1995-2001) - 6 months vs. no ADT
 * Randomized. 206 men. Intermediate/High Risk: T1b-T2b (1992 staging), PSA >= 10 or Gleason >= 7; allowed low risk pts (n=5) if radiographic ECE/SVI based on endorectal MRI. Arm 1) 70 Gy 3D XRT (did not treat the pelvis) vs. Arm 2) 6 months androgen suppression (leuprolide/goserelin + flutamide) beginning 2 months prior to RT.
 * 5-years; 2004 PMID 15315996 &mdash; "6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial." (D'Amico et al. JAMA. 2004 Aug 18;292(7):821-7.) Median F/U 4.5 years
 * Outcome: 5-year OS RT+AST 88% vs RT alone 78% (SS). 5-year survival free of salvage androgen suppression 82% vs 57% (SS). Decreased cancer-specific mortality.
 * Conclusion: Addition of 6 months of AST confers survival benefit
 * 8-years; 2008 PMID 18212313 -- "Androgen suppression and radiation vs radiation alone for prostate cancer: a randomized trial." (D'Amico AV, JAMA. 2008 Jan 23;299(3):289-95.)
 * Postrandomization evaluation of comorbidity impact via ACE-27. Comorbidity none 66%, minimal 11%, moderate 22%, severe 12%. Median F/U 7.6 years
 * Outcome: 8-year OS RT+AST 74% vs. RT alone 61% (SS); PCA-specific mortality significantly better (HR 4.1)
 * Comorbidity: None/minimal OS 90% vs. 64% (SS); moderate/severe OS 25% vs. 54% (NS)
 * Conclusion: Addition of 6 months AST increases OS, though possibly only in men with no/minimal comorbidities
 * ADT Duration; 2008 PMID 18565884 -- "Risk of prostate cancer recurrence in men treated with radiation alone or in conjunction with combined or less than combined androgen suppression therapy." (D'Amico AV, J Clin Oncol. 2008 Jun 20;26(18):2979-83.)
 * Post-hoc analysis. Does duration of ADT impact risk of PSA failure. Groups adjusted for known prognostic factors (PSA level, GS 8-10, cT2). Median F/U 8.2 years
 * Outcome: Each additional ADT month, decreased risk (HR 0.81, SS) of PSA failure
 * Conclusion: Increased risk of recurrence with <6 compared with 6 months of ADT
 * Comorbidities; 2009 PMID 19864082 -- "Radiation With or Without 6 Months of Androgen Suppression Therapy in Intermediate- and High-Risk Clinically Localized Prostate Cancer: A Postrandomization Analysis by Risk Group." (Nguyen PL, Int J Radiat Oncol Biol Phys. 2009 Oct 26. [Epub ahead of print])
 * Post-hoc analysis. Adult Comorbidity Evaluation 27 score used. Median F/U 8.2 year
 * Outcome: ADT benefit restricted to men with no/mild comorbidity in intermediate risk (7-year OS 91% vs. 86%, SS) and high-risk groups (89% vs. 51%, SS). No benefit in either group for men with moderate/severe comorbidity
 * Conclusion: ADT survival benefit seen only in men with no/mild comorbidity, but not in men with moderate/severe comorbidity
 * Failure PSA kinetics; 2009 PMID 19858385 -- "Evaluating the Combined Effect of Comorbidity and Prostate-Specific Antigen Kinetics on the Risk of Death in Men After Prostate-Specific Antigen Recurrence." (Wo JY, J Clin Oncol. 2009 Oct 26. [Epub ahead of print])
 * Post hoc analysis. PSA kinetics after failure reviewed. Median F/U 8.4 years
 * Outcome: 89 PSA failures (43%), all-cause deaths 74 (36%). Increasing PSA velocity at recurrence (HR 1.6, SS) and moderate/severe comorbidity (HR 7.9, SS) associated with all-cause mortality. PSA velocity at recurrence associated with all-cause mortality for no/minimal comorbidity (SS) but not for moderate/severe comorbidity (NS) patients
 * Conclusion: These findings support judicious use of salvage AST, particularly in men with moderate/severe comorbidities
 * Older men; 2010 PMID 19395186 -- "Survival following radiation and androgen suppression therapy for prostate cancer in healthy older men: implications for screening recommendations." (Nguyen PL, Int J Radiat Oncol Biol Phys. 2010 Feb 1;76(2):337-41. Epub 2009 Apr 22.)
 * Post hoc analysis. 78 healthy men older than median age 72, 24 "not healthy" men older than median age 73
 * Outcome: In healthy men (mild/no comorbidity), 8-year mortality RT+ADT 16% vs RT alone 41% (SS). In not healthy men (moderate/severe comorbidity), worse mortality (numbers not given) with RT+ADT than RT alone (HR 5.2, SS). More cardiac deaths with ADT (60% vs 29%)
 * Conclusion: In older healthy men, RT + ADT improved surival, but in men with comorbidities it worsened survival
 * Intermediate risk; 2014 PMID 24604289 -- "The likelihood of death from prostate cancer in men with favorable or unfavorable intermediate-risk disease." (Keane FK, Cancer. 2014 Mar 6. [Epub ahead of print])
 * Using subclassification proposed by Zumsteg, divided intermediate risk pts into unfavorable and favorable intermediate risk groups.
 * Included 197 of 206 pts. High risk (51 pts, 25.9%), Unfavorable Intermediate risk (102, 51.8%), Favorable Intermediate risk (44, 22.3%).
 * Median f/u 14.3 yr. 127 deaths (64.5%), 22/127 deaths from PC (17.3%) -- PCSM: 0 deaths (Fav-Int), 13 (Unfav-Int), 9 (High risk). Increased risk of PCSM for High risk vs Unfav-Int, but NS (HR 1.59). 15-yr PCSM: 20.0% (High risk), 13.1% (Unfav-Int), 0% (Fav-Int).
 * Increased PCSM for RT alone vs RT+HT (HR 4.13), SS.
 * Conclusion: "The lack of PC deaths among men with favorable intermediate-risk PC suggests that adding AST may not reduce their risk of PCSM; whereas many men with unfavorable intermediate-risk PC are at risk for harboring occult PC with Gleason scores from 8 to 10 and, if proven, would benefit from long-term AST. Multiparametric magnetic resonance imaging and targeted biopsy of suspicious lesions should be considered to identify PC with Gleason scores from 8 to 10 in these men."


 * RTOG 94-08 (1994-2001) -- 4 months vs no ADT
 * Randomized. 1979 pts. Lower risk patients (T1b-2b and PSA < 20; any Gleason). Same hormone schema as RTOG 86-10 (flutamide + Lupron/Zoladex, 2 months before + during RT). RT was to the prostate only (not pelvic LN) if PSA < 10 and Gleason 2-6 or if lymph node dissection negative (regardless of PSA). Others received pelvic RT. Total dose 66.6 Gy / 1.8 or 68.4/1.8 (if prostate only).
 * 2011 PMID 21751904 -- "Radiotherapy and short-term androgen deprivation for localized prostate cancer." (Jones CU, N Engl J Med. 2011 Jul 14;365(2):107-18.) -- Median f/u 9.1 yrs
 * Median f/u 9.1 yrs. OS at 10yrs: 62% (RT + Hormones) vs 57% (RT only), SS (HR=1.17). DSS 96% vs 93% (SS; HR 1.84). No difference in deaths from intercurrent disease. Biochemical failure (Phoenix def.) 26% vs 41% (SS, HR=1.74). Positive re-biopsy at 2 yr (of 843 pts biopsied) 21% vs 39% (SS). No increase in acute or late GI, GU, or Heme toxicity.
 * By risk groups: low risk (685 pts), int risk (1068 pts), high risk (226 pts). 8-yr OS: 76%/73% low, 72%/66% int, 66%/58% high risk; DSS 98%/99%, 98%/92%, 92%/88%; biochemical failure: 20%/30%, 25%/42%, 28%/47%.
 * All groups showed improved biochemical failure rate with hormonal therapy. For DSS and OS, largest improvement for intermediate risk group: 8-yr OS 72% vs 66% and DSS 98% vs 92%.
 * Conclusion: Addition of 4 months of HT to RT modestly improved overall survival of early stage prostate cancer pts treated with low dose RT (66 Gy). Improvement seen also in DSS, biochemical failure, and prostate re-biopsy. Intermediate risk subgroup showed the largest improvement. The use of hormones in the low risk population is not supported.


 * Quebec L-101 (1991-94) -- no ADT vs 3 months neoadjuvant vs. neoadjuvant/concurrent/adjuvant 10 months
 * Randomized. 120 patients. T2a-T4. Arm 1) RT 64/32 alone, 2) 3 months neoadjuvant combination hormonal therapy (flutamide + LHRH agonist) + RT (no concurrent), or 3) hormonal therapy 3 months before, during, and 6 months after RT. Endpoint: Biopsy recurrence at 1 year and 2 years. 1-year biopsy compliance 77%, 2-year 57%
 * 1997 PMID 9069293, 1997 &mdash; "Beneficial effect of combination hormonal therapy administered prior and following external beam radiation therapy in localized prostate cancer." (Laverdiere J et al. Int J Radiat Oncol Biol Phys 1997; 37:247-52.)
 * Outcome: 1-year biopsy rate RT 62% vs. RT + 3 months 30% vs. RT + 10 months 4% (SS). 2-year biopsy rate 65% vs. 28% vs. 5% (SS)
 * Conclusion: Higher rate of positive biopsies without ADT
 * 2004 PMID 14767287 &mdash; "The efficacy and sequencing of a short course of androgen suppression on freedom from biochemical failure when administered with radiation therapy for T2-T3 prostate cancer." (Laverdiere J et al. J Urol. 2004 Mar;171(3):1137-40.) Median F/U 5 years
 * Outcome: 7-year bNED RT 42% vs. RT + 3 months 66% (SS) vs. RT + 10 months 69% (SS, NS)
 * Conclusion: Adding short course (6 months) of adjuvant ADT after neoadjuvant/concurrent ADT provided no further advantage


 * RTOG 86-10 "Bulky Trial" (1987-91) - 4 months vs. no ADT
 * Randomized. 471 patients. Bulky primary tumors (T2-T4), palpable tumor 5 x 5 cm. Allowed LN+ if below common iliac. Allowed bulky disease (unlike 85-31). Randomized to goserelin + flutamide 2 months before and 2 months during XRT, versus no AD. XRT to 45 Gy to pelvis, with boost to 65-70 Gy. RT fields to L5/S1 level if LN- but extend to L2-L3 if LN+.
 * 5-years; 1995 PMID 7716842 &mdash; "Androgen deprivation with radiation therapy compared with radiation therapy alone for locally advanced prostatic carcinoma: a randomized comparative trial of the Radiation Therapy Oncology Group." Pilepich et al. Urology. 1995 Apr;45(4):616-23.
 * 5-year PFS 36% vs 15%. No difference in overall survival.
 * 8-years; 2001 PMID 11483335 &mdash; "Phase III radiation therapy oncology group (RTOG) trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate." Pilepich MV et al. Int J Radiat Oncol Biol Phys. 2001 Aug 1;50(5):1243-52.
 * 8-year LC 42% vs 30% (p=0.02), DM 34% vs 45% (p=0.04), DFS 33% vs 21% (p=0.004), bDFS 24% vs 10% (p<0.0001), cause-specific mortality 23% vs 31% (p=0.05), overall survival 53% vs 44% (p=0.10)
 * Beneficial effect in Gleason 2-6, with improved overall survival 70% vs 52% (p=0.015).
 * For Gleason 7-10, no improvement in LRC or OS.
 * 10-years; 2008 PMID 18172188 &mdash; "Short-Term Neoadjuvant Androgen Deprivation Therapy and External-Beam Radiotherapy for Locally Advanced Prostate Cancer: Long-Term Results of RTOG 8610." Roach M et al. J Clin Oncol 2008 Feb 1;26(4):585-91.
 * Outcome: 10-yr OS AST 43% vs control 34% (NS), median OS 8.7 vs 7.3 yrs (NS, p=0.12). Improved DSM (23% vs 36%, SS), DM (35% vs 47%, SS), DFS (11% vs 3%, SS), and BF (65% vs 80%, SS). No difference in fatal cardiac events.
 * Conclusion: Significant improvement in DFS, DSM but no difference in OS. No risk of fatal cardiac events

Concurrent + adjuvant androgen ablation

 * EORTC 22991 (2001-2008) -- RT +/- concurrent/adjuvant ADT x 6 months
 * Protocol
 * Randomized. 819 pts. Enrolled: 1) T1b-T1c N0, PSA > 10 or G ≥ 7; and 2) T2a N0 (Any G, PSA < 50). Includes intermediate risk and high risk.
 * Randomization: 1) RT alone (include 3D or IMRT; dose 70, 74, or 78 Gy physician choice). 2) RT + 6 months hormonal therapy (goserelin 3 month x 2 injections, beginning on first day of RT; bicalutamide x 1 month, starting 7 days prior to LHRH).
 * 2014 ESTRO Annual Meeting 2014 (Apr 4-8, 2014) -- "3D-CRT/IMRT with/without short term androgen deprivation in localized T1b-cT2aN0M0 prostate cancer (EORTC 22991)" (Bolla M, Abstract #OC-0522)
 * Press release
 * Median f/u 7.2 yrs. Biochemical progression reduced by 47% with RT+HT, regardless of RT dose and modality (IMRT or 3D) -- 17.5% vs 30.7%. Improved freedom from clinical progression: 88.7% vs 80.8%.
 * 2016 PMID 26976418 -- "Short Androgen Suppression and Radiation Dose Escalation for Intermediate- and High-Risk Localized Prostate Cancer: Results of EORTC Trial 22991." (Bolla M, J Clin Oncol. 2016 May 20;34(15):1748-56.)
 * Six months of concomitant and adjuvant AS improves biochemical and clinical DFS of intermediate- and high-risk prostate cancer.
 * 12-years; 2021 PMID 34310202 -- "Short Androgen Suppression and Radiation Dose Escalation in Prostate Cancer: 12-Year Results of EORTC Trial 22991 in Patients With Localized Intermediate-Risk Disease" (Bolla M, J Clin Oncol. 2021 Sep 20;39(27):3022-3033. doi: 10.1200/JCO.21.00855. Epub 2021 Jul 26.). Median F/U 12.2 years.
 * Outcome: EFS EBRT+AS 37% vs EBRT 56% (SS). Events PSA relapse 49% or death 45%. 10-year DMFS 79% vs 73% (p 0.06). 10-year OS 80% vs 74% (p=0.08)
 * Conclusion: Concominant/adjuvant AS x6 months significantly improves EFS and DFS, but not OS.
 * Comment: demonstrates improved results with addition of HT in intermediate to high risk pts despite use of higher doses of RT than previously.


 * EORTC 22863 (1987-1995) -- RT +/- concurrent/adjuvant ADT x3 years
 * Randomized. 415 patients with T1-2 WHO grade 3 (GS 8-10) or T3-4 any grade, N0-1. RT alone vs RT + concurrent/adjuvant goserelin. Goserelin monthly starting on first day of RT, total of 3 years. RT pelvis 50/25 + boost 20/10
 * 1997 PMID 9233866 - &mdash; "Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin" Bolla et al. The New England Journal Of Medicine. Volume 337, Issue 5, July 31, 1997, Pages 295-300.
 * 5-years; 2002 PMID 12126818 &mdash; "Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial." Bolla M et al. Lancet. 2002 Jul 13;360(9327):103-6. Median F/U 5.5 years
 * Outcome: 5-yr OS - RT+ADT 78% vs RT alone 62% (SS), disease-specific survival 94% vs 79%, DFS 74% vs 40% (SS).
 * Conclusion: AST during and 3 years after EBRT improves DFS and OS
 * 10-years; 2010 PMID 20933466 -&mdash; "External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study." Bolla M et al. Lancet Oncol 11: 1066-1073, 2010.
 * Outcome: 10 yr OS - RT+ADT 58.1% vs. RT alone 39.8% (SS); DFS - RT+ADT 47.7% vs. RT 22.7% (SS); CaP mortality - RT+ADT 10.3% vs. RT alone 30.4% (SS)

Neoadjuvant/Concurrent vs Adjuvant ADT

 * RTOG 94-13 (1995-99) -- 4 months NACHT vs 4 month AHT (also pelvis vs prostate RT)
 * Randomized. 1323 patients. High risk patients with estimated risk of LN involvement of 15% or more by the Roach equation and PSA < 100. Pts with T2c-T4 tumors and Gleason >=6 were allowed regardless of LN risk. 2x2 randomization. Randomized to whole-pelvic (WP) vs prostate-only (PO) RT, and combined neoadjuvant + concurrent hormonal therapy (NCHT) vs adjuvant hormonal therapy (AHT). ADT: Total androgen suppression with goserelin or leupron + flutamide. For NCHT, total of 4 months - 2 months before and 2 months during RT. For AHT, began following RT for total of 4 months. RT: Dose 70.2 Gy to prostate. For WP RT, 50.4 Gy to pelvis (16x16 field), followed by boost to prostate only. PO RT was to prostate + SV only.
 * See section under "Small vs extended fields" for more details
 * 7-years; 2007 PMID 17531401 -- "An Update of the Phase III Trial Comparing Whole Pelvic to Prostate Only Radiotherapy and Neoadjuvant to Adjuvant Total Androgen Suppression: Updated Analysis of RTOG 94-13, With Emphasis on Unexpected Hormone/Radiation Interactions." (Lawton CA, Int J Radiat Oncol Biol Phys. 2007 Nov 1;69(3):646-55.) Median F/U for alive patients 7.0 years
 * Outcome: PFS WPRT+NHT 62% vs. PORT+NHT 66% vs. WPRT+AHT 69% vs. PORT+AHT 62% (NS); also no difference in OS. By pairs, no difference between WPRT and PORT, and no difference between NHT and AHT. No difference in LF or DM
 * Toxicity: No difference in RT Grade 3+ toxicity among the 4 arms
 * Conclusion: No benefit for NHT + WPRT compared with PORT + AHT
 * Comment: the benefit of neoadjuvant hormones combined with irradiation to the pelvic lymph nodes seen initially implies that the benefit of hormones is in increasing the effectiveness of RT on the lymph nodes (which receive low dose RT) vs that of increasing local control in the prostate which receives a high dose of RT.

Adjuvant androgen deprivation

 * Casodex Early Prostate Cancer Program (EPC) (1995-1998) -- Casodex vs. placebo
 * Randomized, double blind, placebo. 8113 patients. Comprised of 3 separate trials: North America (Trial 23), Europe (Trial 24), and Scandinavia (SPCG-6, Trial 25). Pts with non-metastatic disease on bone scan, stages T1-4. Primary treatment with RT, surgery, or watchful waiting. Randomized to +/- adjuvant bicalutamide (Casodex) 150 mg. For 2 yrs (North America) or until progression (other 2 trials). Localized defined as clinical or pathological T1-T2N0-Nx, locally advanced defined as T3-T4 any N or any TN+. Surgical procedures, RT techniques, and dose-fractionation schedules not specified. Neoadjuvant hormonal therapy permitted in Trials 23-24
 * Original; 2002 PMID 12131282 &mdash; "Bicalutamide as immediate therapy either alone or as adjuvant to standard care of patients with localized or locally advanced prostate cancer: first analysis of the early prostate cancer program." See WA et al. J Urol. 2002 Aug;168(2):429-35.
 * 5-years; 2004 PMID 15540740 &mdash; "Bicalutamide 150 mg in addition to standard care in patients with localized or locally advanced prostate cancer: results from the second analysis of the early prostate cancer program at median followup of 5.4 years." Wirth MP et al. J Urol. 2004 Nov;172(5 Pt 1):1865-70.
 * RT 5-years; 2005 - PMID 16145740 &mdash; "Bicalutamide ('Casodex') 150 mg as adjuvant to radiotherapy in patients with localised or locally advanced prostate cancer: results from the randomised Early Prostate Cancer Programme." Tyrrell CJ et al. Radiother Oncol. 2005 Jul;76(1):4-10.
 * RT subset (n=1370)
 * Outcome: If locally advanced, bicalutamide improved PFS by 53% (SS). Clinical PFS bicalutamide 33% vs. placebo 49% (SS). No difference in localized disease
 * Toxicity: breast pain (75%), gynecomastia (67%) which were mild/moderate >90%
 * Conclusion: Bicalutamide significantly improved PFS in locally advanced patients; there was no significant benefit for localized patients
 * RT 7-years; 2006 PMID 16896884 -- "The addition of bicalutamide 150 mg to radiotherapy significantly improves overall survival in men with locally advanced prostate cancer." (See WA, J Cancer Res Clin Oncol. 2006 Aug;132 Suppl 1:S7-16.) Median F/U 7.2 years
 * RT subset (n=1370); locally advanced 22%, localized 78%. EBRT 93%, EBRT + BT 6%. Median EBRT dose 64 Gy
 * Outcome: Overall events bPFS 57% vs. 47% (SS), cPFS 67% vs. 61% (SS), OS 74% vs. 69% (NS)
 * Locally advanced: bicalutamide improved bPFS by 59% (SS), cPFS by 44% (SS), DSS by 24% (SS), and OS by 35% (SS).
 * Localized: no difference in cPFS or OS, benefit for bPFS 59% vs 53% (SS)
 * Conclusion: In patients with locally advanced disease, survival benefit for adjuvant Casodex, but no benefit in localized prostate cancer
 * SPCG-6; 2006 PMID 17130095 -- "Bicalutamide 150 mg in addition to standard care for patients with early non-metastatic prostate cancer: updated results from the Scandinavian Prostate Cancer Period Group-6 Study after a median follow-up period of 7.1 years." (Iversen P, Scand J Urol Nephrol. 2006;40(6):441-52.)
 * Scandinavian subset. 1218 patients. Watchful waiting 81%. Median F/U 7.1 years
 * Outcome: disease progression bicalutamide 48% vs. placebo 56% (SS), no difference in localized patients (HR 0.85, NS) but significant benefit for locally advanced patients (HR 0.47, SS). Median time-to-progression 8.8 years vs. 7.1 years. Overall survival 39% vs. 40% (NS), trend to worse outcome with bicalutamide in localized disease (HR 1.23, NS), significant benefit in locally advanced disease (HR 0.65, SS)
 * Watchful waiting group: trend to worse outcome with bicalutamide in localized disease (HR 1.18, NS), significant benefit in locally advanced disease (HR 0.67, SS)
 * Toxicity: Breast pain 64%, gynecomastia 58%, impotence 17% (vs. 7%), decreased libido 4% (vs. 1%), abnormal LFTs 3% (vs. 0.8%). Withdrawal due to adverse events 21% vs. 9%
 * Conclusion: Bicalutamide plus standard care offers significant benefit for patients with locally advanced disease, not for localized disease


 * RTOG 85-31 "High Risk Non-Bulky Trial" (1987-92) - long term (indefinite) hormones
 * Randomized. 977 patients. Scheme: XRT alone vs XRT + long-term adjuvant goserelin (Zoladex). Eligibility: cT3 or pT3 (after prostatectomy) or N+ regional nodes (including common iliac or paraaortics). Bulky patients (primary tumor volume > 25 cm by product of two dimensions) not allowed unless they had +LN outside of the pelvis (i.e. common iliac or paraaortic). (Bulky pts were enrolled on parallel study 86-10.) Hormones: Goserelin started during last week of XRT and continued monthly until progression. Radiation technique: For patients with LN+ disease within the pelvis: upper border at L5/S1 interspace, lower border 5-6 cm below pubic symphysis, lateral borders for AP/PA 2cm lateral to pelvic brim. For positive common iliac nodes, extended up to L2/L3 interspace to include paraaortic nodes.  For positive periaortic LN, extend to body of T11.  Dose: 65-70 Gy definitive. 60 Gy for post-op. 44-46 Gy to pelvic field followed by boost.
 * See also: Adjuvant RT for an analysis of post-operative patients treated on 85-31
 * Initial results; 1997 PMID 9060541 &mdash; "Phase III trial of androgen suppression using goserelin in unfavorable-prognosis carcinoma of the prostate treated with definitive radiotherapy: report of Radiation Therapy Oncology Group Protocol 85-31." Pilepich MV et al. J Clin Oncol. 1997 Mar;15(3):1013-21.
 * 8-years; 2001 PMID 11240234 &mdash; Lawton et al. Int J Radiat Oncol Biol Phys. 2001 Mar 15;49(4):937-46. "Updated results of the phase III Radiation Therapy Oncology Group (RTOG) trial 85-31 evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavorable prognosis carcinoma of the prostate."
 * 10-years; 2005 PMID 15817329 &mdash; "Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma--long-term results of phase III RTOG 85-31." (Pilepich MV, Int J Radiat Oncol Biol Phys. 2005 Apr 1;61(5):1285-90.). Median F/U 7.6 years (11 for living patients)
 * 10-year outcome: OS 49% vs. 39% (SS); LF 23% vs. 38% (SS); DM 24% vs. 39% (SS); disease-specific mortality 16% vs. 22% (SS)
 * Conclusion: In unfavorable prognosis, adjuvant AST improves survival
 * N+ patients; 2005 PMID 15681524 &mdash; "Androgen suppression plus radiation versus radiation alone for patients with stage D1/pathologic node-positive adenocarcinoma of the prostate: updated results based on national prospective randomized trial Radiation Therapy Oncology Group 85-31." Lawton CA et al. J Clin Oncol. 2005 Feb 1;23(4):800-7.
 * 173 pts were N+. Median f/u 9.5 yrs for alive pts. PFS (PSA < 1.5) was 54% vs 33% at 5 years and 10% vs 4% at 9 years (This was S.S. both for patients with and without prostatectomy). Distant mets 28% vs 50% at 9 years (S.S. for pts without prostatectomy only). OS 72% vs 50% at 5 years and 62% vs 38% at 9 years. This was S.S. in multivariant analysis but N.S. in univariate analysis.
 * Obesity; 2007 PMID 17999404 -- "Obesity and mortality in men with locally advanced prostate cancer: analysis of RTOG 85-31." (Efstathiou JA, Cancer. 2007 Nov 12; [Epub ahead of print])
 * Outcome: 5-year DSM BMI <25 6% vs. BMI 25-30 13% vs. BMI >30 12% (SS). BMI not associated with non-prostate CA or all-cause mortality. True in multivariate analysis
 * Conclusion: Baseline BMI independently associated with higher PCA specific mortality in locally advanced PCA
 * Cardiovascular; 2008 PMID 19047297 -- "Cardiovascular Mortality After Androgen Deprivation Therapy for Locally Advanced Prostate Cancer: RTOG 85-31." (Efstathiou JA, J Clin Oncol. 2008 Dec 1. [Epub ahead of print])
 * Retrospective analysis. Median F/U 8.1 years
 * Outcome: CV mortality ADT 8% vs. no ADT 11% (NS); not significant on multivariate analysis
 * Conclusion: GnRH agonists do not seem to increase DV mortality in men with locally advanced prostate CA
 * ADT Salvage; 2010 PMID 20356687 -- "Timing of Salvage Hormonal Therapy in Prostate Cancer Patients With Unfavorable Prognosis Treated With Radiotherapy: A Secondary Analysis of Radiation Therapy Oncology Group 85-31." (Souhami L, Int J Radiat Oncol Biol Phys. 2010 Mar 29. [Epub ahead of print])
 * See also: Radiation Oncology/Prostate/Recurrence after RT
 * Subset analysis, relapsing patients in RT alone arm. Defined early salvage as initiated with PSA <10 and late-salvage as >10. Median F/U 11 and 13 years
 * Outcome: Early salvage significantly improved OS (HR 1.5, SS), no difference in local failure or cancer-specific mortality
 * Conclusion: Early introduction of salvage hormonal therapy improved OS but not CSS. Randomized trial is warranted

Adjuvant hormonal therapy after prostatectomy:
 * Trials including RP pts only:
 * See Radiation_Oncology/Prostate/Prostatectomy
 * Trials including RP pts along with RT or WW
 * See above: RTOG 85-31 and Casodex Early Prostate Cancer Program (EPC)

Androgen suppression duration
Randomized
 * DART01/05 GICOR (Spain) (2005-2010) - intermediate and high risk. 4 months neoadj/concur (2/2) vs 28 months (2/2+24).
 * Randomized. 355 pts. Intermediate to high risk. Randomized to: 1) 4 months of neoadjuvant/concurrent (2/2) + RT, or 2) 4 months (2/2) + RT followed by additional 24 months (total of 28 months).
 * RT: 76-82 Gy.
 * ASTRO Annual meeting 2014 slides
 * 2015 PMID 25702876 -- "High-dose radiotherapy with short-term or long-term androgen deprivation in localised prostate cancer (DART01/05 GICOR): a randomised, controlled, phase 3 trial." (Zapatero A, Lancet Oncol. 2015 Mar;16(3):320-7.)
 * Median f/u 5 yrs. Improved 5-yr bDFS (81% vs 90%), OS (95% vs 86%), metastasis-free survival (94% vs 83%). Improvements were more evident in high risk disease patients.
 * Conclusion: Compared with short-term androgen deprivation, 2 years of adjuvant androgen deprivation combined with high-dose radiotherapy improved biochemical control and overall survival in patients with prostate cancer, particularly those with high-risk disease, with no increase in late radiation toxicity. Longer follow-up is needed to determine whether men with intermediate-risk disease benefit from more than 4 months of androgen deprivation.
 * 2022 PMID 35427469 -- "High-dose radiotherapy and risk-adapted androgen deprivation in localised prostate cancer (DART 01/05): 10-year results of a phase 3 randomised, controlled trial." (Zapatero A, Lancet Oncol. 2022 May;23(5):671-681.)
 * Median f/u 10 yrs. No difference in bDFS, OS, or metastasis-free surival. 10-yr bDFS 70.2% for LTAD vs 62.3% STAD (NS); OS 78.4% vs 73.3% STAD (NS) ; metastasis-free survival 76.0% vs 70.9% (NS).
 * For high risk subgroup: bDFS 67.2% vs 53.7% (NS), OS 78.5% vs 67.0% (p=0.05), MFS 76.6% vs 65.0% (NS).  HR = 0.73 (bDFS), 0.58 (OS), 0.89 (MFS).
 * Conclusion: "After an extended 10-year follow-up, we were unable to support the significant benefit of LTAD reported at 5 years. However, the magnitude of the benefit was clinically relevant in high-risk patients. Intermediate-risk patients treated with high-dose radiotherapy do not benefit from LTAD. A biological characterisation with the inclusion of genomic testing is needed in the decision-making process."


 * RTOG 99-10 (1999-2004) - Intermediate risk, 2 vs 7 months neoadjuvant TAA + concurrent (2+2 vs 7+2) for total 4 mo vs 9 mo.
 * Randomized. 1579 pts. Intermediate to high risk. Randomized to: 1) 8 weeks of androgen suppression followed by RT with an additional 8 weeks of concurrent AS (16 weeks total), or 2) 28 weeks followed by RT + 8 weeks concurrent AS (36 weeks total).
 * Allowed Gleason 2-6 with PSA 10-100 (intermediate to high risk); G 7 and PSA < 20 (intermediate risk); and T1, G 8-10, PSA < 20 (high risk). Intermediate risk: 84%, high risk 15%.
 * Antiandrogen (bicalutamide or flutamide) started 14 days before first LHRH injection and continued until last day of RT.
 * RT: 70.2 Gy in 39 fractions. When treated, pelvic lymph nodes were included to 46.8 Gy.
 * 2015 PMID 25534388 -- "Duration of androgen suppression before radiotherapy for localized prostate cancer: radiation therapy oncology group randomized clinical trial 9910." (Pisansky TM, J Clin Oncol. 2015 Feb 1;33(4):332-9.)
 * Median f/u 9.4 yrs. 10 yr DSS 95% vs 96%; OS 66% vs 67%; biochemical failure 27% vs 27%.
 * Conclusion: Extending AS duration from 8 weeks to 28 weeks before radiotherapy did not improve outcomes.


 * PCS IV (Quebec) (2000-2008) -- AST 36 months vs 18 months
 * Randomized. 630 pts. High risk, node-negative (PSA > 20, G >= 8, or T3-T4).
 * RT: 44 Gy to pelvis, 70 Gy to prostate. RT started 4 months after AB. Androgen blockade(AB): bicalutamide 50 mg x 1 month; goserelin q3months for 36 months (arm 1) vs 18 months (arm 2) total.
 * Pt characteristics: Median PSA 16, median Gleason 8. Most had T2 or T3 disease.
 * 2013 ASCO Abstract (Genitourinary Cancers Symposium) Abstract #3 -- "High-risk prostate cancer treated with pelvic radiotherapy and 36 versus 18 months of androgen blockade: Results of a phase III randomized study." (Nabid A, J Clin Oncol 31, 2013 (suppl 6; abstr 3))
 * Median f/u 77 months (6.4 yr).
 * OS+CSS: 5-yr OS 92.1% vs 86.8% (p=0.052). 5-yr CSS 97.6% vs 96.4% (NS). 10-yr OS 63.6% vs 63.2% (NS). 10-yr DSS 87.2% vs 87.2% (NS).
 * Cause of death: 71/310 pts (22.9%) in arm 1 and 76/320 (23.8%) in arm 2 had died. 116 deaths out of 147 (78.9%) were from causes other than prostate cancer.
 * BRFS: No sig. difference in bRFS, RF, or DF.
 * Conclusion: "Our study shows that long term AB can be safely reduced from 36 to 18 months without compromising outcomes. Analysis of treatment impact on quality of life is now under review."
 * 2018 PMID 29980331 -- "Duration of Androgen Deprivation Therapy in High-risk Prostate Cancer: A Randomized Phase III Trial." (Nabid A, Eur Urol. 2018 Jul 3.[Epub ahead of print])
 * Median f/u 9.4 yr. 5-yr OS 91% vs 86% (p=0.07), 10-yr 62% vs 62% (NS); HR 1.02 (NS). QOL favored short arm.
 * Biochemical failure: 5-yr 12% vs 16%, 10-yr 25% vs 31%; HR 0.71 (SS).
 * Disease-specific survival: 10-yr 91% vs 92% (NS). Disease-free survival: 5-yr 77% vs 69% (SS), 10-yr 45% vs 39% (p=0.055); HR 0.84 (p=0.08).
 * Subgroup analysis: no interaction between ADT duration and G8-10 vs G7 or less for any endpoint.
 * Conclusion: In localized HRPC, our results support that 36 mo is not superior to 18 mo of ADT. ADT combined with RT can potentially be reduced to 18 mo in selected men without compromising survival or QoL. Thus, 18 mo of ADT appears to represent a valid option in HRPC.


 * Irish Clinical Oncology Research Group (ICORG) 97-01 (1997-2001) -- AST 4 months vs 8 months prior to RT
 * Randomized. 261 pts. Localized, node-negative, intermediate to high risk: PSA > 20, Gleason 7-10, or T3-T4. Neoadjuvant LHRH (triptorelin) monthly plus flutamide, randomized for duration of 4 months vs 8 months. RT began within 1 month of the end of AST. 70 Gy in 35 fractions prescribed to PTV.
 * 2011 PMID 20797824 -- "A randomized trial (Irish clinical oncology research group 97-01) comparing short versus protracted neoadjuvant hormonal therapy before radiotherapy for localized prostate cancer." (Armstrong JG, Int J Radiat Oncol Biol Phys. 2011 Sep 1;81(1):35-45.)
 * Median f/u 102 mo (8.5 y). No sig. difference in OS, BFFS, or PCSS. 5-yr OS 90% (short) vs 83% (long), NS. BFFS 66% vs 63%.
 * Conclusion: "No statistically significant difference was found in biochemical failure-free survival between 4 months and 8 months of neoadjuvant hormonal therapy before radiotherapy for localized prostate cancer."
 * Salvage Hormonal Therapy: PMID 22658512 -- "Early salvage hormonal therapy for biochemical failure improved survival in prostate cancer patients after neoadjuvant hormonal therapy plus radiation therapy-a secondary analysis of irish clinical oncology research group 97-01." (Mydin AR, Int J Radiat Oncol Biol Phys. 2013 Jan 1;85(1):101-8.)
 * See Recurrence after RT
 * Erectile dysfunction; 2012 PMID 22682750 -- "The effect of short term neo-adjuvant androgen deprivation on erectile function in patients treated with external beam radiotherapy for localised prostate cancer: an analysis of the 4- versus 8-month randomised trial (Irish Clinical Oncology Research Group 97-01)." (Daly PE, Radiother Oncol. 2012 Jul;104(1):96-102.)
 * For details, see page at Erectile dysfunction


 * EORTC 22961 (1997-2002) -- AST 6 months vs. AST 3 years
 * Randomized. 970 men. Locally advanced prostate cancer (T1c-T2b pN1-N2 M0 or cT2c-T4 N0-N2 M0), PSA up to 40x normal, Hb >10. 3D-CRT pelvis + prostate boost 70 Gy. AST 6 months (complete androgen blockade) initiated 1st day of RT. If no progression, Arm 1) observation vs Arm 2) AST 2.5 years (LHRH triptorelin). 72% completed full 3 years. Median F/U 6.4 year
 * 2009 PMID 19516032 -- "Duration of Androgen Suppression in the Treatment of Prostate Cancer" (Bolla M, N Engl J Med. 2009 Jun 11;360(24):2516-2517.)
 * Outcome: 5-year OS 6-months 81% vs. 3-years 85% (HR 1.4, SS); 5-year CSS 95% vs. 97% (HR 1.7, SS).
 * Toxicity: 6 month AST hot flashes 29%, gynecomastia 7%, incontinence 10%. 3 year AST hot flashes 39%, gynecomastia 18%. Quality of life comparable between arms. No difference in fatal cardiac events (4% vs. 3%)
 * Conclusion: Combination of RT + 3 years AST provides superior survival to 6 month AST in locally advanced cancer


 * Canada multicenter (1995-2001) -- ADT 3 vs 8 months prior to RT
 * Randomized. 378 patients. Clinically localized cT1-T4 (low 26%, intermediate 43%, high risk 31%). Median PSA 9.7 ng/ml Arm 1) Flutamide + goserelin x3 months vs. Arm 2) Same x8 months. Subsequently prostate RT 66 Gy. If LN+ risk >10-15%, treated pelvis. No concurrent ADT
 * 2004 PMID 15337535 &mdash; "Report of a multicenter Canadian phase III randomized trial of 3 months vs. 8 months neoadjuvant androgen deprivation before standard-dose radiotherapy for clinically localized prostate cancer." Crook J et al. Int J Radiat Oncol Biol Phys. 2004 Sep 1;60(1):15-23.
 * Median f/u 44 mos. No difference in the 3 yr (66-68%) or 5 yr (61-62%) FFF rate. Suggestion of benefit for 8 month duration of hormones for the high-risk pts for DFS, but N.S.
 * Conclusion: no benefit for longer length of neoadjuvant hormones
 * 2009 PMID 18707821 -- "Final report of multicenter Canadian Phase III randomized trial of 3 versus 8 months of neoadjuvant androgen deprivation therapy before conventional-dose radiotherapy for clinically localized prostate cancer." (Crook J, Int J Radiat Oncol Biol Phys. 2009 Feb 1;73(2):327-33. Epub 2008 Aug 15.) Median F/U 6.6 years
 * Outcome: 5-year bPFS 3 months 72% vs. 8 months 75% (NS); OS 81% vs. 79% (NS). Improved DFS for high-risk patients with 8 months (71% vs. 42%, SS)
 * Conclusion: Longer neoadjuvant HT before standard RT didn't alter patterns of failure
 * PSA response; 2010 PMID 19395187 -- "Is biochemical response more important than duration of neoadjuvant hormone therapy before radiotherapy for clinically localized prostate cancer? An analysis of the 3- versus 8-month randomized trial." (Alexander A, Int J Radiat Oncol Biol Phys. 2010 Jan 1;76(1):23-30.)
 * Subset analysis. Evaluated pre-RT post-hormone PSA (PRPH-PSA)
 * Outcome: bPFS if PRPH-PSA <0.1 55% vs >0.1 49% (SS), no difference by treatment arm. MVA predictors of outcome PRPH-PSA, GS, initial PSA, and Tstage, but not ADT duration
 * Conclusion: Biochemical response to neoadjuvant ADT before RT, not duration necessary to reach it, is crucial determinant of benefit


 * Quebec L-200 (1994-1999) -- Neoadjuvant/concurrent (5 months) vs neoadjuvant/concurrent/adjuvant (10 months) ADT
 * Randomized. 325 patients, cT2-T3 prostate cancer. Arm 1) RT + neoadjuvant/concurrent ADT (5 months) using LHRH agonist + antiandrogen vs. Arm 2) RT + neoadjuvant/concurrent/adjuvant (10 months) ADT. Endpoint bNED by Vancouver definition
 * 2004 PMID 14767287 &mdash; "The efficacy and sequencing of a short course of androgen suppression on freedom from biochemical failure when administered with radiation therapy for T2-T3 prostate cancer." (Laverdiere J et al. J Urol. 2004 Mar;171(3):1137-40.)
 * Outcome: 4-year bNED 65%, no difference between arms
 * Conclusion: Adding short course (5 months) of adjuvant ADT after neoadjuvant/concurrent ADT provided no further advantage


 * RTOG 92-02 (1992-95) -- 4 months versus 2 years ADT
 * Randomized. 1554 patients with locally advanced PCA. T2c-T4 (T2 45%, T3 50%); PSA <150 (PSA <=30 in 67%), allowed N+ (N+ 4%, Nx 87%) but excluded LN+ at common iliac or higher chains. Goserelin 3.6 mg SC qM + flutamide 250 mg TID for 2 months before and 2 months during XRT. Then Arm 1) observation (ST-ADT) vs. Arm 2) 2 years of goserelin (LT-ADT). XRT pelvis 45 Gy, followed by a boost to 65-70 Gy.
 * 5-years; 2003 PMID 14581419 Full Text &mdash; "Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: the Radiation Therapy Oncology Group Protocol 92-02." (Hanks GE, J Clin Oncol. 2003 Nov 1;21(21):3972-8. Median F/U 5.8 years
 * Outcome: 5-year DFS ST-AST 28% vs. LT-AST 46% (SS); LR 12% vs. 6% (SS); OS 78% vs. 80% (NS)
 * Subset analysis (GS 8-10): OS ST-AST 71% vs LT-AST 81% (SS); all other points also (SS)
 * Conclusion: Long-term ADT improves DFS over short-term ADT, survival benefit for GS 8-10 subset
 * 10-years; 2008 PMID 18413638 -- "Ten-Year Follow-Up of Radiation Therapy Oncology Group Protocol 92-02: A Phase III Trial of the Duration of Elective Androgen Deprivation in Locally Advanced Prostate Cancer." (Horwitz EM, J Clin Oncol. 2008 Apr 14 [Epub ahead of print]). Median F/U 11.3 years
 * Outcome: 10-year DFS ST-ADT 13% vs. LT-ADT 22% (SS), DSS 84% vs. 89% (SS), LR 22% vs. 12% (SS); OS 52% vs. 54% (NS)
 * Subset analysis (GS 8-10): OS ST-AST 32% vs. LT-AST 45%; all other points also SS
 * Conclusion: LT-ADT is superior to ST-ADT for DFS; not powered for OS. On subgroup analysis, GS 8-10 has survival advantage

Retrospective
 * Harvard; 2008 PMID 18565884 -- "Risk of prostate cancer recurrence in men treated with radiation alone or in conjunction with combined or less than combined androgen suppression therapy." (D'Amico AV, J Clin Oncol. 2008 Jun 20;26(18):2979-83.)
 * Subset analysis. 206 men with localized unfavorable-risk prostate CA enrolled on Harvard trial RT vs. RT + AST x 6 months. Regression analysis to evaluate impact of duration of antiandrogen use. Median F/U 8.2 years
 * Outcome: Recurrence risk significantly decreased (HR 0.81) with each additional month of ADT, after adjustment for PSA, GS, or cT2
 * Conclusion: Less than 6 months ADT leads to increased risk of recurrence compared with 6 months of ADT


 * Harvard; 2007 (1987-2000) PMID 17397033 -- "Short- vs long-term androgen suppression plus external beam radiation therapy and survival in men of advanced age with node-negative high-risk adenocarcinoma of the prostate." (D'Amico AV, Cancer. 2007 May 15;109(10):2004-10.)
 * Pooled analysis. 311 men on 3 randomized trials. 6 months vs. 3 years of AST for locally advanced or high grade localized PCA. Median F/U 5.9 years
 * No difference between 6 months and 3 years

Sequencing neoadjuvant RT:
 * Columbia University (1997-2002) - phase II. Begin RT after maximum response to AD
 * 123 pts. PSA > 4 or Gleason >= 8 (83% were "high risk"). Pts with PSA > 50 required to have lymphadenectomy. All pts received androgen deprivation (Lupron + Flutamide) for a total of 9 months. RT began after "maximum response to RT", by assessment with PSA and DRE, but no later than 6 months. RT to 70.2 Gy (75.6 Gy in 12 pts). Treatment to prostate + SV (no pelvic lymph nodes?). IMRT allowed but not required.
 * PMID 17194907, 2007 &mdash; "Phase II study of neoadjuvant androgen deprivation followed by external-beam radiotherapy with 9 months of androgen deprivation for intermediate- to high-risk localized prostate cancer." Heymann JJ et al. J Clin Oncol. 2007 Jan 1;25(1):77-84.
 * Median f/u 45 mo. Median time to begin RT 4.7 months after start of AD (28% with undetectable PSA, 46% with unchanged "nadir" PSA, 10% rising, 14% at 6 months). Biochemical failure defined as PSA > 1.5 and 2 consecutive rises. 5-yr bDFS 63%, cDFS 75%, DSS 99%, OS 89%. Pts initiating RT after 6 mos of AD had lower DFS (82% failure rate) vs undetectable PSA (33% failure) and PSA nadir (29%). 65% remained potent.
 * Conclusion: this strategy of timing the start of RT with maximum response to hormonal therapy gives results comparable to past studies. High-risk subgroup (pts without maximum response after 6 months of AD) is identified and warrants further study.

Intermediate Risk Disease
Subclassification: Favorable and Unfavorable Intermediate Risk:
 * see Zumsteg and Spratt et at Radiation_Oncology/Prostate/Prostate_Overview

Androgen Deprivation Therapy + RT in Intermediate Risk Disease:


 * Harvard/DFCI
 * See details at NACHT section
 * Included largely intermediate risk pts with localized prostate cancer, +/- 6 months ADT.
 * Improvement in PCSM for ADT given in pts with Unfavorable Intermediate risk but not in Favorable Intermediate Risk (0% mortality).


 * Review,2012: PMID 22652234 - ADT for intermediate risk prostate cancer with dose escalated EBRT (Zumsteg ZS, Lancet Oncol. 2012 Jun;13(6):e259-69.)


 * MDACC (1993-2008) - Retrospective
 * 3 groups of men were treated with dose-escalated IMRT or 3D conformal RT (75.6-78 Gy). 1) 327 intermediate risk pts, RT alone; 2) 218 intermediate risk pts, RT and <6 months ADT; 3) 274 low risk pts, RT alone.
 * Within the group of intermediate risk pts treated with RT alone, used recursive partitioning analysis using Gleason, T Stage, and PSA to identify prognostic groups based on risk of PSA recurrence.
 * 2011 ASTRO Abstract "Is Androgen Deprivation Therapy Necessary in Intermediate Risk Prostate Cancer Patients Treated in the Dose Escalation Era?" (Castle KO, Int J Radiat Oncol Biol Phys, Volume 81, Issue 2, Supplement, Pages S40-S41, 1 October 2011)
 * 2013 PMID 22836052 "Is Androgen Deprivation Therapy Necessary in Intermediate Risk Prostate Cancer Patients Treated in the Dose Escalation Era?" (Castle KO. Int J Radiat Oncol Biol Phys. 2013 Mar 1;85(3):693-9. Epub 2012 Jul 24).
 * Median f/u 58 mo. Group 1 pts (Intermediate risk, RT alone) were classified into 3 groups based on T stage and Gleason. PSA was not a major contributing factor.
 * Prognostic group 1 ("favorable"): T2b or less, GS 6; or T1c or less, G 3+4 (188 pts)
 * Prognostic group 2 ("marginal"): T2a-b, G 3+4 (71 pts)
 * Prognostic group 3 ("unfavorable"): T2c OR G 4+3 (68 pts)
 * The greatest benefit from ADT was seen for the unfavorable intermediate-risk pts (5-yr bDFS 74% RT alone vs 94% RT+ADT). Favorable: 94% vs 95%. The bDFS for favorable intermediate risk pts treated with RT alone was similar to that for low risk pts treated with RT (98%). Marginal: 91% vs 100% (p=0.07).
 * Conclusion: Pts with favorable int-risk prostate cancer did not benefit from the addition of ADT. However, ADT did improve bDFS for pts with G 4+3 or higher volume disease. Consideration should be given to a personalized approach based on tumor characteristics and comorbidities.

Meta-analysis

 * Combined analysis (3 trials) (1996-2001) -- 3, 4, or 6 months HT
 * Using individual pt data from 3 international randomized trials: TROG 96.01 (NACHT 3 mo vs 6 mo), ICORG 97-01 (NEO 4 mo vs 8 mo), and DFCI 95096 (NACHT 6 mos vs none).
 * 761 "unfavorable risk" pts (GS >= 7, PSA > 10, or T2b or higher). RT doses 66-70 Gy. AST consisted of LHRH agonist + flutamide.
 * 2011 PMID 22042952 -- "Duration of short-course androgen suppression therapy and the risk of death as a result of prostate cancer." (D'Amico AV, J Clin Oncol. 2011 Dec 10;29(35):4682-7.)
 * Median f/u 10.9 y. 263 deaths (111; 42% from PC). 6 months vs 3-4 months of AST associated with reduced risk of PCSM (HR 0.55). By Gleason score, GS <=6 (NS), GS 7 (HR = 0.47, SS), GS 8-10 (NS) for benefit of longer AST.
 * Conclusion: "AST durations of no less than 6 months should be considered when treating GS 7 PC with conventional dose RT."


 * Harvard Meta-analysis; 2011
 * See information below (under AST Toxicity / Cardiovascular)


 * Rome; 2009 PMID 19484790 -- "Does hormone treatment added to radiotherapy improve outcome in locally advanced prostate cancer?: meta-Analysis of Randomized Trials." (Bria E, Cancer. 2009 May 29.)
 * Meta-analysis. 7 trials, 4387 patients
 * Outcome: AST improved bFailure by 10% (RR 0.76, SS), clinical PFS by 8% (RR 0.81, SS), CSS by 5% (RR 0.76, SS), and OS 5% (RR 0.86, SS). Number needed to treat (NNT) 10, 13, 18, and 20 respectively. Local relapse decreased by 36%, distant release by 28%
 * Toxicity: No significant difference
 * Conclusion: AST + RT significantly decreases recurrence and mortality


 * NHS Trust, UK; 2009 PMID 19493624 -- "Adjuvant hormone therapy for localised and locally advanced prostate carcinoma: A systematic review and meta-analysis of randomised trials." (Shelley MD, Cancer Treat Rev. 2009 Jun 1. [Epub ahead of print])
 * Radiation: RT + AHT improved 5-year OS (OR 1.3, SS), DSS (OR 2.1, SS), DFS (OR 1.9, SS)
 * Prostatectomy: No OS benefit, DFS (OR 3.7, SS)
 * Toxicity: gynecomastia, impotence, GI, hematological
 * Conclusion: Significant benefit associated with use of AHT for prostate cancer


 * 'RTOG Meta-analysis; 2000' - PMID 10837944 &mdash; "Predicting long-term survival, and the need for hormonal therapy: a meta-analysis of RTOG prostate cancer trials." Roach M et al. Int J Radiat Oncol Biol Phys. 2000 Jun 1;47(3):617-27.
 * Meta-analysis. 2200 men, from 5 RTOG trials - 7506, 7706, 8307, 8531, 8610. Stratified into 4 RTOG prognostic groups (see here).
 * Overall survival and disease-specific survival benefit with use of long-term hormones for Groups 3 and 4 (high risk). Improved DSS but not OS for short term (4 mos) hormones in Group 2 (int risk, most pts with bulky or T3 disease). Too few pts in Group 1 (low risk) received hormones, so were not analyzed.

Review
 * EORTC; 2007 PMID 17594359 -- "Adjuvant treatment to radiation: combined hormone therapy and external radiotherapy for locally advanced prostate cancer." (Bolla M, BJU Int. 2007 Jul;100 Suppl 2:44-7.)


 * Critical Review; 2010 PMID 20975876 -- "Combining radiation therapy and androgen deprivation for localized prostate cancer-a critical review." (Dal Pra A, Curr Oncol. 2010 Oct;17(5):28-38.)

Gynecomastia

 * ''Please see the Gynecomastia supportive care page

Cardiovascular

 * Decision Analysis; 2013 PMID 23400678 -- "Death from high-risk prostate cancer versus cardiovascular mortality with hormonal therapy: a decision analysis." (Lester-Coll NH, Cancer 2013 May 15;119(10):1808-15.)
 * Markov decision analysis model that compared quality-adjusted life expectancy (QALE) in men aged 50, 60, and 70 years who received RT and no HT, 6 months of HT (short-term), or 3 years of HT (long-term) for high-risk prostate cancer stratified by cardiac risk group.
 * Long-term HT improved QALE (range, 1.4-5.4 years) for men aged 50 or 60 years except those with MI; whereas, for men aged 70 years with 4 cardiac risk factors, short-term and long-term HT yielded identical QALE.
 * Conclusion: Men who received RT for high-risk prostate cancer and had a history of MI experienced net harm when they received HT. Men without MI gained a QALE benefit from HT, even if they had up to 4 cardiac risk factors.


 * Harvard Meta-analysis; 2011 PMID 22147380 -- "Association of androgen deprivation therapy with cardiovascular death in patients with prostate cancer: a meta-analysis of randomized trials." (Nguyen PL, JAMA. 2011 Dec 7;306(21):2359-66.)
 * Meta-analysis of randomized trials of androgen deprivation therapy in non-metastatic prostate cancer. 4141 pts from 8 trials.
 * CV death in pts receiving ADT vs controls not significantly different (11.0% vs 11.2%). No difference seen for long-duration ADT (>= 3 yrs): 11.5% vs 11.5%; or with short-duration (6 months or less): 10.5% vs 10.3%.
 * ADT associated with lower PCSM 13.5% vs 22.1% and lower all-cause mortality 37.7% vs 44.4%.
 * Conclusion: ADT use was not associated with increased cardiovascular death but was associated with lower PCSM and mortality.


 * Toremifene Trial (2003-2005)
 * Randomized. 1389 men, prostate cancer, receiving long-term ADT (>6 months, or intermittently for >12 months, or bilateral orchiectomy). Arm 1) Toremifene 80 mg/d (second generation SERM) vs. Arm 2) placebo
 * Lipid effect; 2008 PMID 18398147 -- "Toremifene improves lipid profiles in men receiving androgen-deprivation therapy for prostate cancer: interim analysis of a multicenter phase III study." (Smith MR< J Clin Oncol. 2008 Apr 10;26(11):1824-9.)
 * Interim analysis of 188 patients. Fasting serum lipids compared at baseline and 1 year later
 * Outcome: total cholesterol toremifene -8% vs. placebo -1% (SS); LDL -8% vs. +1% (SS); HDL +0.5% vs. -5% (SS); triglycirides -13% vs. +7% (SS)
 * Conclusion: Tofemifene significantly improved lipid profile


 * Harvard, 2007 (1995-2001) PMID 17557956 -- "Influence of androgen suppression therapy for prostate cancer on the frequency and timing of fatal myocardial infarctions." (D'Amico AV, J Clin Oncol. 2007 Jun 10;25(17):2420-5.)
 * Retrospective pooled analysis. 3 trials evaluating AST (0 vs. 3 vs. 6; 3 vs. 8; 0 vs. 6)
 * Age >65: 6 month AST shorter time to fatal MI vs. no AST (SS); no difference between 3 months and 6-8 months
 * Conclusion: 6+ month AST leads to earlier onset of fatal MI in age >65. Recommend cardiac evaluation and/or intervention prior to starting AST