# Radiation Oncology/Prostate/Advanced disease

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This page is for the treatment of metastatic prostate cancer.
    See also: Radiation Oncology/Prostate/Chemotherapy
    See also: Radiation Oncology/Prostate/Hormones for other aspects of hormonal therapy, such as the use of combined androgen blockade vs GnRH agonist alone

## Guidelines

ASCO Practice Guideline: Initial Hormonal Management of Androgen-Sensitive Metastatic, Recurrent, or Progressive Prostate Cancer
* 2006 - PMID 17404365 — "Initial Hormonal Management of Androgen-Sensitive Metastatic, Recurrent, or Progressive Prostate Cancer: 2006 Update of an American Society of Clinical Oncology Practice Guideline." Loblaw DA et al. J Clin Oncol. 2007 Apr 20;25(12):1596-605.
** 1) Standard treatment options: bilateral orchiectomy or LHRH agonists
** 2) Non-steroidal anti-androgens (NSAA) may be discussed as an alternative; steroidal anti-androgens should not be offered
** 3) Combined androgen blockade should be offered
** 4) Early androgen deprivation compared to symptomatic initiation shows moderate (17%) decrease in relative risk of PCA-specific mortality, but moderate (15%) increase in relative risk of non-PCA-specific mortality. There is no overall survival difference. Some prognostic factors (PSAdt, GS, PSA response to ADT, age) may be considered in treatment decisions
** 5) There is insufficient data for intermittent androgen blockade, and it should not be used outside of clinical trials
* 2004: - PMID 15184404, 2004 — "American Society of Clinical Oncology recommendations for the initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer." Loblaw DA et al. J Clin Oncol. 2004 Jul 15;22(14):2927-41.

## Hormonal Therapy +/- Prostate Radiation

* STAMPEDE (2013-2016) - multicenter trial in Switzerland and UK
** Randomized. 2061 patients, newly diagnosed metastatic prostate cancer. Arm 1) lifelong ADT Arm 2) lifelong ADT plus radiation (trial later amended to allow upfront docetaxel in either arm)
** 2018 PMID 30355464 -- "Radiotherapy to the Primary Tumour for Newly Diagnosed Metastatic Prostate Cancer (STAMPEDE): a Randomized Controlled Phase 3 Trial" (Parker CC, et al, Lancet. 2018;392:2353-66)
*** Methods: Radiation was either 55 Gy in 20 fractions or 36 Gy in 6 weekly fractions.
*** Outcome: Radiation improved failure free survival (HR 0.76 CI 0.68-0.84) but not overall survival for the entire group. For patients with low metastatic burden (<4 bone mets, no visceral mets) 3-year OS control 73% vs. RT 81% (SS)
*** Conclusion: No benefit for unselected patients. Low metastatic burden patients may benefit from addition of radiation (but not primary endpoint of trial).
* National Cancer Database (2004-2012) (Rusthoven, et al, "Improved Survival With Prostate Radiation in Addition to Androgen Deprivation Therapy for Men With Newly Diagnosed Metastatic Prostate Cancer" J Clin Oncol. 2016 Jun 20. pii: JCO67478) PMID 27325855
** 6,382 men with metastatic PCa at diagnosis, all treated with androgen deprivation therapy (ADT) +/- prostate RT (8.4%).
** Prostate RT associated with improved OS on univariate (p<.001) and multivariate analyses (hazard ratio, 0.624; 95% CI, 0.551 to 0.706; P < .001) adjusted for age, year, race, comorbidity score, PSA level, Gleason score, T stage, N stage, chemotherapy administration, treating facility, and insurance status)
** Propensity score analysis with matched baseline characteristics demonstrated superior median (55 v 37 months) and 5-year OS (49% v 33%) with prostate RT plus ADT compared with ADT alone (P < .001).
** Patients receiving higher-dose RT (≥ 65Gy) had improved OS compared to lower-dose RT.
* Conclusion: "In this large contemporary analysis, men with mPCa receiving prostate RT and ADT lived substantially longer than men treated with ADT alone."
* HORRAD Trial (2004-2014) Multicenter randomized trial in The Netherlands.
** 432 patients with bone metastatic prostate cancer and PSA > 20 were randomized to lifelong androgen deprivation with or without radiation therapy to the prostate.
** Radiation dose was either 70 Gy in 35 fractions or 57.76 Gy in 19 fractions delivered 3 fractions per week.
** 2018 Boevé et al, "Effect on survival of androgen deprivation therapy alone compared to androgen deprivation therapy combined with concurrent radiation therapy to the prostate in patients with primary bone metastatic prostate cancer in a prospective randomised clinical trial: data from the HORRAD trial" Eur Urol. 2018; PMID 30266309
*** Conclusion: There was no difference in overall survival. However, an unplanned subgroup analysis suggested a survival benefit for patients with <4 bone metastases. (HR 0.68, 95% CI 0.42-1.10)

## Hormonal Therapy

* Also please see Radiation_Oncology/Prostate/Hormones section

### Dose

* CALGB 9181 (1992-1994) -- low-dose vs. high-dose Megace
** Randomized. 149 ment with HRPC, with progressive metastatic or LN carcinoma; only 1 prior hormonal therapy allowed. Arm 1) oral megestrol acetate 160 mg/day (low dose) vs. Arm 2) oral megestrol acetate 640 mg/day (high dose). Primary endpoint tumor response
** 2000 PMID 10679652 -- "A randomized study comparing standard versus moderately high dose megestrol acetate for patients with advanced prostate carcinoma: cancer and leukemia group B study 9181." (Dawson NA, Cancer. 2000 Feb 15;88(4):825-34.)
*** Outcome: Tumor response comparable. Median OS low dose 11.2 months vs. high dose 12.1 months (NS). Most (91%) died of prostate cancer
*** Toxicity: comparable, but 7% had acute pain flare
*** Conclusion: Megestrol acetate has limited activity in HRPC; there is no apparent dose-response correlation

### Immediate vs delayed hormonal therapy

    See also: Primary ADT vs. Deferred ADT in the hormonal therapy chapter (mostly patients with localized prostate cancer)
* EORTC 30846 - Phase III
** 302 pts with positive lymph nodes (N1-3, M0) without local treatment of the primary tumor. Of these, 234 were randomized.
** 2004 PMID 15310999 -- "Early versus delayed endocrine treatment of pN1-3 M0 prostate cancer without local treatment of the primary tumor: results of European Organisation for the Research and Treatment of Cancer 30846--a phase III study." (Schroder FH, J Urol. 2004 Sep;172(3):923-7.)
*** Median f/u 9.6 yr, 190 pts (62.9%) died, including 76% from prostate ca. HR for survival for delayed vs immediate treatment was 1.23 (NS)
*** Median time off treatment on the DET arm: 18 months
*** Conclusion: "While this study suggests an advantage for early treatment, it is under powered to show equivalence or superiority for the early or delayed approach. When dealing with individual patients, the potential survival advantage on early treatment must be balanced against potential advantages in quality of life on delayed treatment."
* Medical Research Council (-1993)
** 934 pts. Locally advanced or metastatic (and asymptomatic) prostate cancer. Randomized to immediate hormonal therapy (orchidectomy or LHRH agonist) or the same treatment delayed until the patient became symptomatic (from local progression or metastasis)
** 2000 (Abstract only) -- no PMID; PDF (appears as MP6.1.07 on page 3) -- "Immediate vs. deferred hormone treatment for prostate cancer: How safe is androgen deprivation?" (Kirk D, Br J Urol 86(suppl 3):S220, 2000)
*** 815 pts (85%) have died (399 - immediate, 416 deferred).
*** Improved disease-specific survival with immediate treatment. Overall survival is less.
*** 277 died from other causes (147 immediate, 129 deferred)
*** Cancer deaths (other than prostate cancer): 27 vs 15. Cardiovascular deaths: 77 vs 91.
*** TURPs performed: 74 vs 149. Ureteric obstruction: 43 vs 59. Spinal cord compression: 10 vs 23.
*** Conclusion: "Immediate hormone treatment has an impact on advanced prostate cancer, reducing complications and improving disease specific survival." ... "However, the reduction in an overall survival difference seen on long-term follow-up suggests an adverse effect of prolonged hormone treatment in increasing mortality from other causes. An excess of cardiovascular disease is not apparent in immediate patients, but more died from nonprostate cancer."
** 1997 - PMID 9052476 — "Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council Trial. The Medical Research Council Prostate Cancer Working Party Investigators Group." Br J Urol. 1997 Feb;79(2):235-46.
*** Immediate treatment resulted in fewer pts progressing to metastatic disease, fewer needed TURP, fewer pathologic fractures, spinal cord compressions, ureteral obstructions, and extra-skeletal metastases. 257 deaths from prostate cancer in deferred arm vs 203 in immediate arm (S.S.).
** Conclusion: Immediate treatment improves DSS but there is no impact on OS with long-term follow-up.

### Total Androgen Suppression

* Scandinavian SPCG-5 (1992-1997) -- parenteral estrogen vs. total androgen blockade
** Randomized. 910 patients, metastatic prostate cancer. Arm 1) parenteral estrogen 240 mg/month vs. Arm 2) flutamide 250 mg TID + triptorelin 3.75 mg or bilateral orchidectomy
** 2008 PMID 18432528 -- "Parenteral estrogen versus combined androgen deprivation in the treatment of metastatic prostatic cancer: part 2. Final evaluation of the Scandinavian Prostatic Cancer Group (SPCG) Study No. 5." (Hedlund PO, Scand J Urol Nephrol. 2008;42(3):220-9.
*** Outcome: No difference in bPFS, cPFS, DSS, or OS
*** Toxicity: No difference in CV mortality, but increased cardiovascular events in parenteral estrogen arm. Increased skeletal events/osteoporosis in androgen arm
*** Conclusion: No difference in outcome. Toxicity profiles different
* Scandinavian SPCG-2 (1984-1989) -- bilateral orchiectomy +/- cyproterone
** Randomized. 294 patients, metastatic PCA, Grade 1-2. Arm 1) bilateral orchiectomy vs. Arm 2) bilateral orchiectomy + cyproterone
** 1993 PMID 8287887 -- "Total androgen suppression: experience from the Scandinavian Prostatic Cancer Group Study No. 2." (Jorgensen T, Eur Urol. 1993;24(4):466-70.)
*** Outcome: No difference in disease progression, or overall survival
*** Conclusion: Total androgen blockade with cyproterone not superior to orchiectomy
* Abstract not available — Denis L et al. Overview of phase III trials on combined androgen treatment in patients with metastatic prostate cancer. Cancer 1993;72:Suppl:3888-3895.
* PMID 8367920, 1993 — "Goserelin acetate and flutamide versus bilateral orchiectomy: a phase III EORTC trial (30853)." Denis LJ et al. Urology 1993;42:119-129.
** 327 pts. Improved survival for combined arm.
* PMID 7678043, 1993 — "Orchiectomy and nilutamide or placebo as treatment of metastatic prostatic cancer in a multinational double-blind randomized trial." Janknegt RA et al. J Urol 1993;149:77-82.
** Improvement in several outcome measures (not survival) for combined group.
* PMID 2503724 — "A controlled trial of leuprolide with and without flutamide in prostatic carcinoma." Crawford ED et al. N Engl J Med. 1989 Aug 17;321(7):419-24.
** 603 pts. Randomized, double blind. Randomized to leuprolide vs leuprolide + flutamide.
** Longer progression-free survival (16.5 vs 13.9 months) and median survival (35.6 vs 28.3) for the combined group.
* PMID 9761805 Full text — "Bilateral orchiectomy with or without flutamide for metastatic prostate cancer." Eisenberger MA et al. N Engl J Med. 1998 Oct 8;339(15):1036-42.
** 1387 pts. Randomized to bilateral orchiectomy vs orchiectomy + flutamide.
** No difference in overall survival or PFS. Better PSA response in combined treatment group.
* Meta-analysis: Prostate Cancer Trialists' Collaborative Group, 1995 - PMID 7630245 — "Maximum androgen blockade in advanced prostate cancer: an overview of 22 randomised trials with 3283 deaths in 5710 patients." Lancet 1995;346:265-269.
** Compared castration (surgical or medical) vs MAB. Median f/u 40 months. Crude mortality rate 58% for castration alone vs 56%. 5-year OS difference 3.5%, non-significant.
* Meta-analysis: PMID 9000189 — "Maximum androgen blockade in advanced prostate cancer: a meta-analysis of published randomized controlled trials using nonsteroidal antiandrogens." Caubet JF et al. Urology 1997;49:71-78
** Compared antiandrogen combined with orchiectomy or LHRH agonist vs orchiectomy/LHRH alone. Nine studies. RR was 0.78 to 0.84 in favor of combined arm.

## PSA-only recurrence

Early vs delayed hormonal therapy for PSA-only recurrence:
* Multicenter; 2004 (1988-2002) PMID 14767288 -- "Early versus delayed hormonal therapy for prostate specific antigen only recurrence of prostate cancer after radical prostatectomy." (Moul JW, J Urol. 2004 Mar;171(3):1141-7.)
** Retrospective. Of 4967 pts undergoing RP, 1352 had PSA-only recurrence (> 0.2 ng/ml). Early HT group (n=355) = received HT before clinical metastases. Late HT group (n=997) = received no HT before clinical metastasis or by current follow-up.
** Clinical metastases developed in 103 (7.6%). Early HT associated with delayed metastasis in pts with Gleason > 7 or PSA-DT <= 12 months.
** Conclusion: "The retrospective observational multicenter database analysis demonstrated that early HT administered for PSAR after prior RP was an independent predictor of delayed clinical metastases only for high-risk cases at the current followup. Further study with longer followup and randomized trials are needed to address this important issue."

## Castrate-Resistant Prostate Cancer

* ARTO Trial (2019 - 2022) - Abiraterone acetate with prednisone +/- SBRT
** Randomized. 157 patients, oligometastatic (1-3 nonvisceral metastases), castrate-resistant prostate cancer. Arm 1) Abitarone acetate and prednisone (AAP) vs Arm 2) Addition of SBRT with BED >100 Gy. Primary endpoint biochemical response (BR) as PSA decrease >=50% from baseline after 6 months. Complete BR is PSA <0.2 ng/ml at 6 months.
** Outcome; 2023 PMID 37733977 -- "Stereotactic Body Radiation Therapy and Abiraterone Acetate for Patients Affected by Oligometastatic Castrate-Resistant Prostate Cancer: A Randomized Phase II Trial (ARTO)" (Grancolini G, J Clin Oncol. 2023 Dec 20;41(36):5561-5568. doi: 10.1200/JCO.23.00985. Epub 2023 Sep 21.)
*** Outcome: BR control 68% vs SBRT 92% (SS). Complete BR 23% vs 56% (SS). Significant PFS (HR 0.35, SS)
*** Conclusion: SBRT improves biochemical control and progression free survival in metastatic castration-resistant prostate cancer

## Chemotherapy

* Historically, prostate cancer which became refractory to hormonal treatment was considered resistant to chemotherapy
* In 1996, mitoxantrone with prednisone was shown to have a role in palliation of pain (Canada trial); the study was not powered for survival. The benefit was confirmed in the CALGB 9182 study
* In 2004, two studies (TAX 327 and SWOG 9916) showed a survival benefit for docetaxel-based therapy compared with mitoxantrone
* In HRPC patients, docetaxel every 3 weeks with prednisone is currently the preferred treatment
* Atrasentan - endothelin-A receptor antagonist
** Randomized. 809 men with HRPC. Arm 1) atrasentan 10 mg vs. Arm 2) placebo. Endpoint TTP
** 2007 PMID 17886253 -- "A phase 3 randomized controlled trial of the efficacy and safety of atrasentan in men with metastatic hormone-refractory prostate cancer." (Carducci MA, Cancer. 2007 Nov 1;110(9):1959-66.)
*** Outcome: No difference in time-to-progression; most progressed radiographically within 12 weeks; no difference in PSA progression
*** Toxicity: Well tolerated
*** Conclusion: No difference in delay of disease progression
* TAX 327 (2000-2002) -- Docetaxel + prednisone vs. mitoxantrone + prednisone
** Randomized. 1006 patients with HRPC. Arm 1) docetaxel q3 weeks + prednisone (D3P) vs. Arm 2) docetaxel q1 week + prednisone (D1P) vs. Arm 3) mitoxantrone + prednisone (MP).
** 2004 PMID 15470213 -- "Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer." (Tannock IF, N Engl J Med. 2004 Oct 7;351(15):1502-12.)
*** Outcome: median OS D3P 18.9 months vs. D1P 17.4 months vs. MP 16.5 months (SS). Improved QoL: 23% vs. 22% vs. 13% (SS)
*** Conclusion: Docetaxel q3 weeks + prednisone led to improved survival and quality of life
** 2008 PMID 18182665 -- "Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study." (Berthold DR, J Clin Oncol. 2008 Jan 10;26(2):242-5.)
*** Outcome: median OS: D3P 19.2 months vs. D1P 17.8 months vs. MP 16.3 months (SS); 3-year OS 18.6% vs. 16.6% vs. 13.5%. Similar outcome regardless of age, pain, or baseline PSA
*** Conclusion: Survival longer after docetaxel q3 weeks with prednisone
* SWOG 9916 (1999-2003) -- Docetaxel + estramustine + dexamethasone vs. mitoxantrone + prednisone
** Randomized. 674 men with HRPC. Arm 1) docetaxel + estramustine + dexamethasone q3 weeks vs. Arm 2) mitoxantrone + prednisone q3 weeks
** 2004 PMID 15470214 -- "Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer." (Petrylak DP, N Engl J Med. 2004 Oct 7;351(15):1513-20.)
*** Outcome: median OS DED 17.5 months vs. MP 15.6 months (SS). Median TTP 6.3 months vs. 3.2 months (SS). Pain relief comparable
*** Toxicity: Grade 3-4 neutropenic fever, N/V, and CV events more common in docetaxel group
*** Outcome: Improved median survival with docetaxel + estramustine
* CALGB 9182 -- Mitoxantrone + hydrocortisone vs. hydrocortisone alone
** Randomized. 242 patients with HRPC. Arm 1) mitoxantrone + hydrocortisone (MH) vs. Arm 2) hydrocortisone alone (H).
** 1999 PMID 10561316 -- "Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer: results of the cancer and leukemia group B 9182 study." (Kantoff PW, J Clin Oncol. 1999 Aug;17(8):2506-13.)
*** Outcome: MH better in TTTF, response rate, pain control, and QoL. No difference in survival (12.3 months vs. 12.6 months, NS)
*** Conclusion: Mitoxantrone with hydrocortisone had more frequent response, delay to progression, and pain control than hydrocortisone alone
* Canada -- Mitoxantrone + prednisone vs. prednisone alone
** Randomized. 161 HRPC with pain. Arm 1) mitoxantrone + prednisone vs. Arm 2) prednisone alone. Primary end point palliative response (1/3 pain decrease)
** 1996 PMID 8656243 -- "Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points." (Tannock IF, J Clin Oncol. 1996 Jun;14(6):1756-64.)
*** Outcome: Palliative response MP 29% vs. P 12% (SS). Duration of palliation MP 9.9 months vs. P 4.1 months (SS)
*** Conclusion: Chemotherapy with mitoxantrone and prednisone provides palliation for some patients with symptomatic HRPC
* Scandinavian SPCG-1 (1984-1989) -- diethylstilbestrol vs. estramustine
** Randomized. 197 patients with high grade metastatic PCA (M1, G2-3). Arm 1) estramustine 560 mg vs Arm 2) diethylstilbestrol (DES) 3 mg
** 1997 PMID 9165581 -- "Treatment of high-grade, high-stage prostate cancer with estramustine phosphate or diethylstilbestrol. A double-blind study. The SPCG-1 Study Group. Scandinavian Prostate Cancer Group." (Hedlund PO, Scand J Urol Nephrol. 1997 Apr;31(2):167-72.)
*** Outcome: DES better for time-to-progression (p=0.05), treatment failure (SS), CSS (p=0.07), and OS (SS)
*** Conclusion: Treatment with DES had relatively good effect
* Orebro, Sweden -- medroxyprogesterone vs. estramustine
** Randomized. 105 patients, metastatic HRPC. Arm 1) medroxyprogesterone 1000 mg vs. Arm 2) estramustine 280 mg
** 1991 PMID 1831397 -- "High-dose medroxyprogesterone acetate versus estramustine in therapy-resistant prostatic cancer: a randomised study." (Johannson JE, Br J Urol. 1991 Jul;68(1):67-73.)
*** Outcome: Response rate better with MPA. No difference in PFS or OS
*** Conclusion: Response rate better with MPA, with fewer side effects

## Role of Prostate Biopsy?

* SEER/U. Colorado - "The prognostic significance of Gleason scores in metastatic prostate cancer" (Rusthoven CG. Urol Oncol. 2014. Epub ahead of print. PMID 24629494)
** 4,654 patients with metastatic disease at diagnosis or within 4 months of presentation
** For Gleason 6, 7, 8, 9, and 10:
*** 4-year OS rates 51%, 45%, 34%, 25%, and 15%
*** 4-year CSS rates 69%, 57%, 44%, 33%, and 21%
** Differences between Gleason 7 vs 8, 8 v 9, 9 vs 10 significant on univariate/multivariate analyses (all p<.001)
** Gleason pattern 5 was an independent prognostic factor, both overall for patients with GS 6 to 10 and on primary-secondary Gleason pattern comparisons within the GS 8 (4+4 vs. 3+5 and 5+3) and GS 9 (4+5 vs. 5+4) subgroups
** Gleason was the strongest prognostic factor for CSS (more important than PSA and age)
** Conclusion: "Stratified survival outcomes were observed for GS 6 to 10, with sequential comparisons of GS 7 to 10, and the presence and extent of Gleason pattern 5 representing independent prognostic factors in the metastatic setting"

## SBRT in Oligometastatic Disease

* ARTO Trial, 2024 (2019-2022) PMID 37733977 -- Stereotactic Body Radiation Therapy and Abiraterone Acetate for Patients Affected by Oligometastatic Castrate-Resistant Prostate Cancer: A Randomized Phase II Trial (ARTO)" (Francolini G, J Clin Oncol. 2023 Dec 20;41(36):5561-5568. doi: 10.1200/JCO.23.00985. Epub 2023 Sep 21.)
** Randomized Phase II. 157 patients, oligometastatic (<=3 nonvisceral metastases). Arm 1) Abiraterone Acetate alone vs Arm 2) AAP + SBRT to all sites of disease. SBRT physician choice, with BED >100 Gy using a/b = 3. AAP 100 mg daily + prednisone 5 mg twice daily. Concomitant ADT.
** Outcome: Biochemical response control 68% vs SBRT 80% (SS). Complete BR 23% vs 56% (SS). PFS HR 0.35 (SS)
** Conclusion: SBRT improved biochemical control and PFS