Patterns of Clinical Progression in Radiorecurrent High-Risk Prostate Cancer - Beyond the Abstract

High-risk prostate cancer (HRPCa) – defined by the NCCN as the presence of Gleason grade group 4-5 disease, clinical T stage 3-4, or PSA>20 – is an aggressive disease entity with a high risk of biochemical failure, up to 50% with extended follow-up. In recent years, we have learned that upfront management with external beam radiotherapy (EBRT), especially combined with brachytherapy (EBRT+BT), is one of the optimal strategies for definitive local therapy.1 While the natural history of high-risk prostate cancer is fairly well described 2 the natural history of clinical progression in men with radiorecurrent high-risk prostate cancer has not been well delineated.

To better understand this natural history, we evaluated 978 men with HRPCa treated from 1997-2015 across 15 institutions with either EBRT (n=654, 67%) or EBRT+BT (n=324, 33%), who subsequently developed BCR (defined by PSA nadir + ≥2 ng/mL).2  Ninety percent of these men received some form of androgen deprivation therapy (median duration 23 months with EBRT and 8 months with EBRT+BT). We examined rates of distant metastasis (DM) and prostate cancer-specific mortality (PCSM) following BCR. Multivariable cox proportional hazards models were also constructed to evaluate predictors of DM and PCSM in this population.

Median follow-up was 8.9 years from initial radiotherapy and 3.7 years from BCR in men who did not die (10.5 years and 5.2 years, respectively, in all patients). This was a fairly aggressive cohort – approximately 70% of patients had grade group 4 or 5 disease, and 41% of patients with at least two NCCN high-risk factors.

Local salvage was performed in only 21 patients after EBRT and 8 patients after EBRT+BT. Systemic therapy as salvage for radiorecurrence was much more common but not ubiquitous – 390 and 103 men received systemic salvage therapy after EBRT and EBRT+BT, respectively.

The 5-year cumulative incidence of DM was 50% in men treated with EBRT and 34% in men treated with EBRT+BT. Among the 435 men who developed DM, a majority occurred early on following BCR. Specifically, 189 men (58%, EBRT) and 59 men (63%, EBRT+BT) developed DM within one year or less following BCR. We hypothesize that the prevalence of early DMs may be the manifestation of occult micrometastatic disease that was actually present initially but masked by androgen suppression, later progressing to meet BCR criteria once androgen suppression was removed.

The 5-year cumulative incidence of PCSM was 27% overall, with incidences of 27% after EBRT and 29% after EBRT+BT. This rate was surprisingly high, matching rates seen with de novo metastatic disease.3 This again supports the theory that a substantial portion of the clinical progression seen in men with radiorecurrent HRPCa may be in fact related to occult micrometastatic disease. Again in support of this theory, the most salient predictor for both DM and PCSM was shorter interval to biochemical failure.

Overall, this study highlights the aggressive natural history and rapid clinical progression of men with radiorecurrent HRPCa. However, it is important to note that local salvage was minimally utilized, systemic therapy salvage was not ubiquitous. In addition, due to the era in which these men were treated, many would not have had access to the advances that have been made in the systemic salvage setting in recent years.4 Ultimately, improvement in upfront risk-stratification strategies for high-risk patients such as PSMA imaging5 and genomics6 may help us identify pre-existing micrometastatic disease, or patients at high risk for harboring it, and thus intensify treatment where applicable to optimize outcomes.

Written by: Rebecca Philipson, MD,1 & Amar U. Kishan, MD,2

  1. Radiation Oncologist, Torrance Memorial Medical Center, Los Angeles, California, United States
  2. Assistant Professor, Chief of Genitourinary Oncology Service, Vice Chair of Clinical and Translational Research, Department of Radiation Oncology, University of California, Los Angeles


  1. Kishan AU, Cook RR, Ciezki JP, et al. Radical Prostatectomy, External Beam Radiotherapy, or External Beam Radiotherapy With Brachytherapy Boost and Disease Progression and Mortality in Patients With Gleason Score 9-10 Prostate Cancer. JAMA. 2018;319(9):896-905. doi:10.1001/jama.2018.0587
  2. Moris L, Cumberbatch MG, Van den Broeck T, et al. Benefits and Risks of Primary Treatments for High-risk Localized and Locally Advanced Prostate Cancer: An International Multidisciplinary Systematic Review. Eur Urol. 2020;77(5):614-627. doi:
  3. Borno HT, Cowan JE, Zhao S, Broering JM, Carroll PR, Ryan CJ. Examining initial treatment and survival among men with metastatic prostate cancer: An analysis from the CaPSURE registry. Urol Oncol. 2020;38(10):793.e1-793.e11. doi:10.1016/j.urolonc.2020.07.012
  4. Wang L, Paller CJ, Hong H, De Felice A, Alexander GC, Brawley O. Comparison of Systemic Treatments for Metastatic Castration-Sensitive Prostate Cancer: A Systematic Review and Network Meta-analysis. JAMA Oncol. 2021;7(3):412-420. doi:10.1001/jamaoncol.2020.6973
  5. Calais J, Kishan AU, Cao M, et al. Potential Impact of (68)Ga-PSMA-11 PET/CT on the Planning of Definitive Radiation Therapy for Prostate Cancer. J Nucl Med. 2018;59(11):1714-1721. doi:10.2967/jnumed.118.209387
  6. Al Hussein Al Awamlh B, Shoag JE. Genomics and risk stratification in high-risk prostate cancer. Nat Rev Urol. 2019;16(11):641-642. doi:10.1038/s41585-019-0227-x

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