Editing Prostate Cancer: Management of Locally Advanced Prostate Cancer (section)

==== Adjuvant vs. early salvage radiation ====

===== Evidence =====

*'''ARTISTIC Meta-analysis'''
** Included 2153 patients from RADICALS, GETUG-17 and RAVES trials which evaluated adjuvant radiation therapy vs. surveillance with early salvage radiation therapy for PSA increase in patients with high-risk localized prostate cancer following radical prostatectomy.
***Criteria for early salvage therapy was a PSA >0.1 ng/mL or >0.2 ng/mL depending on the trial
***The proportion of patients in the early salvage therapy groups that received radiation therapy ranged from one third to one half.
** '''Results'''
*** '''No difference in event-free survival''' based on meta-analysis of 3 trials (pooled HR 0.95, 95% CI 0.75 to 1.21)
***'''Adjuvant radiation was associated with increased risk of genitourinary toxicity'''
*** '''Overall, there were few patients with high-risk features'''
** [https://pubmed.ncbi.nlm.nih.gov/33002431/ Vale, Claire L., et al.]" Adjuvant or early salvage radiotherapy for the treatment of localised and locally advanced prostate cancer: a prospectively planned systematic review and meta-analysis of aggregate data." ''The Lancet'' (2020).
**'''RADICALS'''
*** 1,396 males from multiple countries that underwent prostatectomy for non-metastatic prostate cancer with undetectable PSA and ≥1 risk factor:
**** pT stage ≥3
**** Grade group ≥2
**** Positive margins
**** Preoperative PSA ≥ 10 ng/mL
*** Randomized to adjuvant radiation vs. early salvage (with second randomization on duration of ADT 6 vs. 24 months)
**** Salvage radiation administered for PSA biochemical progression, defined as either:
***** 2 consecutive rising PSA amounts with a PSA > 0.1 ng/mL
***** 3 consecutive rising PSA
*** Outcomes:
**** Primary: distant metastasis-free survival (though initially was disease-specific survival)
**** Secondary: disease-specific survival, overall survival, initiation of non-protocol hormone therapy, treatment toxicity, and patient-reported outcomes.
*** Results:
**** Median follow-up: 5 years
**** Distant metastasis-free survival outcome data not mature
**** No significant difference in biochemical progression-free survival (85% radiation vs. 88% salvage at 5-years (HR 1.10, 95% CI 0.81-1.49))
*** Parker, Christopher C., et al."Timing of radiotherapy after radical prostatectomy (RADICALS-RT): a randomised, controlled phase 3 trial." ''The Lancet'' 396.10260 (2020): 1413-1421.
** '''GETUG-17'''
*** The French Groupe d’Étude des Tumeurs Uro-Génitales (GETUG-17) trial will evaluate a similar patient population but will randomize patients to immediate adjuvant radiation therapy versus observation patients and treating with salvage radiation when PSA levels reach a level of 0.2 ng/mL.
** '''RAVES''': Radiotherapy—Adjuvant versus Early Salvage trial
*** A phase III trial randomizing patients with pathologic T3 disease and/or positive margins. Primary end point is biochemical cancer control with secondary outcomes including quality of life, toxicity, anxiety/depression, biochemical failure–free survival, overall survival, disease-specific survival, time to distant failure, time to local failure, time to initiation of androgen ablation, quality adjusted life years, and cost-utility.
*** Trial terminated due to poor accrual

===== Recommendations =====

====== NCCN ======
*'''2023 NCCN (PROS 10, PROS G 5/7)'''
**'''If life expectancy ≤ 5 years, observation'''
**'''If life expectancy > 5 years,''' 
***'''Adjuvant RT if pT3a disease, positive margin(s), or seminal vesicle involvement'''
****'''. Patients with positive surgical margins may benefit the most'''
***'''Salvage RT if an undetectable PSA that becomes subsequently detectable and increases on 2 measurements or a PSA that remains persistently detectable after RP'''
***PSA persistence/recurrence after RP is defined as failure of PSA to fall to undetectable levels (PSA persistence) or undetectable PSA after RP with a subsequent detectable PSA that increases on 2 or more determinations (PSA recurrence) or that increases to PSA >0.1 ng/mL
****'''Treatment is more effective when pre-treatment PSA is low and PSADT is long.'''

====== AUA ======
*'''2023 AUA Guidelines on Clinically Localized Prostate Cancer'''
**'''Adjuvant radiotherapy'''
***'''<span style="color:#ff0000">Should not be routinely recommended</span>'''
****'''<span style="color:#ff0000">Patients should be initially managed with PSA surveillance after radical prostatectomy</span>'''
***'''There may be a role for adjuvant radiation in patients with high-risk features (e.g., Gleason 8 to 10 disease with extraprostatic extension, positive lymph nodes); there were few of these patients in the trials'''

*'''2019 AUA guidelines (published before publication of RCTs comparing adjuvant vs. early salvage)'''
**'''ART should be offered if pT3a disease, positive margin(s), or seminal vesicle involvement'''
**'''SRT should be offered to patients with PSA or local recurrence after radical prostatectomy in whom there is no evidence of distant metastatic disease'''
**
*'''2022 EAU guidelines[https://uroweb.org/guidelines/prostate-cancer/chapter/treatment]''' 
**'''Only offer adjuvant intensity-modulated radiation therapy (IMRT)/volumetric modulated arc therapy (VMAT) plus image-guided radiation therapy (IGRT) to high-risk patients (pN0) with at least two out of three high-risk features (ISUP grade group 4–5, pT3, positive margins).'''
**'''PSA persistence after surgery'''
***'''Offer a prostate-specific membrane antigen positron-emission tomography (PSMA PET) scan to men with a persistent prostate-specific antigen > 0.2 ng/mL if the results will influence subsequent treatment decisions.'''
***'''Treat men with no evidence of metastatic disease with salvage radiotherapy and additional hormonal therapy.'''
**'''Recommendations for biochemical recurrence (BCR) after radical prostatectomy'''
***'''Offer early salvage intensity-modulated radiotherapy/volumetric arc radiation therapy plus image-guided radiotherapy to men with two consecutive PSA rises.'''
***'''Do not wait for a PSA threshold before starting treatment. Once the decision for SRT has been made, SRT (at least 64 Gy) should be given as soon as possible.'''