**10. Adjuvant and early salvage radiotherapy**

Unfortunately, 20–50% of patients may experience either biochemical recurrence or a persistently-elevated PSA within 5–10 years after prostatectomy [37]. Three randomized trials established the benefit of adjuvant radiotherapy, which improved the 10-year biochemical recurrence-free survival to about 60% from about 30–40% [38]. There has been ongoing debate as to the timing of radiotherapy, i.e. whether it should be delivered in the adjuvant setting (within 12–16 weeks post-prostatectomy while PSA remains undetectable) or as salvage radiotherapy (initiated in the presence of detectable PSA or a palpable nodule on DRE). The ARTISTIC meta-analysis found that adjuvant RT did not improve the 5-year event free survival over salvage radiotherapy in localized or locally-advanced disease, supporting the use of early salvage treatment [39].

The decision of whether to treat should include risk stratification based on multiple factors such as age, co-morbidities, size/number of positive margin(s), the absolute PSA level, PSA doubling time, nomograms, and molecular assays (e.g., Decipher® Score). Given conflicting conclusions in studies comparing adjuvant versus salvage radiotherapy, the NCCN recommends curative intent adjuvant or early salvage radiotherapy in patients with life expectancies >5 years with detectable PSA and adverse pathologic features (e.g., positive margins, seminal vesical invasion or extra-prostatic extension), or positive nodes [8]. The work-up for post-operative patients with evidence of persistent or recurrent disease includes H&P, DRE, PSA, MRI, and PSMA PET/CT (preferred over CT plus bone scan, per NCCN 2023 update), consecutive PSA measurements ≥0.2 ng/ml, and potentially a biopsy of the prostate bed.

The ASTRO/AUA guidelines recommend at least 64–65 Gy in the post-operative setting, with no distinction between adjuvant and salvage treatment [40]. Hypofractionated regimens in the adjuvant and salvage setting are currently being investigated. Three phase 2 trials utilized regimens of 65 Gy/26 fractions, 54 Gy/18 fractions, and 51 Gy/17 fractions, and demonstrated excellent efficacy and low rates of toxicity [41–43]. The NRG-GU003 phase 3 trial is randomizing patients to conventional fractionation (66.6 Gy/37) vs. hypofractionation (62.5 Gy/25 fx); it is currently closed to accrual, with expected completion in 2026 [44].

The RTOG 96–01 trial assessed the addition of 24 months of bicalutamide to radiotherapy in patients with biochemical failure, and demonstrated improved 12 year OS in salvage patients with PSA >0.61 ng/mL, but men with PSA ≤ 0.6 ng/mL (i.e., early salvage patients) experienced increased other-cause mortality and cardiac events [45]. The GETUG-AFU 16 trial assessed the addition of 6 months of ADT for patients with biochemical failure; at 120 months, the progression-free survival was

64% for patients with radiotherapy plus goserelin and 49% for patients with radiotherapy alone (HR = 0.54, p < 0.0001) [46]. The NRG Oncology/RTOG 05–34 SPPORT trial has demonstrated an improved 5-year freedom from progression with the addition of ADT to prostate bed radiotherapy (PBRT) over PBRT alone, 81% vs. 71% [47]. The SPPORT trial is also assessing the addition of pelvic nodal radiotherapy to PBRT+ADT, and demonstrated an improved 5-year freedom from progression (87%) versus the groups mentioned above. Acute toxicities are significantly worse with the addition of ADT and with ADT + pelvic nodal radiotherapy, but no differences were seen in late toxicities.

The NCCN now recommends obtaining the Decipher® molecular assay to help individualize treatment decisions in the post-operative setting; patients with a high Decipher® genomic classifier Score (>0.6) should be strongly considered for EBRT with ADT in patients who have not received early salvage therapy [8].
