Radical treatment, whether it is radical prostatectomy (RP) or radiotherapy (RT) provides excellent oncological outcomes in most men with localized prostate cancer. Nevertheless, 5% to 30% of patients will eventually relapse, depending on disease characteristic at diagnosis.1,2 The vast majority of these relapses are isolated PSA elevation, often below of 0.2 ng/mL, with no detectable metastases on conventional imaging assessment (e.g., 99mTc bone scintigraphy and computed tomography of pelvic, abdomen and thorax). These relapses are thus coined biochemical recurrence (BCR). Patients presenting with a BCR have a very heterogeneous disease natural history in terms of metastasis-free survival (MFS), cancer-specific, or overall survival (OS). While BCR predicts an increased risk of disease progression and death, it is, however, not a direct surrogate for OS, stressing the need to identify risk factors for adverse oncologic outcomes in this setting. A seminal work from Johns Hopkins group has established the central role of the Gleason score, the time interval between primary treatment and recurrence, and the PSA doubling time (PSADT) as the key factors in predicting outcomes.3 In a retrospective analysis of 1997 patients after RP with no neoadjuvant or adjuvant therapy before documented metastases, 315 men developed a BCR3; among these 315 men, 103 developed metastases, with a median time from PSA elevation to the onset of metastases being 8 years. Time to biochemical progression, Gleason score, and PSADT were predictive of the probability and time to the development of metastatic disease. The same authors later confirmed that these 3 factors also predict prostate cancer death following RP.4 These studies have helped identify the group of patients at risk of dying of prostate cancer recurrence following BCR but also identified a group of patients with relatively indolent disease and prolonged survival. Recently, 2 systematic reviews on BCR after curative treatment for nonmetastatic prostate cancer were performed to identify prognostic factors for oncological outcomes.5,6 In the first one, based almost exclusively on retrospective studies, after RP, BCR was associated with worse survival rates mainly in patients with short PSADT (< 12 months) and a high Gleason score (≥ ISUP 4) on prostatectomy specimen.5 In contrast, in the second one, based solely on prospective studies, the risk factors with moderate evidence were T stage ≥ pT3, Gleason score (≥ ISUP 4), negative surgical margins, and PSA before salvage treatment of >0.5 ng/Ml.6 Although these results differ, there is no complete discordance. The second review is based only on prospective studies, avoiding the risk of selection bias; it provides the highest level of evidence on this subject. The European Association of Urology (EAU) BCR risk groups were based on the first systematic review results with a high risk BCR being defined as a patient with a PSADT < 12 months or a Gleason score ≥ ISUP 4.7 This BCR risk stratification has been subsequently validated in a retrospective analysis of a cohort of 1125 patients post RP: the 5-yr MFS and prostate cancer specific-free survival were significantly higher among patients with low BCR risk compared to their high-risk counterparts.8 The therapeutic consequences of this risk group classification are debatable. However, one can suggest that patients in the low-risk group may be managed with PSA monitoring only (and treated in case of shortening of the PSADT) and that patients in the high-risk group may benefit from an intensified salvage treatment combining RT and systemic treatment and whose optimal modalities still need to be defined.

Adjuvant RT of the prostatic bed and/or pelvic lymph node has been historically advocated in case of abnormal pathological features (such as a high Gleason score, capsular invasion, positive surgical margins, and/or seminal vesicles invasion) based on the results of 4 prospective randomized controlled trials (RCTs) which have shown an improved biochemical PFS with adjuvant RT vs observation in this group of patients.9, 10, 11, 12 In that group of patients, biochemical PFS is not a valid surrogate of MFS and OS.13 After nearly 13 years of follow-up, only the SWOG S8794 trial showed a benefit in MFS (HR = 0.71; 95% CI: 0.54-0.94; p = 0.016) and OS (HR= 0.72; 95% CI: 0.55-0.96; p = 0.023).12 Of note, only one of the 4 trial was a pure adjuvant trial, that is, enrolling patients with an undetectable PSA.10 Indeed, the proportion of patients with a PSA ≥0,2 ng/mL, was 35% in the SWOG trial,12 29% in the EORTC trial,11 and 48% in the Finnish trial.9 This is a drawback to correctly interpreting these results because patients with detectable PSA nowadays would be considered early salvage RT.10 GU toxicity following prostate bed RT is not negligible. With a standard prostate bed radiation dose of 64 Gy, late grade 2 and 3 GU toxicity after sRT was observed in respectively 21% and 8% of treated patients.14 These numbers are similar to the 4-year grade 2 and 3 GU toxicity rates of 22% and 6%, respectively, observed in a prospective cohort study of men with PCa who received sRT between 2007 and 2015.15 Likewise, in a cross-sectional quality-of-life survey of 2943 men conducted by the European patients coalition Europa UOMO, 17.9% of patients lacked urinary control after surgery and sRT, while self-reported sexual function scores were the lowest for men who underwent surgery and Srt.16,17

To spare some patients an unnecessary RT treatment, 3 RCTs (RADICALS RT,18,19 RAVES,20 and GETUG-AFU-1721) and an individual patient data meta-analysis (ARTISTIC22) have compared early sRT with adjuvant RT in terms of oncological outcomes and toxicity. Adjuvant RT was not superior to sRT regarding PFS and increased genito-urinary (GU) toxicity because approximately two-third of the patients in the sRT group did not receive RT. In light of these results, monitoring of PSA and administering early sRT is currently the most widely adopted practice.

The benefit of sRT compared to no salvage treatment has never been demonstrated in an RCT. However, multiple retrospective analyses validate the benefit of sRT in terms of prostate cancer-specific survival and development of distant metastases. Trock et al.23 conducted a retrospective analysis of a cohort of 635 prostate cancer patients undergoing RP who experienced biochemical and/or local recurrence and received no salvage treatment, sRT alone, or sRT plus hormonal therapy. Compared to individuals who had no salvage treatment, sRT alone was significantly associated with a 3-fold increase in prostate cancer-specific survival (HR = 0.32; 95% CI: 0.19-0.54). Similarly, Tilki et al. evaluated the long-term oncologic outcomes of sRT compared to no RT in PCa patients experiencing BCR after RP. Using a multi-institutional database, 1832 patients were analyzed, with 603 (32.9%) receiving sRT. After propensity score matching, patients treated with sRT had significantly improved MFS and OS at 15 years (84.3% vs. 76.9% and 85.3% vs. 74.4%, respectively). Multivariable analysis confirmed sRT as an independent predictor of reduced metastasis risk (HR= 0.37, p < 0.001) and improved OS (HR = 0.64, p = 0.03).24

In the Trock et al. study, after adjusting for pathological stage and other prognostic factors, the survival benefit of sRT was observed only in patients with a PSA doubling time (PSADT) of less than 6 months, highlighting the importance of early intervention in high-risk cases. More recent retrospective studies have further refined prognostic factors in patients undergoing SRT. Stish et al. analyzed 1,106 patients and found that pathologic tumor stage, Gleason score, and pre-SRT PSA were significant predictors of distant metastases, cancer-specific mortality, and OS (OS). Similarly, Tendulkar et al., in a cohort of 2,460 patients with a median follow-up of 5 years, demonstrated that pre-SRT PSA, Gleason score, seminal vesicle involvement, surgical margins, and the use of androgen deprivation therapy (ADT) were associated with distant metastasis risk.25,26 Finally, a multinational study analyzing 25,551 patients with pT2-4N0 or NXM0 PCa with at least one high-risk factor (pT3/4 or Gleason score 8-10) found that delaying sRT beyond a PSA threshold of 0.25 ng/mL was correlated to a significantly increased risk of all-cause mortality (HR = 1.49; 95% CI:1.11-2.00; p = 0.008) compared to those treated at PSA ≤0.25 ng/mL.27 As a result, current guidelines recommend initiating SRT promptly rather than waiting for a specific PSA threshold, ensuring optimal oncologic outcomes when treatment is deemed necessary by the physician.