# Adjuvant or Salvage Radiation Therapy for Prostate Cancer after Prostatectomy: Current Status, Controversies and Perspectives

Mario Terlizzi, Elaine Johanna Limkin, Yasmina Moukasse, Pierre Blanchard

► To cite this version:

Mario Terlizzi, Elaine Johanna Limkin, Yasmina Moukasse, Pierre Blanchard. Adjuvant or Salvage Radiation Therapy for Prostate Cancer after Prostatectomy: Current Status, Controversies and Perspectives. Cancers, 2022, 14 (7), pp.1688. 10.3390/cancers14071688. hal-04522197

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Review

# Adjuvant or Salvage Radiation Therapy for Prostate Cancer after Prostatectomy: Current Status, Controversies and Perspectives

Mario Terlizzi* ID, Elaine Johanna Limkin, Yasmina Moukasse and Pierre Blanchard ID

Radiation Oncology Department, Institute Gustave Roussy, 94805 Villejuif, France;
elaine.limkin@gustaveroussy.fr (E.J.L.); yasmina.moukasse@gustaveroussy.fr (Y.M.);
pierre.blanchard@gustaveroussy.fr (P.B.)

* Correspondence: mario.terlizzi@gustaveroussy.fr

**Simple Summary:** The management of patients with biochemical recurrence after prostatectomy has undergone significant changes in recent years. Currently, close monitoring of prostate-specific antigen (PSA) with early salvage radiotherapy (RT) in case of recurrence is the standard of care based on several randomized trials and a meta-analysis that has demonstrated its non-inferiority to adjuvant RT. Uncertainties remain regarding the management of patients at very high risk of recurrence, including appropriate selection criteria for adjuvant hormone therapy, and the role of imaging in refining the treatment strategy. This review explains this paradigm shift, raises points of controversy, and suggests ways to think about the future.

**Abstract:** Nearly one-third of the patients who undergo prostatectomy for prostate cancer have a biochemical recurrence (BCR) during follow-up. While several randomized trials have shown that adjuvant radiation therapy (aRT) improves biochemical control, this strategy has not been widely used because of the risk of toxicity and the fear of overtreating patients who would not have relapsed. In addition, the possibility of close PSA monitoring in the era of ultrasensitive assays enables to anticipate early salvage strategies (sRT). Three recent randomized trials and their meta-analysis have confirmed that aRT does not improve event-free survival compared to sRT, imposing the latter as the new standard of treatment. The addition of androgen deprivation therapy (ADT) to RT has been shown to improve biochemical control and metastasis-free survival, but the precise definition of to whom it should be proposed is still a matter of debate. The development of genomic tests or the use of artificial intelligence will allow more individualized treatment in the future. Therapeutic intensification with the combination of new-generation hormone therapy and RT is under study. Finally, the growing importance of metabolic imaging (PET/CT) due to its performance especially for low PSA levels will help in further personalizing management strategies.

**Keywords:** prostate cancer; radiation therapy; adjuvant; salvage

## 1. Introduction

Prostate cancer is currently the second most frequent malignancy in men worldwide, responsible for nearly 360,000 deaths each year [1]. Radical prostatectomy (RP) +/- pelvic lymph node dissection (PLND) is one of the cornerstones of treatment for localized diseases but almost 20-40% of patients all stages combined will present with biochemical recurrence (BCR) in the first 10 years after surgery, requiring additional radiation therapy (RT) to be cured [2]. RT can either be delivered as an adjuvant treatment, based on the assessment of the risk of recurrence using prostatectomy histological criteria, or as a salvage treatment at the time of the BCR. As BCR precedes the appearance of metastases with a mean time of 8 years and specific mortality of about 15 years, this constitutes a window of opportunity that should not be missed from a curative perspective [3]. In recent years,

<figure><img src="image_1.png" /></figure>

### check for updates

**Citation:** Terlizzi, M.; Limkin, E.J.; Moukasse, Y.; Blanchard, P. Adjuvant or Salvage Radiation Therapy for Prostate Cancer after Prostatectomy: Current Status, Controversies and Perspectives. *Cancers* **2022**, *14*, 1688.

https://doi.org/10.3390/cancers14071688

**Academic Editor:** Emmanuel S. Antonarakis

Received: 27 February 2022

Accepted: 23 March 2022

Published: 26 March 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

<figure><img src="image_2.png" /></figure>

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Review

# Adjuvant or Salvage Radiation Therapy for Prostate Cancer after Prostatectomy: Current Status, Controversies and Perspectives

Mario Terlizzi* ID, Elaine Johanna Limkin, Yasmina Moukasse and Pierre Blanchard ID

Radiation Oncology Department, Institute Gustave Roussy, 94805 Villejuif, France;
elaine.limkin@gustaveroussy.fr (E.J.L.); yasmina.moukasse@gustaveroussy.fr (Y.M.);
pierre.blanchard@gustaveroussy.fr (P.B.)

* Correspondence: mario.terlizzi@gustaveroussy.fr

**Simple Summary:** The management of patients with biochemical recurrence after prostatectomy has undergone significant changes in recent years. Currently, close monitoring of prostate-specific antigen (PSA) with early salvage radiotherapy (RT) in case of recurrence is the standard of care based on several randomized trials and a meta-analysis that has demonstrated its non-inferiority to adjuvant RT. Uncertainties remain regarding the management of patients at very high risk of recurrence, including appropriate selection criteria for adjuvant hormone therapy, and the role of imaging in refining the treatment strategy. This review explains this paradigm shift, raises points of controversy, and suggests ways to think about the future.

**Abstract:** Nearly one-third of the patients who undergo prostatectomy for prostate cancer have a biochemical recurrence (BCR) during follow-up. While several randomized trials have shown that adjuvant radiation therapy (aRT) improves biochemical control, this strategy has not been widely used because of the risk of toxicity and the fear of overtreating patients who would not have relapsed. In addition, the possibility of close PSA monitoring in the era of ultrasensitive assays enables to anticipate early salvage strategies (sRT). Three recent randomized trials and their meta-analysis have confirmed that aRT does not improve event-free survival compared to sRT, imposing the latter as the new standard of treatment. The addition of androgen deprivation therapy (ADT) to RT has been shown to improve biochemical control and metastasis-free survival, but the precise definition of to whom it should be proposed is still a matter of debate. The development of genomic tests or the use of artificial intelligence will allow more individualized treatment in the future. Therapeutic intensification with the combination of new-generation hormone therapy and RT is under study. Finally, the growing importance of metabolic imaging (PET/CT) due to its performance especially for low PSA levels will help in further personalizing management strategies.

**Keywords:** prostate cancer; radiation therapy; adjuvant; salvage

## 1. Introduction

Prostate cancer is currently the second most frequent malignancy in men worldwide, responsible for nearly 360,000 deaths each year [1]. Radical prostatectomy (RP) +/- pelvic lymph node dissection (PLND) is one of the cornerstones of treatment for localized diseases but almost 20-40% of patients all stages combined will present with biochemical recurrence (BCR) in the first 10 years after surgery, requiring additional radiation therapy (RT) to be cured [2]. RT can either be delivered as an adjuvant treatment, based on the assessment of the risk of recurrence using prostatectomy histological criteria, or as a salvage treatment at the time of the BCR. As BCR precedes the appearance of metastases with a mean time of 8 years and specific mortality of about 15 years, this constitutes a window of opportunity that should not be missed from a curative perspective [3]. In recent years,

<figure><img src="image_2.png" /></figure>

### check for updates

**Citation:** Terlizzi, M.; Limkin, E.J.; Moukasse, Y.; Blanchard, P. Adjuvant or Salvage Radiation Therapy for Prostate Cancer after Prostatectomy: Current Status, Controversies and Perspectives. *Cancers* **2022**, *14*, 1688.
https://doi.org/10.3390/cancers14071688

Academic Editor: Emmanuel S. Antonarakis

Received: 27 February 2022

Accepted: 23 March 2022

Published: 26 March 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

<figure><img src="image_3.png" /></figure>

**Copyright:** © 2022 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
several studies have changed the paradigm so that the indications for adjuvant therapy have drastically declined.

This review explores currently available evidence guiding the choice between adjuvant and salvage RT, the addition of androgen deprivation therapy (ADT) to RT, the place of advanced imaging, and future avenues for research. Data from published randomized controlled trials or large retrospective studies were used to summarize the available data. This allowed a broad analysis of the literature but didn't exclude selection bias.

## 2. Are All Patients at Equal Risk of Biochemical Relapse?

There is a broad spectrum of patients treated with RP, with variable prognoses. Several pathological factors have been associated with increased risk of BCR after RP: a high Gleason score (≥8), pT3a (extracapsular extension) or pT3b (seminal vesicle invasion), positive margins (R1), and lymph node invasion (N1). A combination of these criteria further increases the risk of BCR. In a series by Abdollah et al., aRT improved survival only in men having less than two factors among Gleason score ≥ 8, pT3b/T4 stage and pN1 stage [4].

The PSA remains to be the most reliable biomarker of disease persistence or recurrence. However, for a long time, there was no universal consensus in the cut-off value defining BCR. A PSA > 0.4 ng/mL was described as the threshold best associated with the development of distant metastases in the post-operative setting [5]. The relevance of this threshold to guide postoperative RT has decreased in the era of the ultrasensitive PSA assay, and since it has been shown that the lower the PSA was at the time of RT, the higher biochemical control and lower distant metastasis (DM) rates [6]. Currently, BCR after RP is defined according to the European Association of Urology (EAU) guidelines as two consecutive PSA values ≥ 0.2 ng/mL [7]. Beyond the absolute value of the PSA, its kinetics (evaluated by the doubling time, PSA-DT) has also a prognostic value [8]. Antonarakis et al. showed in a retrospective series of 450 men treated with RP that PSA-DT was an independent predictive factor of MFS [9].

In order to take into consideration the variability of possible clinical scenarios and assist in decision making the 2019 EAU-ESTRO-ESUR-SIOG guidelines proposed a useful BCR classification system stratifying patients into low (PSA-DT > 1 year and pGS < 8 after RP) or high-risk of BCR (PSA-DT ≤ 1 year or pGS 8–10). This stratification was externally validated by a large cohort of 1125 patients in which the BCR risk grouping was found as an independent predictor for DM (HR 3.46; *p* < 0.001) and prostate cancer-specific mortality (PCSM) (HR 5.12; *p* < 0.001) in multivariate analysis. Moreover, the effect of sRT was maximal for PSA level < 0.5 ng/mL arguing in favor of early delivery (HR 0.32 vs. 0.56 for DM and HR 0.31 vs. 0.58 for PCSM for PSA < 0.5 ng/mL and PSA ≥ 0.5 ng/mL, respectively) [10].

## 3. Radiation Therapy in the Post-Prostatectomy Setting: A Question of Timing

The assessment of the appropriate timing of postoperative RT has been the subject of several large trials that can be separated into older trials that compared aRT to surveillance [11–14] and newer trials that compared aRT to early sRT [15–17].

Four randomized trials have assessed the impact of aRT: SWOG 8794, EORTC 22911, ARO 96-02, and FinnProstate [11–14] (Table 1). Globally, patients with a high risk of relapse based on pathological criteria (pT3 ± positive margins) were randomized between aRT (total dose of 60–66 Gy in the prostate bed) or observation. At 10 years median follow-up, these studies have shown an increase in biochemical control of nearly 20% in favor of aRT. Only the oldest trial (SWOG 8794) has shown a benefit in terms of MFS and overall survival (OS) (HR 0.71; 95% CI 0.54–0.94; *p* = 0.016 and HR 0.72; 95% CI 0.55–0.96; *p* = 0.023 respectively) [11]. There are however several limitations that should be considered, and caution should be exercised when applying the results in clinical decision making. Populations were quite heterogeneous among studies. Only the ARO 96-02 required an undetectable PSA for inclusion (PSA < 0.1 ng/mL) whereas nearly 30% of patients in the
several studies have changed the paradigm so that the indications for adjuvant therapy have drastically declined.

This review explores currently available evidence guiding the choice between adjuvant and salvage RT, the addition of androgen deprivation therapy (ADT) to RT, the place of advanced imaging, and future avenues for research. Data from published randomized controlled trials or large retrospective studies were used to summarize the available data. This allowed a broad analysis of the literature but didn't exclude selection bias.

## 2. Are All Patients at Equal Risk of Biochemical Relapse?

There is a broad spectrum of patients treated with RP, with variable prognoses. Several pathological factors have been associated with increased risk of BCR after RP: a high Gleason score (≥8), pT3a (extracapsular extension) or pT3b (seminal vesicle invasion), positive margins (R1), and lymph node invasion (N1). A combination of these criteria further increases the risk of BCR. In a series by Abdollah et al., aRT improved survival only in men having less than two factors among Gleason score ≥ 8, pT3b/T4 stage and pN1 stage [4].

The PSA remains to be the most reliable biomarker of disease persistence or recurrence. However, for a long time, there was no universal consensus in the cut-off value defining BCR. A PSA > 0.4 ng/mL was described as the threshold best associated with the development of distant metastases in the post-operative setting [5]. The relevance of this threshold to guide postoperative RT has decreased in the era of the ultrasensitive PSA assay, and since it has been shown that the lower the PSA was at the time of RT, the higher biochemical control and lower distant metastasis (DM) rates [6]. Currently, BCR after RP is defined according to the European Association of Urology (EAU) guidelines as two consecutive PSA values ≥ 0.2 ng/mL [7]. Beyond the absolute value of the PSA, its kinetics (evaluated by the doubling time, PSA-DT) has also a prognostic value [8]. Antonarakis et al. showed in a retrospective series of 450 men treated with RP that PSA-DT was an independent predictive factor of MFS [9].

In order to take into consideration the variability of possible clinical scenarios and assist in decision making the 2019 EAU-ESTRO-ESUR-SIOG guidelines proposed a useful BCR classification system stratifying patients into low (PSA-DT > 1 year and pGS < 8 after RP) or high-risk of BCR (PSA-DT ≤ 1 year or pGS 8–10). This stratification was externally validated by a large cohort of 1125 patients in which the BCR risk grouping was found as an independent predictor for DM (HR 3.46; *p* < 0.001) and prostate cancer-specific mortality (PCSM) (HR 5.12; *p* < 0.001) in multivariate analysis. Moreover, the effect of sRT was maximal for PSA level < 0.5 ng/mL arguing in favor of early delivery (HR 0.32 vs. 0.56 for DM and HR 0.31 vs. 0.58 for PCSM for PSA < 0.5 ng/mL and PSA ≥ 0.5 ng/mL, respectively) [10].

## 3. Radiation Therapy in the Post-Prostatectomy Setting: A Question of Timing

The assessment of the appropriate timing of postoperative RT has been the subject of several large trials that can be separated into older trials that compared aRT to surveillance [11–14] and newer trials that compared aRT to early sRT [15–17].

Four randomized trials have assessed the impact of aRT: SWOG 8794, EORTC 22911, ARO 96-02, and FinnProstate [11–14] (Table 1). Globally, patients with a high risk of relapse based on pathological criteria (pT3 ± positive margins) were randomized between aRT (total dose of 60–66 Gy in the prostate bed) or observation. At 10 years median follow-up, these studies have shown an increase in biochemical control of nearly 20% in favor of aRT. Only the oldest trial (SWOG 8794) has shown a benefit in terms of MFS and overall survival (OS) (HR 0.71; 95% CI 0.54–0.94; *p* = 0.016 and HR 0.72; 95% CI 0.55–0.96; *p* = 0.023 respectively) [11]. There are however several limitations that should be considered, and caution should be exercised when applying the results in clinical decision making. Populations were quite heterogeneous among studies. Only the ARO 96-02 required an undetectable PSA for inclusion (PSA < 0.1 ng/mL) whereas nearly 30% of patients in the
SWOG 8794 and EORTC 22911 trials presented with a measurable PSA at inclusion and were therefore in an early salvage setting. Conversely, some patients in the observation arm did not receive sRT despite having measurable PSA. In a recent meta-analysis combining data from these four trials (n = 2068), Bhindi et al. reported a significant benefit in favor of aRT in terms of biochemical progression-free survival (bPFS) and local recurrence-free survival (HR 0.47; 95% CI 0.41–0.54 and HR 0.54; 95% CI 0.39–0.73, respectively). However, the benefit of MFS remains uncertain (mainly driven by the SWOG 8794 trial) and there is no OS benefit (HR 0.79 and 0.90, respectively) [18]. Two counterarguments cautioned against aRT and have led to its limited applicability in clinical practice. First, about one-third of patients in the observation arm did not have biochemical relapse despite their initial pathologic factors: this indicates that further treatment is avoidable for a large proportion of patients. Second, RT increases the rate of GU and GI toxicities when delivered early after RP [19]. In the EORTC 22911 trial, a higher rate of late any grade adverse event was reported in the aRT arm (cumulative incidence of 70.8% vs. 59.7% at 10 years; *p* = 0.001) [12]. Taken together, this suggests that certain patients would not benefit from treatment and could be exposed to unnecessary toxicities.

<table><caption>**Table 1. Randomized trials assessing adjuvant RT for prostate cancer.**</caption><thead><tr><th>Trial, Year</th><th>n</th><th>Inclusion Criteria</th><th>Arms</th><th>Median Follow-Up (Years)</th><th>% of Patients with Salvage RT for BCR in the Observation Arm</th><th>Median PSA at Salvage RT (ng/mL)</th><th>10 Year-bPFS</th><th>10 Year-MFS</th><th>10 Year-OS</th></tr></thead><tbody><tr><td>SWOG 8794 (2009)</td><td>431</td><td>pT3 cN0 ± R1</td><td>60–64 Gy vs. observation</td><td>12.6</td><td>33%</td><td>0.75–1.0</td><td>60.7% vs. 47.4% (p < 0.005)</td><td>71% vs. 61% (p = 0.04) *</td><td>74% vs. 66% (p = 0.023)</td></tr><tr><td>EORTC 22911 (2012)</td><td>1005</td><td>pT2 pN0 R1 pT3 pN0 ± R1</td><td>60 Gy vs. observation</td><td>10.6</td><td>43%</td><td>1.7</td><td>60.6% vs. 41.1% (p < 0.001) *</td><td>89.9% vs. 89% (ns)</td><td>80.7% vs. 76.9% (ns)</td></tr><tr><td>ARO 96-02 (2014)</td><td>388</td><td>pT3 pN0 ± R1 undetectable PSA</td><td>60 Gy vs. observation</td><td>9.3 (adjuvant group), 9.4 (observation)</td><td>NR</td><td>NR</td><td>56% vs. 35% (p = 0.005) *</td><td>84.3% vs. 85.1% (ns)</td><td>82% vs. 86% (ns)</td></tr><tr><td>FinnProstate Group (2019)</td><td>250</td><td>pT2 R1, pT3a</td><td>66.6 Gy vs. observation</td><td>9.3 (adjuvant group), 8.6 (observation)</td><td>86%</td><td>0.7</td><td>82% vs. 61% (p < 0.001) *</td><td>98% vs. 96% (ns)</td><td>92% vs. 87% (ns)</td></tr></tbody></table>

Abbreviations: RT = radiation therapy, BCR = biochemical recurrence, bPFS = biochemical progression-free survival, MFS = metastasis-free survival, OS = overall survival, * indicates the primary endpoint of the trial, ns = no significance.

The treatment strategy has undergone a recent paradigm shift. Indeed, three randomized trials have compared aRT and early sRT at BCR in the era of PSA monitoring after RP: RADICALS-RT, RAVES, and GETUG-AFU 17 [15–17] (Table 2). These trials differed in design, inclusion criteria, PSA threshold triggering sRT, and primary endpoint measured. Considered separately, they showed no significant difference in terms of bRFS (biochemical recurrence-free survival) in delaying RT at biochemical relapse versus aRT. Moreover, long-term toxicity rates were more commonly reported in the aRT group. The collaborative and prospective ARTISTIC meta-analysis collated data from these three trials before the publication of their respective results. In order to homogenize the interpretation, a harmonized definition of event-free survival (EFS) was defined as the time without either BCR (PSA ≥ 0.4 ng/mL and rising after RT), clinical/radiobiological progression, initiation of a non-trial treatment, PSA ≥ 2 ng/mL at any time after randomization or death. The analysis included 2153 men. After a median follow-up ranging from 60 to 78 months among the studies, the EFS was not different between arms (HR 0.95; 95%CI 0.75–1.21; *p* = 0.70; 5-years EFS of 89% versus 88%). Interestingly, nearly 60% of men randomized in the sRT arm did not receive treatment, confirming that a wait-and-see strategy is reasonable in this patient population [20]. These recent data have contributed to recommending sRT as the standard treatment after prostatectomy, even in high-risk patients.
SWOG 8794 and EORTC 22911 trials presented with a measurable PSA at inclusion and were therefore in an early salvage setting. Conversely, some patients in the observation arm did not receive sRT despite having measurable PSA. In a recent meta-analysis combining data from these four trials (n = 2068), Bhindi et al. reported a significant benefit in favor of aRT in terms of biochemical progression-free survival (bPFS) and local recurrence-free survival (HR 0.47; 95% CI 0.41–0.54 and HR 0.54; 95% CI 0.39–0.73, respectively). However, the benefit of MFS remains uncertain (mainly driven by the SWOG 8794 trial) and there is no OS benefit (HR 0.79 and 0.90, respectively) [18]. Two counterarguments cautioned against aRT and have led to its limited applicability in clinical practice. First, about one-third of patients in the observation arm did not have biochemical relapse despite their initial pathologic factors: this indicates that further treatment is avoidable for a large proportion of patients. Second, RT increases the rate of GU and GI toxicities when delivered early after RP [19]. In the EORTC 22911 trial, a higher rate of late any grade adverse event was reported in the aRT arm (cumulative incidence of 70.8% vs. 59.7% at 10 years; *p* = 0.001) [12]. Taken together, this suggests that certain patients would not benefit from treatment and could be exposed to unnecessary toxicities.

<table><caption>**Table 1. Randomized trials assessing adjuvant RT for prostate cancer.**</caption><thead><tr><th>Trial, Year</th><th>n</th><th>Inclusion Criteria</th><th>Arms</th><th>Median Follow-Up (Years)</th><th>% of Patients with Salvage RT for BCR in the Observation Arm</th><th>Median PSA at Salvage RT (ng/mL)</th><th>10 Year-bPFS</th><th>10 Year-MFS</th><th>10 Year-OS</th></tr></thead><tbody><tr><td>SWOG 8794 (2009)</td><td>431</td><td>pT3 cN0 ± R1</td><td>60–64 Gy vs. observation</td><td>12.6</td><td>33%</td><td>0.75–1.0</td><td>60.7% vs. 47.4% (p < 0.005)</td><td>71% vs. 61% (p = 0.04) *</td><td>74% vs. 66% (p = 0.023)</td></tr><tr><td>EORTC 22911 (2012)</td><td>1005</td><td>pT2 pN0 R1 pT3 pN0 ± R1</td><td>60 Gy vs. observation</td><td>10.6</td><td>43%</td><td>1.7</td><td>60.6% vs. 41.1% (p < 0.001) *</td><td>89.9% vs. 89% (ns)</td><td>80.7% vs. 76.9% (ns)</td></tr><tr><td>ARO 96-02 (2014)</td><td>388</td><td>pT3 pN0 ± R1 undetectable PSA</td><td>60 Gy vs. observation</td><td>9.3 (adjuvant group), 9.4 (observation)</td><td>NR</td><td>NR</td><td>56% vs. 35% (p = 0.005) *</td><td>84.3% vs. 85.1% (ns)</td><td>82% vs. 86% (ns)</td></tr><tr><td>FinnProstate Group (2019)</td><td>250</td><td>pT2 R1, pT3a</td><td>66.6 Gy vs. observation</td><td>9.3 (adjuvant group), 8.6 (observation)</td><td>86%</td><td>0.7</td><td>82% vs. 61% (p < 0.001) *</td><td>98% vs. 96% (ns)</td><td>92% vs. 87% (ns)</td></tr></tbody></table>

Abbreviations: RT = radiation therapy, BCR = biochemical recurrence, bPFS = biochemical progression-free survival, MFS = metastasis-free survival, OS = overall survival, * indicates the primary endpoint of the trial, ns = no significance.

The treatment strategy has undergone a recent paradigm shift. Indeed, three randomized trials have compared aRT and early sRT at BCR in the era of PSA monitoring after RP: RADICALS-RT, RAVES, and GETUG-AFU 17 [15–17] (Table 2). These trials differed in design, inclusion criteria, PSA threshold triggering sRT, and primary endpoint measured. Considered separately, they showed no significant difference in terms of bRFS (biochemical recurrence-free survival) in delaying RT at biochemical relapse versus aRT. Moreover, long-term toxicity rates were more commonly reported in the aRT group. The collaborative and prospective ARTISTIC meta-analysis collated data from these three trials before the publication of their respective results. In order to homogenize the interpretation, a harmonized definition of event-free survival (EFS) was defined as the time without either BCR (PSA ≥ 0.4 ng/mL and rising after RT), clinical/radiobiological progression, initiation of a non-trial treatment, PSA ≥ 2 ng/mL at any time after randomization or death. The analysis included 2153 men. After a median follow-up ranging from 60 to 78 months among the studies, the EFS was not different between arms (HR 0.95; 95%CI 0.75–1.21; *p* = 0.70; 5-years EFS of 89% versus 88%). Interestingly, nearly 60% of men randomized in the sRT arm did not receive treatment, confirming that a wait-and-see strategy is reasonable in this patient population [20]. These recent data have contributed to recommending sRT as the standard treatment after prostatectomy, even in high-risk patients.
<table><caption>**Table 2. Randomized trials comparing salvage and adjuvant RT.**</caption><thead><tr><th>Trial</th><th>Design</th><th>Patients Randomized</th><th>Inclusion Criteria</th><th>Trigger for Salvage RT</th><th>RT Schedule</th><th>ADT</th><th>Median Follow-Up (Months)</th><th>BRFS (aRT vs. sRT)</th><th>GU Late Toxicity (aRT vs. sRT)</th><th>GI Late Toxicity (aRT vs. sRT)</th></tr></thead><tbody><tr><td>RADIC ALS-RT</td><td>superiority</td><td>1386</td><td>R1 or pT3a/T3b/T4 or Gleason 7–10</td><td>PSA ≥ 0.1 ng/mL or 3 consecutive rises</td><td>66 Gy/33 or 52.2 Gy/20</td><td>no</td><td>60</td><td>85% versus 88% (p = 0.56)</td><td>G3,4 haematuria 4% vs. &lt;1% (p &lt; 0.0001)<br>G3,4 urethral stricture 6% vs. 4% (p = 0.0025)</td><td>G1,2 diarrhea and proctitis 13–17% vs. 5–8% (p &lt; 0.0001)<br>G3,4 (ns)</td></tr><tr><td>RAVES</td><td>non-inferiority</td><td>333</td><td>R1 or pT3a/T3b</td><td>PSA ≥ 0.2 ng/mL</td><td>64 Gy/32</td><td>no</td><td>73</td><td>86% versus 87% (p = 0.15)</td><td>≥G2 70% vs. 54% (p &lt; 0.001)</td><td>≥G2 14% vs. 10% (ns)</td></tr><tr><td>GETUG-AFU 17</td><td>superiority</td><td>424</td><td>R1 and pT3a/T3b/pT4</td><td>PSA ≥ 0.2 ng/mL</td><td>66 Gy/33</td><td>yes</td><td>47</td><td>92% versus 90% (p = 0.42)</td><td>≥G2 59% vs. 22% (p &lt; 0.0001)</td><td>≥G2 8% vs. 5% (p = 0.24)</td></tr></tbody></table>

Abbreviations: RT = radiation therapy, ADT = androgen deprivation therapy, Gy = Gray, BRFS = biochemical recurrence-free survival, GU = genito urinary, GI = gastrointestinal, PSA = prostate-specific antigen, ns = no significance.

### 4. Is Adjuvant Radiation Therapy Definitively over?

Since the publication of the last three studies and the ARTISTIC meta-analysis, a surveillance strategy based on regular PSA testing with early sRT is the current standard, and aRT is no longer considered by radiation oncologists regardless of post-RP histological features. However, it should be noted that few of the patients included in these trials had highly unfavorable criteria and that these results are likely not applicable to the very high-risk subset of patients (e.g., pT3b Gleason 8–10 patients). Another limitation is that PSA recurrence was the endpoint of these studies, which is not an ideal surrogate for survival and may have been artificially prolonged by the use of ADT in the case of the GETUG-AFU 17 trial [17]. On the basis of a possible immortal time bias, Tilki et al. assessed the impact of aRT versus early sRT on all-cause-mortality (ACM) risk for the subset of men with pN1 or pGS 8–10 and pT3/4 stages. After a median follow-up of 8 years, aRT significantly reduced the ACM risk versus sRT among men with adverse pathology with or without the inclusion of pN1 (HR 0.66; *p* = 0.04 and HR 0.33; *p* = 0.02 respectively) [21]. Prospective studies are eagerly awaited to confirm these findings. Nonetheless, these data are retrospective and sRT should remain standard even in the high-risk population.

### 5. RT Plus ADT: Is It Necessarily a Winning Combo?

Since the combination of ADT and RT has been shown to be beneficial in terms of biochemical control and OS for patients with localized unfavorable intermediate and high-risk prostate cancer, the question of its use in the adjuvant/salvage setting is a matter of interest. However, uncertainties remain regarding patient selection, the duration and form of therapy, and the characteristics of the associated RT. The question has not been widely explored in the context of adjuvant treatment. Only retrospective series have suggested better biochemical control with ADT, particularly for patients at high risk of relapse [22,23].

Two randomized trials have assessed the impact of ADT on RT in the salvage setting. In the placebo-controlled RTOG 9601 trial, 760 patients were randomized between sRT alone versus sRT combined with 24 months of daily bicalutamide. The 12-year OS was increased by 5% in the bicalutamide group (HR 0.77; 95% CI 0.59 to 0.99; *p* = 0.04). Twelve-year MFS and cancer-specific survival (CSS) were also significantly higher among patients having received ADT (9.6% and 7.6%, respectively, *p* < 0.01) [24]. The second trial (GETUG AFU-16) randomized 743 patients between sRT ± 6 months of a GnRH agonist (goserelin). The updated results after a median follow-up of 112 months demonstrated a significantly higher 10-year biochemical and clinical PFS in the RT + ADT group (64% vs. 49%; HR 0.54, 95% CI 0.43–0.68; *p* < 0.0001). The benefit was also described in MFS (75% vs. 69%; HR 0.73, 95% CI 0.54–0.98; *p* = 0.034) [25]. It is important to note that it is difficult to compare the results of these two trials as populations were not similar. In the GETUG-AFU-16 trial, only patients with undetectable post-operative PSA were enrolled (whereas nearly 12% of patients in the RTOG 9601 had a measurable PSA at inclusion) and patients globally harbored more favorable profiles (with lower pre-RT PSA and lower pT3 stages). The decision to initiate ADT concurrently with RT must be carefully weighed against its
<table><caption>**Table 2. Randomized trials comparing salvage and adjuvant RT.**</caption><thead><tr><th>Trial</th><th>Design</th><th>Patients Randomized</th><th>Inclusion Criteria</th><th>Trigger for Salvage RT</th><th>RT Schedule</th><th>ADT</th><th>Median Follow-Up (Months)</th><th>BRFS (aRT vs. sRT)</th><th>GU Late Toxicity (aRT vs. sRT)</th><th>GI Late Toxicity (aRT vs. sRT)</th></tr></thead><tbody><tr><td>RADIC ALS-RT</td><td>superiority</td><td>1386</td><td>R1 or pT3a/T3b/T4 or Gleason 7–10</td><td>PSA ≥ 0.1 ng/mL or 3 consecutive rises</td><td>66 Gy/33 or 52.2 Gy/20</td><td>no</td><td>60</td><td>85% versus 88% (p = 0.56)</td><td>G3,4 haematuria 4% vs. &lt;1% (p &lt; 0.0001)<br>G3,4 urethral stricture 6% vs. 4% (p = 0.0025)</td><td>G1,2 diarrhea and proctitis 13–17% vs. 5–8% (p &lt; 0.0001)<br>G3,4 (ns)</td></tr><tr><td>RAVES</td><td>non-inferiority</td><td>333</td><td>R1 or pT3a/T3b</td><td>PSA ≥ 0.2 ng/mL</td><td>64 Gy/32</td><td>no</td><td>73</td><td>86% versus 87% (p = 0.15)</td><td>≥G2 70% vs. 54% (p &lt; 0.001)</td><td>≥G2 14% vs. 10% (ns)</td></tr><tr><td>GETUG-AFU 17</td><td>superiority</td><td>424</td><td>R1 and pT3a/T3b/pT4</td><td>PSA ≥ 0.2 ng/mL</td><td>66 Gy/33</td><td>yes</td><td>47</td><td>92% versus 90% (p = 0.42)</td><td>≥G2 59% vs. 22% (p &lt; 0.0001)</td><td>≥G2 8% vs. 5% (p = 0.24)</td></tr></tbody></table>

Abbreviations: RT = radiation therapy, ADT = androgen deprivation therapy, Gy = Gray, BRFS = biochemical recurrence-free survival, GU = genito urinary, GI = gastrointestinal, PSA = prostate-specific antigen, ns = no significance.

### 4. Is Adjuvant Radiation Therapy Definitively over?

Since the publication of the last three studies and the ARTISTIC meta-analysis, a surveillance strategy based on regular PSA testing with early sRT is the current standard, and aRT is no longer considered by radiation oncologists regardless of post-RP histological features. However, it should be noted that few of the patients included in these trials had highly unfavorable criteria and that these results are likely not applicable to the very high-risk subset of patients (e.g., pT3b Gleason 8–10 patients). Another limitation is that PSA recurrence was the endpoint of these studies, which is not an ideal surrogate for survival and may have been artificially prolonged by the use of ADT in the case of the GETUG-AFU 17 trial [17]. On the basis of a possible immortal time bias, Tilki et al. assessed the impact of aRT versus early sRT on all-cause-mortality (ACM) risk for the subset of men with pN1 or pGS 8–10 and pT3/4 stages. After a median follow-up of 8 years, aRT significantly reduced the ACM risk versus sRT among men with adverse pathology with or without the inclusion of pN1 (HR 0.66; *p* = 0.04 and HR 0.33; *p* = 0.02 respectively) [21]. Prospective studies are eagerly awaited to confirm these findings. Nonetheless, these data are retrospective and sRT should remain standard even in the high-risk population.

### 5. RT Plus ADT: Is It Necessarily a Winning Combo?

Since the combination of ADT and RT has been shown to be beneficial in terms of biochemical control and OS for patients with localized unfavorable intermediate and high-risk prostate cancer, the question of its use in the adjuvant/salvage setting is a matter of interest. However, uncertainties remain regarding patient selection, the duration and form of therapy, and the characteristics of the associated RT. The question has not been widely explored in the context of adjuvant treatment. Only retrospective series have suggested better biochemical control with ADT, particularly for patients at high risk of relapse [22,23].

Two randomized trials have assessed the impact of ADT on RT in the salvage setting. In the placebo-controlled RTOG 9601 trial, 760 patients were randomized between sRT alone versus sRT combined with 24 months of daily bicalutamide. The 12-year OS was increased by 5% in the bicalutamide group (HR 0.77; 95% CI 0.59 to 0.99; *p* = 0.04). Twelve-year MFS and cancer-specific survival (CSS) were also significantly higher among patients having received ADT (9.6% and 7.6%, respectively, *p* < 0.01) [24]. The second trial (GETUG AFU-16) randomized 743 patients between sRT ± 6 months of a GnRH agonist (goserelin). The updated results after a median follow-up of 112 months demonstrated a significantly higher 10-year biochemical and clinical PFS in the RT + ADT group (64% vs. 49%; HR 0.54, 95% CI 0.43–0.68; *p* < 0.0001). The benefit was also described in MFS (75% vs. 69%; HR 0.73, 95% CI 0.54–0.98; *p* = 0.034) [25]. It is important to note that it is difficult to compare the results of these two trials as populations were not similar. In the GETUG-AFU-16 trial, only patients with undetectable post-operative PSA were enrolled (whereas nearly 12% of patients in the RTOG 9601 had a measurable PSA at inclusion) and patients globally harbored more favorable profiles (with lower pre-RT PSA and lower pT3 stages). The decision to initiate ADT concurrently with RT must be carefully weighed against its
potential side effects. In a recent secondary analysis of the RTOG 9601 trial, Dess et al. demonstrated the prognostic value of pre-RT PSA level on oncological outcomes: ADT was associated with a 12-year OS improvement for patients with PSA > 1.5 ng/mL (25% versus 1% for these with PSA ≤ 1.5 ng/mL). For the subgroup of patients with PSA ≤ 0.6 ng/mL, not only did ADT provide no OS benefit, it also tripled the risk of developing a grade 3 to 5 neurological or cardiac late event and doubled the risk of treatment-related mortality [26].

Several accruing trials will help better define the duration of concurrent ADT. The LOBSTER phase 2b trial (NCT04242017) will compare 6 versus 24 months of triptorelin both combined with sRT (70 Gy/35) for men experiencing BCR after pN0 RP.

# 6. Discussion and Perspectives

## 6.1. Will the Future Come from Metabolic Imaging?

The place of imaging remains debated in the post-operative setting and is often left to the discretion of the radiation oncologist. The main interest of imaging is as a tool to improve patient selection and be able to offer the most appropriate radiation treatment in terms of technique, fields, and dose; to improve oncological outcomes. Conventional imaging (bone scan and computed tomography) is classically unsuccessful in detecting sites of failure at low PSA levels in the setting of BCR. Several studies have indeed suggested that they both should be considered only in the case of high PSA levels (>10 ng/mL), high velocity, or for symptomatic patients [27,28]. In a previous study by Okotie et al., patients with PSA < 10 ng/mL after RP had positive findings on CT and bone scan in 0% and 11%, respectively (vs 57% and 46% for men with PSA > 10 ng/mL) [29]. For the detection of local recurrences, multiparametric MRI (mpMRI) of the pelvis has proven its accuracy, although it remains dependent on PSA levels [30].

Metabolic imaging with PET/CT has widely proven superior diagnostic performances for lower PSA. Several radiotracers—including choline, fluciclovine, and PSMA- are available. Positive findings of PET-choline are still dependent on the PSA level: the detection rate decreases from 76% to 20% for PSA decreasing from >2 to <1 ng/mL [31]. Pooled sensitivities and specificities of choline-PET were found to be 85% and 88% for local recurrence and 100% and 82% for nodal relapse, respectively [32,33]. Conversely, PSMA-PET/CT is currently the metabolic imaging that offers the best diagnostic performance for low PSA levels. In a retrospective series of 119 patients with a PSA < 0.5 mg/mL, ⁶⁸Ga-PSMA-11 PET/CT demonstrated a detection rate of nearly 35%, surpassing the performance of PET/CT with other radiotracers [34]. A large systematic review and meta-analysis of 4790 patients by Perera et al. identified a strong correlation between increasing PSA levels and the probability of detection of distant relapse using ⁶⁸Ga-PSMA. In the post-prostatectomy cohort, the proportions of positive imaging were 33%, 46%, 75%, 82%, and 97% for PSA categories 0–0.19, 0.2–0.49, 0.5–0.99, 1–1.99 and ≥2 ng/mL, respectively [35]. Several studies have evaluated the effect of metabolic imaging on RT planning. Specifically, in the context of BCR, the findings of ⁶⁸Ga-PSMA-11-PET/CT induced change on the planned RT in 20 to 60% of cases [34,36–39] (Table 3). Calais et al. reported a prospective head-to-head comparison between ¹⁸F-fluciclovine-PET/CT and ⁶⁸Ga-PSMA-11-PET/CT in 143 patients with low PSA concentrations (<2.0 ng/mL) in the BCR context. The metastasis detection rate was lower with ¹⁸F-fluciclovine-PET/CT than with ⁶⁸Ga-PSMA-11-PET/CT (26% versus 56%; OR 4.8, 95%CI 1.6–19.2; *p* = 0.0026). The authors concluded that PSMA should be the preferred radiotracer for decision making in the BCR context [40].
potential side effects. In a recent secondary analysis of the RTOG 9601 trial, Dess et al. demonstrated the prognostic value of pre-RT PSA level on oncological outcomes: ADT was associated with a 12-year OS improvement for patients with PSA > 1.5 ng/mL (25% versus 1% for these with PSA ≤ 1.5 ng/mL). For the subgroup of patients with PSA ≤ 0.6 ng/mL, not only did ADT provide no OS benefit, it also tripled the risk of developing a grade 3 to 5 neurological or cardiac late event and doubled the risk of treatment-related mortality [26].

Several accruing trials will help better define the duration of concurrent ADT. The LOBSTER phase 2b trial (NCT04242017) will compare 6 versus 24 months of triptorelin both combined with sRT (70 Gy/35) for men experiencing BCR after pN0 RP.

# 6. Discussion and Perspectives

## 6.1. Will the Future Come from Metabolic Imaging?

The place of imaging remains debated in the post-operative setting and is often left to the discretion of the radiation oncologist. The main interest of imaging is as a tool to improve patient selection and be able to offer the most appropriate radiation treatment in terms of technique, fields, and dose; to improve oncological outcomes. Conventional imaging (bone scan and computed tomography) is classically unsuccessful in detecting sites of failure at low PSA levels in the setting of BCR. Several studies have indeed suggested that they both should be considered only in the case of high PSA levels (>10 ng/mL), high velocity, or for symptomatic patients [27,28]. In a previous study by Okotie et al., patients with PSA < 10 ng/mL after RP had positive findings on CT and bone scan in 0% and 11%, respectively (vs 57% and 46% for men with PSA > 10 ng/mL) [29]. For the detection of local recurrences, multiparametric MRI (mpMRI) of the pelvis has proven its accuracy, although it remains dependent on PSA levels [30].

Metabolic imaging with PET/CT has widely proven superior diagnostic performances for lower PSA. Several radiotracers—including choline, fluciclovine, and PSMA- are available. Positive findings of PET-choline are still dependent on the PSA level: the detection rate decreases from 76% to 20% for PSA decreasing from >2 to <1 ng/mL [31]. Pooled sensitivities and specificities of choline-PET were found to be 85% and 88% for local recurrence and 100% and 82% for nodal relapse, respectively [32,33]. Conversely, PSMA-PET/CT is currently the metabolic imaging that offers the best diagnostic performance for low PSA levels. In a retrospective series of 119 patients with a PSA < 0.5 mg/mL, ⁶⁸Ga-PSMA-11 PET/CT demonstrated a detection rate of nearly 35%, surpassing the performance of PET/CT with other radiotracers [34]. A large systematic review and meta-analysis of 4790 patients by Perera et al. identified a strong correlation between increasing PSA levels and the probability of detection of distant relapse using ⁶⁸Ga-PSMA. In the post-prostatectomy cohort, the proportions of positive imaging were 33%, 46%, 75%, 82%, and 97% for PSA categories 0–0.19, 0.2–0.49, 0.5–0.99, 1–1.99 and ≥2 ng/mL, respectively [35]. Several studies have evaluated the effect of metabolic imaging on RT planning. Specifically, in the context of BCR, the findings of ⁶⁸Ga-PSMA-11-PET/CT induced change on the planned RT in 20 to 60% of cases [34,36–39] (Table 3). Calais et al. reported a prospective head-to-head comparison between ¹⁸F-fluciclovine-PET/CT and ⁶⁸Ga-PSMA-11-PET/CT in 143 patients with low PSA concentrations (<2.0 ng/mL) in the BCR context. The metastasis detection rate was lower with ¹⁸F-fluciclovine-PET/CT than with ⁶⁸Ga-PSMA-11-PET/CT (26% versus 56%; OR 4.8, 95%CI 1.6–19.2; *p* = 0.0026). The authors concluded that PSMA should be the preferred radiotracer for decision making in the BCR context [40].
<table><caption>**Table 3.** Selected studies assessing the impact of ⁶⁸Ga-PSMA-11-PET/CT findings on the salvage RT planning.</caption><thead><tr><td>Author, Year</td><td>Population</td><td>Median PSA (ng/mL) (Range)</td><td>Overall Detection Rate (%)</td><td>Extra-Pelvic Uptake (%)</td><td>RT Planning Change among Positive PET/CT (%)</td></tr></thead><tbody><tr><td>Habl, 2017</td><td>100</td><td>1.0 (0.12–14.7)</td><td>76</td><td>7</td><td>59</td></tr><tr><td>Calais, 2018</td><td>270</td><td>0.48 (0.03–1)</td><td>49</td><td>12</td><td>19 (post-hoc)</td></tr><tr><td>Farolfi, 2019</td><td>119</td><td>0.34 (0.20–0.50)</td><td>34.4</td><td>21</td><td>30.2</td></tr><tr><td>Boreta, 2019</td><td>125</td><td>0.40 (0.28–0.63)</td><td>53</td><td>38</td><td>30</td></tr><tr><td>Bottke, 2021</td><td>76</td><td>0.25 (0.07–0.5)</td><td>54</td><td>8</td><td>28</td></tr></tbody></table>

In order to take all these elements into consideration, some authors have proposed algorithms for decision making. Based on clinicobiological features (time to biochemical relapse since surgery, PSA and PSA-DT) and pathological features (Gleason score, status margins, and pT/pN stages), a risk analysis can be carried out and lead to mpMRI in the case of low risk of metastases or metabolic imaging in the case of a suspected distant recurrence (the radiotracer is then chosen according to the PSA level) [41]. It is only recently that the impact of such imaging on oncological outcomes has begun to show promising results. The EMPIRE-1 (Emory Molecular Prostate Imaging for Radiotherapy Enhancement) trial was the first randomized phase 2/3 trial to assess the impact of metabolic imaging exclusively on post-prostatectomy relapsing patients. Patients with detectable PSA after RP and with negative conventional imaging were randomized between RT directed by conventional imaging or by conventional imaging combined with fluciclovine-PET/CT. In the PET/CT arm, RT decisions and planning followed the imaging findings: RT was canceled in the case of extra-pelvic uptake, maintained with adapted treatment fields in the case of prostate bed ± nodal uptake, and finally focused only on the prostate bed if no uptake. The 3-year event-free survival was significantly higher in the PET-directed RT arm (75.5% vs. 63%, *p* = 0.0028) and toxicity rates were similar between groups [42]. Currently, the EMPIRE-2 trial (NCT 03762759), randomly assigning patients to fluciclovine-PET/CT or PSMA-PET/CT RT directed, is recruiting. Whether treatment adaptations induced by metabolic imaging will influence survival outcomes remains a challenging question.

The main question that currently remains open is what strategy to adopt in the case of negative findings on PET imaging. A wait-and-see attitude with repeated imaging until a target is identified is a highly interesting proposal, as it would have the advantage of sparing RT for patients without proven relapse and then offering salvage treatment with appropriate doses and treatment fields in the case of a macroscopic target (instead of doses of about 60–65 Gy in a large volume). This strategy could be proposed for highly selected patients: in a retrospective study about 103 men with negative PSMA-PET/CT at BCR and followed up for at least one year, Celli et al. reported a higher clinical recurrence-free survival in case of PSA < 0.5 ng/mL and low-grade cancer on RP specimens (ISUP 1 and 2) [43]. Conversely, a study by Emmett et al. showed that PSMA-PET/CT was predictive of 3-year PFS for men treated by sRT. While a negative finding on PSMA-PET/CT was a more important predictor of long-term sRT control than other risk factors, this could indicate that such patients even benefit from prostate bed RT. Finally, 34% of men with negative imaging did not receive sRT and were free of relapse at three years, suggesting the possibility of close monitoring in a selected subgroup [44]. In the EMPIRE-1 trial, salvage RT to the prostate bed was delivered even in the case of no uptake on PET/CT.

There is no current robust consensus regarding the place of metabolic imaging in the setting of biochemical relapse, but further changes are to be expected. The current EAU guidelines suggest the use of PSMA-PET/CT or choline/fluciclovine-PET/CT in the case of PSA > 0.2 and PSA > 1 ng/mL, respectively, and if an impact on the management strategy is expected [45].
<table><caption>**Table 3.** Selected studies assessing the impact of <sup>68</sup>Ga-PSMA-11-PET/CT findings on the salvage RT planning.</caption><thead><tr><td>Author, Year</td><td>Population</td><td>Median PSA (ng/mL) (Range)</td><td>Overall Detection Rate (%)</td><td>Extra-Pelvic Uptake (%)</td><td>RT Planning Change among Positive PET/CT (%)</td></tr></thead><tbody><tr><td>Habl, 2017</td><td>100</td><td>1.0 (0.12–14.7)</td><td>76</td><td>7</td><td>59</td></tr><tr><td>Calais, 2018</td><td>270</td><td>0.48 (0.03–1)</td><td>49</td><td>12</td><td>19 (post-hoc)</td></tr><tr><td>Farolfi, 2019</td><td>119</td><td>0.34 (0.20–0.50)</td><td>34.4</td><td>21</td><td>30.2</td></tr><tr><td>Boreta, 2019</td><td>125</td><td>0.40 (0.28–0.63)</td><td>53</td><td>38</td><td>30</td></tr><tr><td>Bottke, 2021</td><td>76</td><td>0.25 (0.07–0.5)</td><td>54</td><td>8</td><td>28</td></tr></tbody></table>

In order to take all these elements into consideration, some authors have proposed algorithms for decision making. Based on clinicobiological features (time to biochemical relapse since surgery, PSA and PSA-DT) and pathological features (Gleason score, status margins, and pT/pN stages), a risk analysis can be carried out and lead to mpMRI in the case of low risk of metastases or metabolic imaging in the case of a suspected distant recurrence (the radiotracer is then chosen according to the PSA level) [41]. It is only recently that the impact of such imaging on oncological outcomes has begun to show promising results. The EMPIRE-1 (Emory Molecular Prostate Imaging for Radiotherapy Enhancement) trial was the first randomized phase 2/3 trial to assess the impact of metabolic imaging exclusively on post-prostatectomy relapsing patients. Patients with detectable PSA after RP and with negative conventional imaging were randomized between RT directed by conventional imaging or by conventional imaging combined with fluciclovine-PET/CT. In the PET/CT arm, RT decisions and planning followed the imaging findings: RT was canceled in the case of extra-pelvic uptake, maintained with adapted treatment fields in the case of prostate bed ± nodal uptake, and finally focused only on the prostate bed if no uptake. The 3-year event-free survival was significantly higher in the PET-directed RT arm (75.5% vs. 63%, *p* = 0.0028) and toxicity rates were similar between groups [42]. Currently, the EMPIRE-2 trial (NCT 03762759), randomly assigning patients to fluciclovine-PET/CT or PSMA-PET/CT RT directed, is recruiting. Whether treatment adaptations induced by metabolic imaging will influence survival outcomes remains a challenging question.

The main question that currently remains open is what strategy to adopt in the case of negative findings on PET imaging. A wait-and-see attitude with repeated imaging until a target is identified is a highly interesting proposal, as it would have the advantage of sparing RT for patients without proven relapse and then offering salvage treatment with appropriate doses and treatment fields in the case of a macroscopic target (instead of doses of about 60–65 Gy in a large volume). This strategy could be proposed for highly selected patients: in a retrospective study about 103 men with negative PSMA-PET/CT at BCR and followed up for at least one year, Celli et al. reported a higher clinical recurrence-free survival in case of PSA < 0.5 ng/mL and low-grade cancer on RP specimens (ISUP 1 and 2) [43]. Conversely, a study by Emmett et al. showed that PSMA-PET/CT was predictive of 3-year PFS for men treated by sRT. While a negative finding on PSMA-PET/CT was a more important predictor of long-term sRT control than other risk factors, this could indicate that such patients even benefit from prostate bed RT. Finally, 34% of men with negative imaging did not receive sRT and were free of relapse at three years, suggesting the possibility of close monitoring in a selected subgroup [44]. In the EMPIRE-1 trial, salvage RT to the prostate bed was delivered even in the case of no uptake on PET/CT.

There is no current robust consensus regarding the place of metabolic imaging in the setting of biochemical relapse, but further changes are to be expected. The current EAU guidelines suggest the use of PSMA-PET/CT or choline/fluciclovine-PET/CT in the case of PSA > 0.2 and PSA > 1 ng/mL, respectively, and if an impact on the management strategy is expected [45].
## 6.2. Towards A Personalization of Treatments

Recent developments in genomics may offer additional tools in the individualization of treatments, by identifying the subset of patients at high risk of recurrence eligible for intensified therapy. Most of the current data concerns the Decipher test (Decipher Biosciences, San Diego, CA, USA), a 22 gene-genomic classifier (GC) developed in the post-prostatectomy setting and having shown its predictive value in distant metastases (DM) [46]. Several validation series have demonstrated their superiority in their accuracy and prognostic value in comparison to clinical and pathological models [47,48]. Feng et al. recently published an ancillary study where Decipher was generated from 352 patients enrolled in the RTOG 9601 trial with a 13-year median follow-up. After adjusting for several clinical and pathological parameters, the Decipher test was independently associated with DM (HR 1.17; 95% CI 1.05–1.32; *p* = 0.006), PCSM (HR 1.39; 95% CI 1.20–1.63; *p* < 0.001), and OS (HR 1.17; 95% CI 1.06–1.29; *p* = 0.002) in multivariable analysis. Interestingly, in patients having received sRT for PSA < 0.7 ng/mL, the addition of ADT was beneficial in terms of DM and OS only in the case of intermediate-to-high GC (versus low GC) [49]. These data would therefore allow further refinement of the therapeutic strategy and the indications for concurrent ADT. Finally, promising preliminary data have shown that artificial intelligence-derived pathology-based biomarkers could help in predicting the benefit of ADT for localized stages. Its place in the post-operative setting represents a large area to be explored [50].

## 6.3. Is Drug Intensification the Key?

Studies of patterns of relapse after post-prostatectomy RT have shown that the first site of recurrence was mainly distant but that 1/5 of patients had an in-field relapse [51]. This indicates the need to improve both locoregional control (and thus overcome radioresistance mechanisms) and distant control (by eradicating the micrometastatic cells). Since new-generation hormone therapies have proven their benefit in increasing survival for metastatic and more recently for high-risk localized stages, their relevance in the salvage setting is a current challenge. Their use in concomitance with RT seems promising, with in vitro series suggesting enhanced radiosensitization of some androgen receptor inhibitors compared to ADT [52]. The phase 2 STREAM study was the first to investigate the combination of enzalutamide concurrently with RT and ADT. The 2-year PFS was 65% and a 29% toxicity grade 3 rate was reported [53]. The French randomized phase 3 CARLHA-2/GETUG-AFU 33 trial (NCT04181203) comparing prostate bed and pelvic RT with 6 months of ADT ± apalutamide for high-risk relapsing patients is currently recruiting. Other therapies targeting the PI3K/Akt/mTOR pathway or glucose metabolism (such as metformin) are under investigation [54]. Finally, the use of therapeutic PSMA radiopharmaceuticals, such as Lu-PSMA, will also be of interest in this population with microscopic residual disease (Table 4).

<table><caption>**Table 4.** The management of BCR after RP: an overview of current status and trends.</caption><thead><tr><th rowspan="2" colspan="2"></th><th colspan="2">PSA Recurrence<br/>(>0.2 ng/mL on Two Consecutive Tests)</th></tr><tr><th>no</th><th>yes</th></tr></thead><tbody><tr><th rowspan="2" scope="rowgroup">Adverse pathological factors</th><th scope="row">no</th><td colspan="2">PSA monitoring (SOC)</td></tr><tr><th scope="row">yes</th><td colspan="2">Adjuvant RT for highly selected cases?</td></tr><tr><td colspan="4">Areas of research and future development<br/>Advanced imaging<br/>Therapeutic intensification (ADT ± NHT)<br/>AI-guided management: genomics/pathomics</td></tr></tbody></table>

Abbreviations: RT = radiation therapy, SOC = standard of care, ADT = androgen deprivation therapy, NHT = second-generation novel hormonal therapy, AI = artificial intelligence
## 6.2. Towards A Personalization of Treatments

Recent developments in genomics may offer additional tools in the individualization of treatments, by identifying the subset of patients at high risk of recurrence eligible for intensified therapy. Most of the current data concerns the Decipher test (Decipher Biosciences, San Diego, CA, USA), a 22 gene-genomic classifier (GC) developed in the post-prostatectomy setting and having shown its predictive value in distant metastases (DM) [46]. Several validation series have demonstrated their superiority in their accuracy and prognostic value in comparison to clinical and pathological models [47,48]. Feng et al. recently published an ancillary study where Decipher was generated from 352 patients enrolled in the RTOG 9601 trial with a 13-year median follow-up. After adjusting for several clinical and pathological parameters, the Decipher test was independently associated with DM (HR 1.17; 95% CI 1.05–1.32; *p* = 0.006), PCSM (HR 1.39; 95% CI 1.20–1.63; *p* < 0.001), and OS (HR 1.17; 95% CI 1.06–1.29; *p* = 0.002) in multivariable analysis. Interestingly, in patients having received sRT for PSA < 0.7 ng/mL, the addition of ADT was beneficial in terms of DM and OS only in the case of intermediate-to-high GC (versus low GC) [49]. These data would therefore allow further refinement of the therapeutic strategy and the indications for concurrent ADT. Finally, promising preliminary data have shown that artificial intelligence-derived pathology-based biomarkers could help in predicting the benefit of ADT for localized stages. Its place in the post-operative setting represents a large area to be explored [50].

## 6.3. Is Drug Intensification the Key?

Studies of patterns of relapse after post-prostatectomy RT have shown that the first site of recurrence was mainly distant but that 1/5 of patients had an in-field relapse [51]. This indicates the need to improve both locoregional control (and thus overcome radioresistance mechanisms) and distant control (by eradicating the micrometastatic cells). Since new-generation hormone therapies have proven their benefit in increasing survival for metastatic and more recently for high-risk localized stages, their relevance in the salvage setting is a current challenge. Their use in concomitance with RT seems promising, with in vitro series suggesting enhanced radiosensitization of some androgen receptor inhibitors compared to ADT [52]. The phase 2 STREAM study was the first to investigate the combination of enzalutamide concurrently with RT and ADT. The 2-year PFS was 65% and a 29% toxicity grade 3 rate was reported [53]. The French randomized phase 3 CARLHA-2/GETUG-AFU 33 trial (NCT04181203) comparing prostate bed and pelvic RT with 6 months of ADT ± apalutamide for high-risk relapsing patients is currently recruiting. Other therapies targeting the PI3K/Akt/mTOR pathway or glucose metabolism (such as metformin) are under investigation [54]. Finally, the use of therapeutic PSMA radiopharmaceuticals, such as Lu-PSMA, will also be of interest in this population with microscopic residual disease (Table 4).

<table><caption>**Table 4.** The management of BCR after RP: an overview of current status and trends.</caption><thead><tr><th rowspan="2" colspan="2"></th><th colspan="2">PSA Recurrence<br/>(>0.2 ng/mL on Two Consecutive Tests)</th></tr><tr><th>no</th><th>yes</th></tr></thead><tbody><tr><th rowspan="2" scope="rowgroup">Adverse pathological factors</th><th scope="row">no</th><td colspan="2">PSA monitoring (SOC)</td></tr><tr><th scope="row">yes</th><td colspan="2">Adjuvant RT for highly selected cases?</td></tr><tr><td colspan="4">Areas of research and future development<br/>Advanced imaging<br/>Therapeutic intensification (ADT ± NHT)<br/>AI-guided management: genomics/pathomics</td></tr></tbody></table>

Abbreviations: RT = radiation therapy, SOC = standard of care, ADT = androgen deprivation therapy, NHT = second-generation novel hormonal therapy, AI = artificial intelligence
## 7. Conclusions

For several years, the timing of post-prostatectomy RT has been the subject of intense debate. The current data argue in favor of delivering early sRT, when BCR occurs (PSA > 0.2 ng/mL on two consecutive assays). This strategy results in improved biochemical outcomes while sparing patients who have not had a recurrence from potential toxicities. However, survival data are not sufficiently mature and long-term results are needed to confirm the strategy. Some uncertainties remain, such as the appropriate selection of patients requiring concomitant ADT, and its duration. Intensified therapy strategies involving new molecules such as new-generation hormone therapy are being currently evaluated. Finally, the growing importance of metabolic imaging, in particular PSMA-PET/CT, and genomic data should allow more personalized therapeutic strategies in the future.

**Author Contributions:** Writing—original draft preparation, M.T.; writing—review and editing, M.T., E.J.L. and Y.M.; supervision, P.B.; validation, M.T., E.J.L., Y.M. and P.B. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Conflicts of Interest:** The authors declare no conflict of interest.

## References

1. Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. *CA. Cancer J. Clin.* **2018**, *68*, 394–424. [CrossRef] [PubMed]

2. Van den Broeck, T.; van den Bergh, R.C.N.; Arfi, N.; Gross, T.; Moris, L.; Briers, E.; Cumberbatch, M.; De Santis, M.; Tilki, D.; Fanti, S.; et al. Prognostic Value of Biochemical Recurrence Following Treatment with Curative Intent for Prostate Cancer: A Systematic Review. *Eur. Urol.* **2019**, *75*, 967–987. [CrossRef] [PubMed]

3. Pound, C.R.; Partin, A.W.; Eisenberger, M.A.; Chan, D.W.; Pearson, J.D.; Walsh, P.C. Natural history of progression after PSA elevation following radical prostatectomy. *JAMA* **1999**, *281*, 1591–1597. [CrossRef]

4. Abdollah, F.; Suardi, N.; Cozzarini, C.; Gallina, A.; Capitanio, U.; Bianchi, M.; Sun, M.; Fossati, N.; Passoni, N.M.; Fiorino, C.; et al. Selecting the optimal candidate for adjuvant radiotherapy after radical prostatectomy for prostate cancer: A long-term survival analysis. *Eur. Urol.* **2013**, *63*, 998–1008. [CrossRef]

5. Amling, C.L.; Bergstrahl, E.J.; Blute, M.L.; Slezak, J.M.; Zincke, H. Defining prostate specific antigen progression after radical prostatectomy: What is the most appropriate cut point? *J. Urol.* **2001**, *165*, 1146–1151. [CrossRef]

6. Tendulkar, R.D.; Agrawal, S.; Gao, T.; Efstathiou, J.A.; Pisansky, T.M.; Michalski, J.M.; Koontz, B.F.; Hamstra, D.A.; Feng, F.Y.; Liauw, S.L.; et al. Contemporary Update of a Multi-Institutional Predictive Nomogram for Salvage Radiotherapy After Radical Prostatectomy. *J. Clin. Oncol.* **2016**, *34*, 3648–3654. [CrossRef]

7. Aus, G.; Abbou, C.C.; Bolla, M.; Heidenreich, A.; Schmid, H.-P.; van Poppel, H.; Wolff, J.; Zattoni, F. European Association of Urology EAU guidelines on prostate cancer. *Eur. Urol.* **2005**, *48*, 546–551. [CrossRef] [PubMed]

8. Ahlering, T.E.; Skarecky, D.W. Long-term outcome of detectable PSA levels after radical prostatectomy. *Prostate Cancer Prostatic Dis.* **2005**, *8*, 163–166. [CrossRef] [PubMed]

9. Antonarakis, E.S.; Feng, Z.; Trock, B.J.; Humphreys, E.B.; Carducci, M.A.; Partin, A.W.; Walsh, P.C.; Eisenberger, M.A. The natural history of metastatic progression in men with prostate-specific antigen recurrence after radical prostatectomy: Long-term follow-up. *BJU Int.* **2012**, *109*, 32–39. [CrossRef]

10. Tilki, D.; Preisser, F.; Graefen, M.; Huland, H.; Pompe, R.S. External Validation of the European Association of Urology Biochemical Recurrence Risk Groups to Predict Metastasis and Mortality After Radical Prostatectomy in a European Cohort. *Eur. Urol.* **2019**, *75*, 896–900. [CrossRef]

11. Thompson, I.M.; Tangen, C.M.; Paradelo, J.; Lucia, M.S.; Miller, G.; Troyer, D.; Messing, E.; Forman, J.; Chin, J.; Swanson, G.; et al. Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: Long-term followup of a randomized clinical trial. *J. Urol.* **2009**, *181*, 956–962. [CrossRef]

12. Bolla, M.; van Poppel, H.; Collette, L.; van Cangh, P.; Vekemans, K.; Da Pozzo, L.; de Reijke, T.M.; Verbaey's, A.; Bosset, J.-F.; van Velthoven, R.; et al. Postoperative radiotherapy after radical prostatectomy: A randomised controlled trial (EORTC trial 22911). *Lancet* **2005**, *366*, 572–578. [CrossRef]

13. Wiegel, T.; Bartkowiak, D.; Bottke, D.; Bronner, C.; Steiner, U.; Siegmann, A.; Golz, R.; Störkel, S.; Willich, N.; Semjonow, A.; et al. Adjuvant radiotherapy versus wait-and-see after radical prostatectomy: 10-year follow-up of the ARO 96-02/AUO AP 09/95 trial. *Eur. Urol.* **2014**, *66*, 243–250. [CrossRef] [PubMed]

14. Hackman, G.; Taari, K.; Tammela, T.L.; Matikainen, M.; Kouri, M.; Joensuu, T.; Luukkaala, T.; Salonen, A.; Isotalo, T.; Pétas, A.; et al. Randomised Trial of Adjuvant Radiotherapy Following Radical Prostatectomy Versus Radical Prostatectomy Alone in Prostate Cancer Patients with Positive Margins or Extracapsular Extension. *Eur. Urol.* **2019**, *76*, 586–595. [CrossRef]
## 7. Conclusions

For several years, the timing of post-prostatectomy RT has been the subject of intense debate. The current data argue in favor of delivering early sRT, when BCR occurs (PSA > 0.2 ng/mL on two consecutive assays). This strategy results in improved biochemical outcomes while sparing patients who have not had a recurrence from potential toxicities. However, survival data are not sufficiently mature and long-term results are needed to confirm the strategy. Some uncertainties remain, such as the appropriate selection of patients requiring concomitant ADT, and its duration. Intensified therapy strategies involving new molecules such as new-generation hormone therapy are being currently evaluated. Finally, the growing importance of metabolic imaging, in particular PSMA-PET/CT, and genomic data should allow more personalized therapeutic strategies in the future.

**Author Contributions:** Writing—original draft preparation, M.T.; writing—review and editing, M.T., E.J.L. and Y.M.; supervision, P.B.; validation, M.T., E.J.L., Y.M. and P.B. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Conflicts of Interest:** The authors declare no conflict of interest.

## References

1. Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. *CA. Cancer J. Clin.* **2018**, *68*, 394–424. [CrossRef] [PubMed]

2. Van den Broeck, T.; van den Bergh, R.C.N.; Arfi, N.; Gross, T.; Moris, L.; Briers, E.; Cumberbatch, M.; De Santis, M.; Tilki, D.; Fanti, S.; et al. Prognostic Value of Biochemical Recurrence Following Treatment with Curative Intent for Prostate Cancer: A Systematic Review. *Eur. Urol.* **2019**, *75*, 967–987. [CrossRef] [PubMed]

3. Pound, C.R.; Partin, A.W.; Eisenberger, M.A.; Chan, D.W.; Pearson, J.D.; Walsh, P.C. Natural history of progression after PSA elevation following radical prostatectomy. *JAMA* **1999**, *281*, 1591–1597. [CrossRef]

4. Abdollah, F.; Suardi, N.; Cozzarini, C.; Gallina, A.; Capitanio, U.; Bianchi, M.; Sun, M.; Fossati, N.; Passoni, N.M.; Fiorino, C.; et al. Selecting the optimal candidate for adjuvant radiotherapy after radical prostatectomy for prostate cancer: A long-term survival analysis. *Eur. Urol.* **2013**, *63*, 998–1008. [CrossRef]

5. Amling, C.L.; Bergstralh, E.J.; Blute, M.L.; Slezak, J.M.; Zincke, H. Defining prostate specific antigen progression after radical prostatectomy: What is the most appropriate cut point? *J. Urol.* **2001**, *165*, 1146–1151. [CrossRef]

6. Tendulkar, R.D.; Agrawal, S.; Gao, T.; Efstathiou, J.A.; Pisansky, T.M.; Michalski, J.M.; Koontz, B.F.; Hamstra, D.A.; Feng, F.Y.; Liauw, S.L.; et al. Contemporary Update of a Multi-Institutional Predictive Nomogram for Salvage Radiotherapy After Radical Prostatectomy. *J. Clin. Oncol.* **2016**, *34*, 3648–3654. [CrossRef]

7. Aus, G.; Abbou, C.C.; Bolla, M.; Heidenreich, A.; Schmid, H.-P.; van Poppel, H.; Wolff, J.; Zattoni, F. European Association of Urology EAU guidelines on prostate cancer. *Eur. Urol.* **2005**, *48*, 546–551. [CrossRef] [PubMed]

8. Ahlering, T.E.; Skarecky, D.W. Long-term outcome of detectable PSA levels after radical prostatectomy. *Prostate Cancer Prostatic Dis.* **2005**, *8*, 163–166. [CrossRef] [PubMed]

9. Antonarakis, E.S.; Feng, Z.; Trock, B.J.; Humphreys, E.B.; Carducci, M.A.; Partin, A.W.; Walsh, P.C.; Eisenberger, M.A. The natural history of metastatic progression in men with prostate-specific antigen recurrence after radical prostatectomy: Long-term follow-up. *BJU Int.* **2012**, *109*, 32–39. [CrossRef]

10. Tilki, D.; Preisser, F.; Graefen, M.; Huland, H.; Pompe, R.S. External Validation of the European Association of Urology Biochemical Recurrence Risk Groups to Predict Metastasis and Mortality After Radical Prostatectomy in a European Cohort. *Eur. Urol.* **2019**, *75*, 896–900. [CrossRef]

11. Thompson, I.M.; Tangen, C.M.; Paradelo, J.; Lucia, M.S.; Miller, G.; Troyer, D.; Messing, E.; Forman, J.; Chin, J.; Swanson, G.; et al. Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: Long-term followup of a randomized clinical trial. *J. Urol.* **2009**, *181*, 956–962. [CrossRef]

12. Bolla, M.; van Poppel, H.; Collette, L.; van Cangh, P.; Vekemans, K.; Da Pozzo, L.; de Reijke, T.M.; Verbaey, A.; Bosset, J.-F.; van Velthoven, R.; et al. Postoperative radiotherapy after radical prostatectomy: A randomised controlled trial (EORTC trial 22911). *Lancet* **2005**, *366*, 572–578. [CrossRef]

13. Wiegel, T.; Bartkowiak, D.; Bottke, D.; Bronner, C.; Steiner, U.; Siegmann, A.; Golz, R.; Störkel, S.; Willich, N.; Semjonow, A.; et al. Adjuvant radiotherapy versus wait-and-see after radical prostatectomy: 10-year follow-up of the ARO 96-02/AUO AP 09/95 trial. *Eur. Urol.* **2014**, *66*, 243–250. [CrossRef] [PubMed]

14. Hackman, G.; Taari, K.; Tammela, T.L.; Matikainen, M.; Kouri, M.; Joensuu, T.; Luukkaala, T.; Salonen, A.; Isotalo, T.; Pétas, A.; et al. Randomised Trial of Adjuvant Radiotherapy Following Radical Prostatectomy Versus Radical Prostatectomy Alone in Prostate Cancer Patients with Positive Margins or Extracapsular Extension. *Eur. Urol.* **2019**, *76*, 586–595. [CrossRef]
15. Parker, C.C.; Clarke, N.W.; Cook, A.D.; Kynaston, H.G.; Petersen, P.M.; Catton, C.; Cross, W.; Logue, J.; Parulekar, W.; Payne, H.; et al. Timing of radiotherapy after radical prostatectomy (RADICALS-RT): A randomised, controlled phase 3 trial. *Lancet* **2020**, *396*, 1413–1421. [CrossRef]

16. Kneebone, A.; Fraser-Browne, C.; Duchesne, G.M.; Fisher, R.; Frydenberg, M.; Herschtal, A.; Williams, S.G.; Brown, C.; Delprado, W.; Haworth, A.; et al. Adjuvant radiotherapy versus early salvage radiotherapy following radical prostatectomy (TROG 08.03/ANZUP RAVES): A randomised, controlled, phase 3, non-inferiority trial. *Lancet Oncol.* **2020**, *21*, 1331–1340. [CrossRef]

17. Sargos, P.; Chabaud, S.; Latorzeff, I.; Magné, N.; Benyoucef, A.; Supiot, S.; Pasquier, D.; Abdiche, M.S.; Gilliot, O.; Graff-Cailleaud, P.; et al. Adjuvant radiotherapy versus early salvage radiotherapy plus short-term androgen deprivation therapy in men with localised prostate cancer after radical prostatectomy (GETUG-AFU 17): A randomised, phase 3 trial. *Lancet Oncol.* **2020**, *21*, 1341–1352. [CrossRef]

18. Bhindi, B.; Lokeshwar, S.D.; Klaassen, Z.; Klotz, L.; Wallis, C.J.D. Systematic review and meta-analysis of trials evaluating the role of adjuvant radiation after radical prostatectomy for prostate cancer: Implications for early salvage. *Can. Urol. Assoc. J.* **2020**, *14*, 330–336. [CrossRef] [PubMed]

19. Wallis, C.J.D.; Cheung, P.; Herschorn, S.; Saskin, R.; Su, J.; Klotz, L.H.; Kulkarni, G.S.; Lee, Y.; Kodama, R.T.; Narod, S.A.; et al. Complications following surgery with or without radiotherapy or radiotherapy alone for prostate cancer. *Br. J. Cancer* **2015**, *112*, 977–982. [CrossRef] [PubMed]

20. Vale, C.L.; Fisher, D.; Kneebone, A.; Parker, C.; Pearse, M.; Richaud, P.; Sargos, P.; Sydes, M.R.; Brawley, C.; Brihoum, M.; 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. *Lancet* **2020**, *396*, 1422–1431. [CrossRef]

21. Tilki, D.; Chen, M.-H.; Wu, J.; Huland, H.; Graefen, M.; Wiegel, T.; Böhmer, D.; Mohamad, O.; Cowan, J.E.; Feng, F.Y.; et al. Adjuvant Versus Early Salvage Radiation Therapy for Men at High Risk for Recurrence Following Radical Prostatectomy for Prostate Cancer and the Risk of Death. *J. Clin. Oncol.* **2021**, *39*, 2284–2293. [CrossRef] [PubMed]

22. Pai, H.H.; Eldridge, B.; Bishop, D.; Alexander, A.; Lesperance, M.; Blood, P.; Lim, J.; Ludgate, C. Does neoadjuvant hormone therapy improve outcome in prostate cancer patients receiving radiotherapy after radical prostatectomy? *Can. J. Urol.* **2009**, *16*, 4541–4552.

23. Ost, P.; De Troyer, B.; Fonteyne, V.; Oosterlinck, W.; De Meerleer, G. A matched control analysis of adjuvant and salvage high-dose postoperative intensity-modulated radiotherapy for prostate cancer. *Int. J. Radiat. Oncol. Biol. Phys.* **2011**, *80*, 1316–1322. [CrossRef] [PubMed]

24. Shipley, W.U.; Seiferheld, W.; Lukka, H.R.; Major, P.P.; Heney, N.M.; Grignon, D.J.; Sartor, O.; Patel, M.P.; Bahary, J.-P.; Zietman, A.L.; et al. Radiation with or without Antiandrogen Therapy in Recurrent Prostate Cancer. *N. Engl. J. Med.* **2017**, *376*, 417–428. [CrossRef]

25. Carrie, C.; Magné, N.; Burban-Provost, P.; Sargos, P.; Latorzeff, I.; Lagrange, J.-L.; Supiot, S.; Belkacemi, Y.; Peiffert, D.; Allouache, N.; et al. Short-term androgen deprivation therapy combined with radiotherapy as salvage treatment after radical prostatectomy for prostate cancer (GETUG-AFU 16): A 112-month follow-up of a phase 3, randomised trial. *Lancet Oncol.* **2019**, *20*, 1740–1749. [CrossRef]

26. Dess, R.T.; Sun, Y.; Jackson, W.C.; Jairath, N.K.; Kishan, A.U.; Wallington, D.G.; Mahal, B.A.; Stish, B.J.; Zumsteg, Z.S.; Den, R.B.; et al. Association of Presalvage Radiotherapy PSA Levels After Prostatectomy With Outcomes of Long-term Antiandrogen Therapy in Men With Prostate Cancer. *JAMA Oncol.* **2020**, *6*, 735–743. [CrossRef]

27. Kane, C.J.; Amling, C.L.; Johnstone, P.A.S.; Pak, N.; Lance, R.S.; Thrasher, J.B.; Foley, J.P.; Riffenburgh, R.H.; Moul, J.W. Limited value of bone scintigraphy and computed tomography in assessing biochemical failure after radical prostatectomy. *Urology* **2003**, *61*, 607–611. [CrossRef]

28. Beresford, M.J.; Gillatt, D.; Benson, R.J.; Ajithkumar, T. A systematic review of the role of imaging before salvage radiotherapy for post-prostatectomy biochemical recurrence. *Clin. Oncol.* **2010**, *22*, 46–55. [CrossRef]

29. Okotie, O.T.; Aronson, W.J.; Wieder, J.A.; Liao, Y.; Dorey, F.; Dekernion, J.B.; Freedland, S.J. Predictors of metastatic disease in men with biochemical failure following radical prostatectomy. *J. Urol.* **2004**, *171*, 2260–2264. [CrossRef]

30. Coppola, A.; Platania, G.; Ticca, C.; De Mattia, C.; Bortolato, B.; Palazzi, M.F.; Vanzulli, A. Sensitivity of CE-MRI in detecting local recurrence after radical prostatectomy. *Radiol. Med.* **2020**, *125*, 683–690. [CrossRef]

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32. Umbehr, M.H.; Müntener, M.; Hany, T.; Sulser, T.; Bachmann, L.M. The role of 11C-choline and 18F-fluorocholine positron emission tomography (PET) and PET/CT in prostate cancer: A systematic review and meta-analysis. *Eur. Urol.* **2013**, *64*, 106–117. [CrossRef] [PubMed]

33. Evangelista, L.; Zattoni, F.; Guttilla, A.; Saladini, G.; Zattoni, F.; Colletti, P.M.; Rubello, D. Choline PET or PET/CT and biochemical relapse of prostate cancer: A systematic review and meta-analysis. *Clin. Nucl. Med.* **2013**, *38*, 305–314. [CrossRef]

34. Farolfi, A.; Ceci, F.; Castellucci, P.; Graziani, T.; Siepe, G.; Lambertini, A.; Schiavina, R.; Lodi, F.; Morganti, A.G.; Fanti, S. 68Ga-PSMA-11 PET/CT in prostate cancer patients with biochemical recurrence after radical prostatectomy and PSA < 0.5 ng/mL. Efficacy and impact on treatment strategy. *Eur. J. Nucl. Med. Mol. Imaging* **2019**, *46*, 11–19. [CrossRef]
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16. Kneebone, A.; Fraser-Browne, C.; Duchesne, G.M.; Fisher, R.; Frydenberg, M.; Herschtal, A.; Williams, S.G.; Brown, C.; Delprado, W.; Haworth, A.; et al. Adjuvant radiotherapy versus early salvage radiotherapy following radical prostatectomy (TROG 08.03/ANZUP RAVES): A randomised, controlled, phase 3, non-inferiority trial. *Lancet Oncol.* **2020**, *21*, 1331–1340. [CrossRef]

17. Sargos, P.; Chabaud, S.; Latorzeff, I.; Magné, N.; Benyoucef, A.; Supiot, S.; Pasquier, D.; Abdiche, M.S.; Gilliot, O.; Graff-Cailleaud, P.; et al. Adjuvant radiotherapy versus early salvage radiotherapy plus short-term androgen deprivation therapy in men with localised prostate cancer after radical prostatectomy (GETUG-AFU 17): A randomised, phase 3 trial. *Lancet Oncol.* **2020**, *21*, 1341–1352. [CrossRef]

18. Bhindi, B.; Lokeshwar, S.D.; Klaassen, Z.; Klotz, L.; Wallis, C.J.D. Systematic review and meta-analysis of trials evaluating the role of adjuvant radiation after radical prostatectomy for prostate cancer: Implications for early salvage. *Can. Urol. Assoc. J.* **2020**, *14*, 330–336. [CrossRef] [PubMed]

19. Wallis, C.J.D.; Cheung, P.; Herschorn, S.; Saskin, R.; Su, J.; Klotz, L.H.; Kulkarni, G.S.; Lee, Y.; Kodama, R.T.; Narod, S.A.; et al. Complications following surgery with or without radiotherapy or radiotherapy alone for prostate cancer. *Br. J. Cancer* **2015**, *112*, 977–982. [CrossRef] [PubMed]

20. Vale, C.L.; Fisher, D.; Kneebone, A.; Parker, C.; Pearse, M.; Richaud, P.; Sargos, P.; Sydes, M.R.; Brawley, C.; Brihoum, M.; 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. *Lancet* **2020**, *396*, 1422–1431. [CrossRef]

21. Tilki, D.; Chen, M.-H.; Wu, J.; Huland, H.; Graefen, M.; Wiegel, T.; Böhmer, D.; Mohamad, O.; Cowan, J.E.; Feng, F.Y.; et al. Adjuvant Versus Early Salvage Radiation Therapy for Men at High Risk for Recurrence Following Radical Prostatectomy for Prostate Cancer and the Risk of Death. *J. Clin. Oncol.* **2021**, *39*, 2284–2293. [CrossRef] [PubMed]

22. Pai, H.H.; Eldridge, B.; Bishop, D.; Alexander, A.; Lesperance, M.; Blood, P.; Lim, J.; Ludgate, C. Does neoadjuvant hormone therapy improve outcome in prostate cancer patients receiving radiotherapy after radical prostatectomy? *Can. J. Urol.* **2009**, *16*, 4541–4552.

23. Ost, P.; De Troyer, B.; Fonteyne, V.; Oosterlinck, W.; De Meerleer, G. A matched control analysis of adjuvant and salvage high-dose postoperative intensity-modulated radiotherapy for prostate cancer. *Int. J. Radiat. Oncol. Biol. Phys.* **2011**, *80*, 1316–1322. [CrossRef] [PubMed]

24. Shipley, W.U.; Seiferheld, W.; Lukka, H.R.; Major, P.P.; Heney, N.M.; Grignon, D.J.; Sartor, O.; Patel, M.P.; Bahary, J.-P.; Zietman, A.L.; et al. Radiation with or without Antiandrogen Therapy in Recurrent Prostate Cancer. *N. Engl. J. Med.* **2017**, *376*, 417–428. [CrossRef]

25. Carrie, C.; Magné, N.; Burban-Provost, P.; Sargos, P.; Latorzeff, I.; Lagrange, J.-L.; Supiot, S.; Belkacemi, Y.; Peiffert, D.; Allouache, N.; et al. Short-term androgen deprivation therapy combined with radiotherapy as salvage treatment after radical prostatectomy for prostate cancer (GETUG-AFU 16): A 112-month follow-up of a phase 3, randomised trial. *Lancet Oncol.* **2019**, *20*, 1740–1749. [CrossRef]

26. Dess, R.T.; Sun, Y.; Jackson, W.C.; Jairath, N.K.; Kishan, A.U.; Wallington, D.G.; Mahal, B.A.; Stish, B.J.; Zumsteg, Z.S.; Den, R.B.; et al. Association of Presalvage Radiotherapy PSA Levels After Prostatectomy With Outcomes of Long-term Antiandrogen Therapy in Men With Prostate Cancer. *JAMA Oncol.* **2020**, *6*, 735–743. [CrossRef]

27. Kane, C.J.; Amling, C.L.; Johnstone, P.A.S.; Pak, N.; Lance, R.S.; Thrasher, J.B.; Foley, J.P.; Riffenburgh, R.H.; Moul, J.W. Limited value of bone scintigraphy and computed tomography in assessing biochemical failure after radical prostatectomy. *Urology* **2003**, *61*, 607–611. [CrossRef]

28. Beresford, M.J.; Gillatt, D.; Benson, R.J.; Ajithkumar, T. A systematic review of the role of imaging before salvage radiotherapy for post-prostatectomy biochemical recurrence. *Clin. Oncol.* **2010**, *22*, 46–55. [CrossRef]

29. Okotie, O.T.; Aronson, W.J.; Wieder, J.A.; Liao, Y.; Dorey, F.; Dekernion, J.B.; Freedland, S.J. Predictors of metastatic disease in men with biochemical failure following radical prostatectomy. *J. Urol.* **2004**, *171*, 2260–2264. [CrossRef]

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37. Calais, J.; Czernin, J.; Cao, M.; Kishan, A.U.; Hegde, J.V.; Shaverdian, N.; Sandler, K.; Chu, F.-I.; King, C.R.; Steinberg, M.L.; et al. 68Ga-PSMA-11 PET/CT Mapping of Prostate Cancer Biochemical Recurrence After Radical Prostatectomy in 270 Patients with a PSA Level of Less Than 1.0 ng/mL: Impact on Salvage Radiotherapy Planning. *J. Nucl. Med.* **2018**, *59*, 230–237. [CrossRef]

38. Boreta, L.; Gadzinski, A.J.; Wu, S.Y.; Xu, M.; Greene, K.; Quanstrom, K.; Nguyen, H.G.; Carroll, P.R.; Hope, T.A.; Feng, F.Y. Location of Recurrence by Gallium-68 PSMA-11 PET Scan in Prostate Cancer Patients Eligible for Salvage Radiotherapy. *Urology* **2019**, *129*, 165–171. [CrossRef]

39. Bottke, D.; Miksch, J.; Thamm, R.; Krohn, T.; Bartkowiak, D.; Beer, M.; Bolenz, C.; Beer, A.J.; Prasad, V.; Wiegel, T. Changes of Radiation Treatment Concept Based on 68Ga-PSMA-11-PET/CT in Early PSA-Recurrences After Radical Prostatectomy. *Front. Oncol.* **2021**, *11*, 665304. [CrossRef]

40. Calais, J.; Ceci, F.; Eiber, M.; Hope, T.A.; Hofman, M.S.; Rischpler, C.; Bach-Gansmo, T.; Nanni, C.; Savir-Baruch, B.; Elashoff, D.; et al. 18F-fluciclovine PET-CT and 68Ga-PSMA-11 PET-CT in patients with early biochemical recurrence after prostatectomy: A prospective, single-centre, single-arm, comparative imaging trial. *Lancet Oncol.* **2019**, *20*, 1286–1294. [CrossRef]

41. Bhargava, P.; Ravizzini, G.; Chapin, B.F.; Kundra, V. Imaging Biochemical Recurrence After Prostatectomy: Where Are We Headed? *AJR Am. J. Roentgenol.* **2020**, *214*, 1248–1258. [CrossRef]

42. Jani, A.B.; Schreibmann, E.; Goyal, S.; Halkar, R.; Hershatter, B.; Rossi, P.J.; Shelton, J.W.; Patel, P.R.; Xu, K.M.; Goodman, M.; et al. 18F-fluciclovine-PET/CT imaging versus conventional imaging alone to guide postprostatectomy salvage radiotherapy for prostate cancer (EMPIRE-1): A single centre, open-label, phase 2/3 randomised controlled trial. *Lancet* **2021**, *397*, 1895–1904. [CrossRef]

43. Celli, M.; De Giorgi, U.; Caroli, P.; Di Iorio, V.; Fantini, L.; Rossetti, V.; Foca, F.; Nicolini, S.; Giganti, M.; Paganelli, G.; et al. Clinical value of negative 68Ga-PSMA PET/CT in the management of biochemical recurrent prostate cancer patients. *Eur. J. Nucl. Med. Mol. Imaging* **2021**, *48*, 87–94. [CrossRef]

44. Emmett, L.; Tang, R.; Nandurkar, R.; Hruby, G.; Roach, P.; Watts, J.A.; Cusick, T.; Kneebone, A.; Ho, B.; Chan, L.; et al. 3-Year Freedom from Progression After 68Ga-PSMA PET/CT-Triaged Management in Men with Biochemical Recurrence After Radical Prostatectomy: Results of a Prospective Multicenter Trial. *J. Nucl. Med.* **2020**, *61*, 866–872. [CrossRef]

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47. Karnes, R.J.; Bergstrahl, E.J.; Davicioni, E.; Ghadessi, M.; Buerki, C.; Mitra, A.P.; Crisan, A.; Erho, N.; Vergara, I.A.; Lam, L.L.; et al. Validation of a genomic classifier that predicts metastasis following radical prostatectomy in an at risk patient population. *J. Urol.* **2013**, *190*, 2047–2053. [CrossRef]

48. Spratt, D.E.; Yousefi, K.; Deheshi, S.; Ross, A.E.; Den, R.B.; Schaeffer, E.M.; Trock, B.J.; Zhang, J.; Glass, A.G.; Dicker, A.P.; et al. Individual Patient-Level Meta-Analysis of the Performance of the Decipher Genomic Classifier in High-Risk Men After Prostatectomy to Predict Development of Metastatic Disease. *J. Clin. Oncol.* **2017**, *35*, 1991–1998. [CrossRef]

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50. An AI-derived digital pathology-based biomarker to predict the benefit of androgen deprivation therapy in localized prostate cancer with validation in NRG/RTOG 9408. *J. Clin. Oncol.* Available online: https://ascopubs.org/doi/abs/10.1200/JCO.2022.4 0.6_suppl.223 (accessed on 27 February 2022).

51. Rowe, L.S.; Harmon, S.; Horn, A.; Shankavaram, U.; Roy, S.; Ning, H.; Lindenberg, L.; Mena, E.; Citrin, D.E.; Choyke, P.; et al. Pattern of failure in prostate cancer previously treated with radical prostatectomy and post-operative radiotherapy: A secondary analysis of two prospective studies using novel molecular imaging techniques. *Radiat. Oncol.* **2021**, *16*, 32. [CrossRef]

52. Ghashghaei, M.; Niazi, T.M.; Heravi, M.; Bekerat, H.; Trifiro, M.; Paliouras, M.; Muanza, T. Enhanced radiosensitization of enzalutamide via schedule dependent administration to androgen-sensitive prostate cancer cells. *Prostate* **2018**, *78*, 64–75. [CrossRef]

53. Bitting, R.L.; Healy, P.; George, D.J.; Anand, M.; Kim, S.; Mayer, T.; Winters, C.; Riggan, C.; Rasmussen, J.; Wilder, R.; et al. Phase II Trial of Enzalutamide and Androgen Deprivation Therapy with Salvage Radiation in Men with High-risk Prostate-specific Antigen Recurrent Prostate Cancer: The STREAM Trial. *Eur. Urol. Oncol.* **2021**, *4*, 948–954. [CrossRef]

54. Cailleteau, A.; Sargos, P.; Saad, F.; Latorzeff, I.; Supiot, S. Drug Intensification in Future Postoperative Radiotherapy Practice in Biochemically-Relapsing Prostate Cancer Patients. *Front. Oncol.* **2021**, *11*, 780507. [CrossRef]