








































This is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited.  
© 2023 The Authors. Société Internationale d'Urologie Journal, published by the Société Internationale d'Urologie, Canada.

Key Words Competing Interests Article Information

Prostatic neoplasms, prostatectomy, risk 
factors, adjuvant radiotherapy, salvage 
therapy

None declared. Received on June 13, 2022 
Accepted on August 8, 2022 
This article has been peer reviewed.

Soc Int Urol J. 2023;4(1):40–50

DOI: 10.48083/MSVK1934

Salvage Versus Adjuvant Radiation Therapy 
Following Radical Prostatectomy in Localised 
Prostate Cancer: A War Without a Winner
Lara Rodriguez-Sanchez,1 Petr Macek,1 Camille Lanz,1 Qusay Mandoorah,1 Nuno Dias,1,2  
Gianmarco Colandrea,1,3 Fernando P. Secin,4 Amandeep M. Arora,5 Rafael Sanchez-Salas,6  
Xavier Cathelineau1

1 Department of Urology, Institut Mutualiste Montsouris, Université Paris-Descartes, Paris, France 2 Department of Urology, São João Hospital and University Center, 
Porto, Portugal 3 Unit of Urology, Division of Experimental Oncology, URI - Urological Research Institute, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele 
University, Milan, Italy 4 Discipline of Urology, University of Buenos Aires School of Medicine, Buenos Aires, Argentina 5 Division of Urology, Department of Surgical 
Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, India 6 Department of Surgery, Division of Urology, McGill University Health Center, 
Montreal, Canada

Abstract

Objective To review current literature regarding the efficacy of adjuvant radiation therapy (ART) and salvage 
radiation therapy (SRT) following radical prostatectomy (RP) in patients with undetectable postoperative prostate-
specific antigen (PSA) levels and high-risk features of prostate cancer (PCa) recurrence.

Methods Seven randomized controlled trials focused on the use of ART compared with either observation or SRT 
after RP that had been published in PubMed up to May 2022 were reviewed.

Results The use of ART following RP has been the treatment of choice over the past decade. Three RCTs comparing 
ART with early SRT show that SRT given as soon as biochemical recurrence (BCR) is detected is not inferior to 
ART while it offers the opportunity to avoid overtreatment and potential RT-related side effects. A meta-analysis 
summarizing the results from these trials supports these findings.

Conclusions Early SRT may be suggested as the standard of care for patients with PCa and high-risk features for 
disease recurrence following RP. Nevertheless, further investigations are needed to identify those patients who will 
benefit from ART, particularly, in case of lymph node involvement. Moreover, some patients might avoid SRT despite 
reaching detectable postoperative serum PSA levels.

Introduction

Because of its complexity and heterogeneity, prostate cancer (PCa) management at any disease stage is under constant 
debate[1–3], and the use of adjuvant radiation therapy (ART) following radical prostatectomy (RP) to address risk 
factors for disease recurrence has been questioned in recent years[4].

While earlier randomized controlled trials (RCTs) showed a biochemical recurrence (BCR)-free survival benefit 
with ART, a meta-analysis published in 2020 has shown no event-free survival benefit compared with salvage RT 
[5–9]. Nevertheless, the impact of each of the risk factors and their combination on recurrence remain under 
debate[10].

In this respect, the last European Association of Urology (EAU) guidelines, published in 2022, propose ART be 
offered to a select group of patients: (a) patients without lymph node involvement but adverse pathology such as 
International Society of Urologic Pathologists (ISUP) grade group 4–5 and pT3 with or without positive margins and, 

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(b) patients with lymph node metastasized PCa with > 2 
nodes involved[11].

In this review, we discuss the RCTs evaluating ART and 
salvage radiation therapy (SRT) for patients treated with RP 
who had high-risk features for disease recurrence.

Methods
We searched RCTs and meta-analyses published up 
to May 2022, using the following terms: “adjuvant 
radiotherapy, prostatectomy,” salvage radiotherapy, 
prostatectomy,” and “postoperative radiotherapy, 
prostatic neoplasm.” Articles not written in English were 
excluded. Conference abstracts that did not provide 
enough information, case reports, review articles, and 
editorial comments were also excluded from review. 
Seven RCTs focused on the use of ART compared  
with either observation or SRT after RP were included in 
our review.

Results
Available evidence
Approximately 25% of men will experience recurrence 
of their cancer following RP for localised PCa[10]. ART 
has been the treatment of choice since the publication 
of 3 RCTs over the past decade: the SWOG 8794[6], the 
European Organisation for Research and Treatment 
of Cancer (EORTC 22911)[7], and the German Cancer 
Society (ARO 96–02/AUO AP 09/95)[8] trials, with 
their last results published in 2009, 2012, and 2014, 
respectively.

The SWOG 8794 trial[6] (Table 1) was the first 
randomized study to support the use of ART in patients 
with unfavourable pathologic features (pT3 disease or 
positive surgical margins). Thomson et al. proved that 
the use of ART leads to better oncologic outcomes in 

Abbreviations 
ADT androgen-deprivation therapy
ART adjuvant radiation therapy
BCR biochemical recurrence
CT computed tomography
MFS metastasis-free survival
OS overall survival
PCa prostate cancer
PET positron emission tomography
PFS progression-free survival
PSADT PSA doubling time
RCT randomized controlled trial
RP radical prostatectomy
SRT salvage radiation therapy

terms of metastasis-free survival (MFS) and overall 
survival (OS). Nevertheless, it is important to note that 
the patients enrolled were randomized to ART or obser-
vation instead of SRT. Hence, not every patient with BCR 
received timely SRT. Accordingly, the median serum 
PSA level at the time of SRT in the case of PSA-only 
relapse was 0.75 ng/dL, and 37% of patients receiving 
SRT had already experienced objective cancer recur-
rence. In addition, 33% of patients included in this trial 
did not have undetectable postoperative PSA levels.

Similarly, Bolla et al.[7] (Table 1) randomized 1005 
patients with pT3 disease or positive surgical margins 
following RP to ART or a wait-and-see/obser va-
tion policy. According to the SWOG 8794 trial, ART 
improved biochemical progression-free survival (PFS) 
and local control compared with observation. Unfor-
tunately, half of the patients in the wait-and-see arm 
experienced only BCR (defined as an increase in PSA 
concentration > 0.2 ng/dL after the lowest postoperative 
value was measured), but only 14.5% of them received 
SRT. Thus, at least 30% of patients with BCR after 
surgery did not receive SRT as the first active salvage 
therapy. In addition, although pre-SRT PSA values were 
not reported, the median PSA value before any type of 
active salvage treatment was 1.7 ng/dL, and 14 patients 
received SRT despite a PSA level that had not reached a 
nadir below 0.2 ng/mL after RP.

The ARO 96–02/AUO AP 09/95[8] study (Table 1) 
included only patients with undetectable postoperative 
serum PSA levels. The results of this study also favoured 
ART. ART reduced the risk of progression (biochemical 
progression, local or distant clinical recurrence, or death 
from any cause) by 49%. In any case, no patient enrolled 
in the wait-and-see arm received additional treatment, 
so we cannot deduce whether the use of SRT could have 
decreased the differences between study arms.

Following this, many retrospective studies were 
reported that focused on the effect of SRT given to those 
patients with unfavourable clinical and pathologic 
features[10]. Aiming to shed light on this topic, Tao et 
al.[10] published a systematic review and meta-analysis 
that included 15 studies published between 2002 and 
2018 comparing the prognosis of ART and SRT. It must 
be noted that this review did not include the above 3 
RCTs as those RCTs compared ART with observation, 
while the review focused on ART versus SRT. There-
fore, all studies considered for analysis were retrospec-
tive. According to this meta-analysis, the use of ART 
following RP reduces the risk of BCR and 5-year overall 
mortality, although no benefit from ART was demon-
strated in terms of patient survival at 10 years from RP. 
Importantly, (a) all patients considered had received 
either ART or SRT, which means that all patients 
included in the SRT group had developed BCR, which 

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in turn may imply a greater predisposition to unfavour-
able disease, and (b) no improvement in BCR in the ART 
arm was observed when only early SRT (defined as SRT 
given at PSA levels < 0.5 ng/dL) was considered.

Finally, a Finnish trial published in July 2019 (Table 1) 
randomized 250 patients with pT2 disease and positive 
margins or pT3a disease (irrespective of margin status) 
to ART or observation[9]. ART prolonged BCR-free 
survival compared with RP alone, but (a) the increase in 
PSA levels before receiving SRT was counted as an event, 
while nearly three-quarters of patients achieved PSA 
remission after SRT; (b) 29% of patients in the obser-
vation group whose disease progressed locally did not 
receive SRT; and (c) the median PSA level at SRT was 
0.7 ng/mL (range, 0.42 to 8.2).

In short, the above-mentioned studies support the use 
of ART when it is compared with observation or salvage 
radiotherapy, but they do not provide adequate outcome 
information about early SRT.

In this vein, several retrospective studies have 
suggested that early initiation of SRT will not compro-
mise cancer control but rather reduce the overtreatment 
that is associated with ART[12–15]. In 2020, a meta-anal-
ysis showed that SRT results may not differ from ART 
results if the postoperative serum PSA value is below 
0.2 ng/mL at the time of treatment[5]. Consequently, it 
has recently been disputed whether the use of SRT as 
soon as PSA values reach a detectable level may have an 
important impact when SRT is compared with ART.

New investigations and findings
At present, SRT is recommended when the postoperative 
serum PSA value is ≤  0.5  ng/mL[13,16]. It has been 
observed, however, that 5-year freedom from BCR after 
SRT was 71% for those patients with a pre-SRT PSA 
level ≤ 0.2 ng/mL, 63% for those with a PSA of 0.21 to 
0.50  ng/mL, 54% for those with a PSA value between 
0.51 and 1.0 ng/mL, and 37% for those with a PSA value 
≥ 2.0 ng/mL[17]. Hence, the timing of SRT may alter its 
effectiveness[18].

Three RCTs — RADICALS-RT, RAVES, and GETUG- 
AFU-17 — were aimed at answering a hitherto unre-
solved dilemma: “What is the best timing for post-
operative RT?”[19–21] (Table 1). In this case, patients 
were randomized to ART or observation followed 
by SRT when the PSA level was ≥  0.2  ng/dL[19,20] or 
even ≥  0.1  ng/dL[21]. A collaborative and prospec-
tively designed systematic review and meta-analysis 
that included these 3 trials suggested that ART does 
not improve event-free survival in men with localised 
or locally advanced PCa compared with SRT. Five-year 
event-free survival in ART and SRT were 89% and 88%, 
respectively[5]. Of interest, more than half of the patients 
included in the SRT group did not meet the BCR crite-

ria avoiding overtreatment and potential RT-related-side 
effects, including sexual, urinary, and bowel dysfunc-
tions[5,22]. The RADICALS-RT, RAVES, and GETUG-
AFU-17 trials[19–21] revealed that RT toxicity was more 
common among patients randomized to ART compared 
with SRT. Grade 1 to 2 events were about twice as preva-
lent in the ART group; grade 3 to 4 events were uncom-
mon in both groups.

Data from these RCTs support the notion that early 
SRT avoids overtreatment without compromising the 
oncologic outcome. Therefore, it seems reasonable to 
adopt this approach as the standard of care following RP 
for localised prostate cancer. Nevertheless, can we gener-
alise it to all patients? Should we give special consider-
ation to the different risk factors for recurrence and their 
combination? Will the development of biomarkers and 
imaging techniques allow us to identify the best timing 
for RT after surgery?

Discussion
Accurate risk of recurrence estimation
Extracapsular extension, seminal vesicle invasion, 
positive surgical margins, high Gleason score, and 
lymph node involvement are the main independent 
predictors of BCR[10,23,24]. However, the increasing 
use of genomic biomarkers to identify both germline 
and somatic variations may provide a more precise 
assessment of patients at risk of recurrence[25,26].

The heterogeneity of PCa, with variable responses to 
treatment, is probably related to the molecular hetero-
geneity of this disease, which in turn is closely related 
to its genetic profile. Thus, germline testing together 
with molecular profiling or tumour genomic profiling 
may lead us to understand more about the biology of the 
tumour, and distinguish PCa with indolent behaviour 
from those cases with a lethal course[27]. Approximately 
5% of patients with localised PCa harbour germline vari-
ations[28,29], such as BRCA2, and ATM variations that 
are associated with both PCa susceptibility and higher 
risk of aggressive disease[28]. In this regard, BRCA1/2 
carriers with localised PCa have a 16% increased abso-
lute risk of developing metastases[30]. Therefore, the 
identification of these variations may have a role in the 
management of patients at risk of BCR after RP.

Somatic changes in DNA repair genes are found in 
nearly 10% of PCa tumours confined to the prostate 
gland[31]. Spratt et al. evaluated a 22-marker genomic 
classifier (GC; DatabasE of genomiC varIation and 
Phenotype in Humans using Ensembl Resources [DECI-
PHER], Sanger Institute) to predict metastasis through 
a metanalysis of 5 studies. The authors proved that GC 
was an independent predictor of metastases. Likewise, 
the 5-year cumulative incidence of metastasis was 2.4% 
for patients with a low GC score but 15.2% for patients 

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TABLE 1.

Adjuvant radiation therapy randomized controlled trials  

SWOG  
8794[6]

EORTC 
22911[7]

ARO  
9602[8] 

FP/FINROG 
0301[9]

GETUG- 
AFU 17[19]

RADICALS- 
RT[21]

RAVES[20]

Publication 2009 2012 2014 2019 2020 2020 2020

Number of 
patients

425 1005 307 250 424 1396 333

Randomisation
ART group: 214

Observation 
group: 211

ART group: 502
Observation 
group: 503

ART group: 148
Observation 
group: 159

ART group: 126
Observation 
group: 124

ART group: 212
SRT group: 212

ART group: 697
SRT group: 699

ART group: 166 
SRT group: 167

Inclusion 
criteria

Extracapsular 
extension
and/or SVI
and/or R1
N0M0 Any 

postoperative 
PSA

pT2–3 with at 
least one of the 
following risk 

factors:
Capsular  

perforation
SVI
R1

N0M0
Any 

postoperative 
PSA

pT3–4 /R1–0
N0M0

Postoperative
PSA <0.1 ng/dL

pT2/R1 or pT3a/
R0-1

N0M0
Postoperative

PSA < 0.5 ng/dL

≥ pT3/R1
N0M0

Postoperative
PSA ≤ 0.1 ng/dL

≥ pT3 and/or
preoperative 

PSA ≥ 10ng/mL
and/or

Gleason-score 
≥ 7 and/or

R1 N0/1M0  
(5% pN1) 

Postoperative 
PSA ≤ 0.1 ng/dL

pT3 or R1 
N0M0 

Postoperative 
PSA ≤ 0.2 ng/dL

Primary 
outcome

MFS
BCR-free 
survival

PFS (BCR,  
clinical 

recurrence, or 
death)

BCR-free  
survival

Event-free  
survival  
(disease 

relapse, BCR or 
death)

Freedom  
from distant 
metastases

Freedom from 
biochemical 
progression

Median  
follow-up 
(years)

ART group: 12.7
Observation 
group: 12.5

10.6
ART group: 9.25 

Observation 
group: 9.4

ART group:  
9.3 Observation 

group: 8.6
6.25 4.1 6.1

HT added to 
SRT/ART

Not defined Not defined Not defined Not defined

6 months of HT 
together with 
ART and SRT
(All patients 

included in the 
trial) 

Randomization 
to 0 vs 6 months 

vs 24 months 
of HT together 
with ART and 

SRT
(Some patients 
included in the 

trial)

No

RT dose 60–64Gy 60Gy 60Gy 66.6Gy 66Gy 66Gy or 52.5Gy 64Gy

Use of 
SRT in the 
observation 
group 

33% 31% — 30% 54% 33% 50%

PSA: Prostate specific antigen; HT: hormonotherapy; BCR: biochemical recurrence; SRT: salvage radiotherapy; ART: adjuvant radiotherapy;  
SVI: seminal vesicle invasion; R1: positive surgical margins; MFS: metastasis-free survival; PFS: progression-free survival; OS: overall survival.
*All patients in the observation group who received SRT

continued on page 44

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TABLE 1.

Adjuvant radiation therapy randomized controlled trials  

SWOG  
8794[6]

EORTC 
22911[7]

ARO  
9602[8] 

FP/FINROG 
0301[9]

GETUG- 
AFU 17[19]

RADICALS- 
RT[21]

RAVES[20]

Early or  
late SRT

Late (median 
PSA 1 ng/dL*)

Unknown 
(median PSA 

unknown)
—

Late (median 
PSA 0.7 ng/dL*)

Early (median 
PSA 0.24 ng/dL)

Early (median 
PSA 0.2 ng/dL)

Early (median 
PSA 0.2 ng/dL)

5-year event-
free survival

ART group: 92%
SRT group: 90%

HR 0.81 [95% 
CI 0.48–1.36], 

P = 0.42

5-year  
BCR-free 
survival

ART group: 85%
SRT group: 88%

HR 1.10 [95% 
CI 0.81–1.49], 

P = 0.56

ART group: 86%
SRT group: 87%

HR 1.12 [95% 
CI 0.65–1.90], 

P = 0.15

10-year PFS

ART group: 56% 
Observation 
group: 35%

HR: 0.51 [95% 
CI 0.37–0.70], 

P < 0.0001

10-year BCR 

ART group: 53%
Observation 
group: 30%

HR 0.43 [95% CI
0.31–0.58],  
P < 0.001

ART group: 
60.6%

Observation 
group: 41.1%

HR 0.49 [95% 
CI 0·41–0·59], 

P < 0.0001

ART group: 82%
Observation 
group: 61%

HR 0.26 [95% 
CI 0.14–0.48], 

P < 0.001

10-year MFS

ART group: 71%
Observation 
group: 61%

HR 0.71 [95% 
CI 0.54–0.94], 

P = 0.016

ART group: 
76.5%

Observation 
group: 71.3%

ART group: 98%
Observation 
group: 96%

HR 0.49 [95% 
CI 0.09-2.68], 

P = 0.4

10-year OS

ART group: 74%
Observation 
group: 66%

HR 0.72 [95% 
CI 0.55–0.96], 

P = 0.023

ART group: 
60.6%

Observation 
group: 41.1%

HR 0.49 [95% 
CI 0·41–0·59], 

P < 0.0001

ART group: 92% 
Observation 
group: 87%

HR 0.69 [95% 
CI 0.29–1.60], 

P = 0.4

PSA: Prostate specific antigen; HT: hormonotherapy; BCR: biochemical recurrence; SRT: salvage radiotherapy; ART: adjuvant radiotherapy;  
SVI: seminal vesicle invasion; R1: positive surgical margins; MFS: metastasis-free survival; PFS: progression-free survival; OS: overall survival.
*All patients in the observation group who received SRT

, Cont’d 

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with high-risk GC scores[32]. Later, Marascio et al. 
explored the clinical benefit of decision-making based 
on DECIPHER CG testing after RP. This prospective 
observational study revealed that patients with high  
GC risk who received ART had a 2-year cumulative  
incidence of PSA recurrence 8 times lower than those 
who did not.

How should patients with very high-risk 
features and a combination of high-risk 
features and undetectable postoperative 
serum PSA levels be treated?

Subgroup analysis in the ARTISTIC meta-analysis 
was limited by the low event rate, while the effect of 
RT timing could not be properly evaluated in patients 
with high-risk features for BCR such as seminal vesicle 
involvement (20% of patient enrolled), Gleason score 
≥ 8 (15% of patients enrolled) or node-positive disease 
(3% of patients enrolled)[5]. Hence, there are still doubts 
about how to manage those patients with undetectable 
postoperative PSA levels together with high-risk features, 
such as node-positive disease, Gleason score > 8, and/or 
pT3b disease or higher[4]. In addition, investigators in 
the EORTC 22911 trial determined that patients with 
2 risk factors (eg, pT3a-b plus positive surgical margins) 
tended to have a greater risk of BCR and death if they 
received ART compared with those who presented 
with a single risk factor[7]. No combination of adverse 
pathologic features was evaluated in the ARTISTIC 
meta-analysis[5], preventing us from knowing which is 
the best management option for these patients.

Particularly controversial has been the management 
of pathologically node-positive PCa patients given 
the prognostic variability according to the number 
of affected nodes and tumour characteristics. In this 
regard, Abdollah et al. suggested that patients with high-
risk features for BCR (pathological stage > T3a and/or 
positive surgical margins together with Gleason score 7 
to 10) may benefit from ART even when the number of 
lymph nodes involved is lower than 3[33,34].

In a systematic review of 26 studies published in 2018, 
only one propensity score-matched study provided infor-
mation about the effectiveness of initial observation and 
SRT versus ART in the pN1 PCa setting[34,35]. The study 
proved a benefit in terms of 4-year MFS for those patients 
receiving ART regardless of disease characteristic[35].

Recently, Tilki et al., showed that ART may be better 
when compared to SRT. Moreover, the benefit seems to 
be directly related to the number of lymph nodes affected. 
Therefore, ART might be avoided when ≤  3 positive 
lymph nodes are found (notably if at least 12 lymph nodes 
are sampled) but the impact that combination of positive 
lymph nodes with other risk factors for BCR may have on 
oncological outcomes was not explored[36].

In summary, RCTs will be needed to determine the 
benefit of ART in positive lymph node PCa patients. 
Until then, the use of ART should be always considered 
in this group of patients, especially if more than 2 lymph 
nodes are involved and/or other risk factors for BCR are 
associated.

Impact of novel imaging techniques on 
treatment
The detection rate of different imaging modalities is 
determined by PSA level. Thus, the lower the PSA value, 
the lower the possibility of identifying locoregional or 
distant disease[37,38]. The decision to initiate ART 
after RP should be made when serum PSA values are 
< 0.5 ng /mL (or ideally < 0.2 ng/mL); therefore, the use 
of sensitive and accurate imaging techniques is of special 
interest. Choline-based positron emission tomography 
(PET)/computed tomography (CT) detection rate is 30% 
when the serum PSA level is ≤ 1 ng/mL after RP, while 
the corresponding detection rate is 60% for gallium 68 
prostate-specific membrane antigen (68Ga-PSMA) PET/
CT. Furthermore, when serum PSA is below 0.2 ng/mL 
the estimated detection rate for 68Ga-PSMA) PET/CT 
is 40%[38,39]. PET imaging with 68Ga-PSMA ligand 
was approved on December 1, 2020, by the US Food and 
Drug Administration to detect PCa recurrence after 
RP[40].

A meta-a na lysis of 15 st ud ies showed t hat 
68Ga-PSMA PET results after RP influenced the type 
and characteristics of treatment. The number of patients 
who received an increased dose or target volume of SRT 
rose after 68Ga-PSMA PET[41]. Similar results were 
presented at ASCO 2022. Armstrong et al. random-
ized 193 patients who experienced BCR to undergo 
any conventional imaging or 68Ga-PSMA-11 PET/CT 
scan prior to SRT (median PSA before SRT of 0.3 ng/
mL). Seventy-one percent of major changes, defined as 
change of androgen-deprivation therapy (ADT) dura-
tion ≥ 3 months, change of standard RT volumes, target 
volume delineation beyond standard RT field, simulta-
neous-integrated boost beyond standard RT fields, and 
initiation of advanced systemic therapy, were PSMA- 
related[42].

Pending final results of the Radiation Therapy Oncol-
ogy Group (RTOG) 0534 SPPORT trial, which explores 
the effect of ADT with or without pelvic lymph node 
treatment added to the prostate bed together with 
SRT[43], novel imaging techniques may be useful in 
identifying patients who may benefit from whole-pelvis 
SRT, although its association with improved oncologic 
outcomes is not yet known[44].

RT technique
RT techniques in PCa have advanced significantly in 
the past decades. For example, intensity-modulated RT 

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(IMRT) is now the gold standard for external beam RT 
(EBRT)[5]. Although the benefit of dose escalation to 
78 Gy or higher for definitive localised PCa RT is well 
known, its effect in the postoperative setting is still 
in doubt. A systematic review and meta-analysis of 
71  retrospective studies demonstrated a proportional 
gain in BCR-free survival of 2% per incremental Gy 
when escalating SRT > 70 Gy was given. A randomized 
phase 3 study that randomized patients with BCR 
following RP to either 64-Gy or 70-Gy SRT showed that 
dose escalation had a minor impact on quality of life but 
led to significant worsening of urinary symptoms[45]. 
Thus, neither National Comprehensive Cancer Network 
(NCCN) nor EAU guidelines specify the appropriate 
dose to be administered and recommend doses of at least 
66 Gy up to 72 Gy[11,46].

Stereotactic body RT (SBRT) that accurately delivers a 
high radiation dose to an extracranial target in 1 or a few 
treatment fractions (extreme hypofractionation)[47] has 
been suggested as a safe procedure for patients with BCR 
and detectable local recurrence. Although further inves-
tigations are needed, this emerging treatment option for 
isolated relapse may reduce the undesirable side effects 
of RT without compromising oncologic outcomes[48].

None of the studies included in the ARTISTIC 
meta-analysis administered RT doses higher than 66 Gy 
or used hypofractionation techniques. Therefore, new 
advances in RT may still improve oncologic outcomes 
following SRT.

Timing and duration of ADT with SRT
The optimal duration of ADT together with SRT is 
uncertain. The RTOG 9601 trial supports the addition 
of 2 years of daily bicalutamide 150 mg to SRT because 
a benefit in OS at 10-year follow-up was observed (16% 
reduction in risk of death)[49]. Similarly, the results 
of the GETUG-AFU 16 trial, which randomized 743 
patients to SRT alone or SRT plus 6 months of quarterly 
goserelin, confirmed that the addition of ADT led 
to a 27% reduced risk of metastasis[50]. Fossati et al. 
retrospectively explored the impact of ADT duration on 
oncologic outcomes following SRT and concluded that 
patients with more than one risk factor (≥ pT3b, ISUP 
> 3, or PSA level at SRT > 0.5 ng/mL) may benefit from 
long-term ADT, whereas patients with a single risk factor 
may receive < 12 months of ADT without compromising 
oncological outcomes. Patients without any risk factors 
did not show a significant benefit from concomitant 
ADT[51]. Irrespective of the study arm, some patients 
enrolled in the RADICALS trial were randomized to 0 
versus 6 versus 12 months of ADT, but results regarding 
ADT effect are still unknown[21]. Likewise, the ongoing 
LOBSTER tria l investigates whet her prolonging 
the duration of ADT from 6 to 24 months improves 

oncologic outcomes. Result from these 2 RCTs will allow 
us to define the most appropriate treatment time for 
patients receiving SRT.

Several ongoing RCTs are evaluating the role of new 
androgen receptor pathway targeting agents in combi-
nation with SRT. For instance, the SALV-ENZA trial[52] 
compares SRT plus placebo with SRT plus enzalutamide, 
while the STEEL trial[53] compares SRT plus standard 
ADT with SRT plus standard ADT plus enzalutamide. 
The CARLHA-2 trial is exploring the effect of adding 
apalutamide to SRT and standard ADT[54]. Finally, the 
FORMULA-509 trial is studying the addition of apalut-
amide, abiraterone, and prednisone to SRT plus stan-
dard ADT[55].

Benefit of SRT in cases of BCR
Lastly, which patients would truly benefit from SRT in 
the case of BCR? Beyond reporting the role of ART in 
the presence of high-risk features for BCR, the SWOG 
8794[6],EORTC 22911[7], ARO 96–02/AUO AP 09/95[8], 
and Finnish[9] trials provided information about the 
natural history of PCa. They revealed that median MFS 
and clinical PFS rates were > 10 years even among men 
included in the observation arm. These findings raise 
the question of whether all patients with BCR would 
benefit from SRT and suggest that some patients with 
BCR following RP who receive SRT may be overtreated. 
For instance, Pak et al. retrospectively analysed 817 
patients with BCR after RP. Patients were categorised 
into 3 groups according to time from RP to BCR: an 
early group (median BCR-free survival of 8.5 months), 
an intermediate group (median BCR-free survival of 17.5 
months), and a late group (median BCR-free survival 
of 70 months). The authors found that 8-year distant 
MFS and 8-year CSS were significantly better among 
patients receiving early SRT (with or without ADT) 
than among those receiving ADT alone in cases of early 
BCR, but no differences were found in cases of late BCR. 
Because patients included in the early BCR group had 
worse clinical and oncologic characteristics, such as 
higher NCCN risk group, preoperative PSA >  20  ng/
mL, Gleason score 9 to 10, and pT3b-stage disease, more 
challenging tumour biology may explain these results. 
Nevertheless, not all studies published to date support 
time from RP to BCR as an independent risk factor for 
worse oncologic outcomes[56,57].

Although PSA doubling time (PSADT) is not always 
associated with short BCR-free survival, it has been 
noted that these variables are interconnected[56]. Thirty-
six retrospective studies evaluating prognostic factors in 
patients with BCR following RP that were included in a 
systematic review and subsequent meta-analysis showed 
a significant relationship between shorter PSADT and 
higher risk of distant metastasis, PCa-specific mortality, 

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and overall mortality, whereas BCR-free survival was  
also related to PCa-specific mortality and overall 
mortality.

In contrast, after PSADT, PCa Gleason score based 
on prostatectomy histology report was recognized as 
a second factor more strongly associated with worse 
oncologic outcomes following RP as a primary treat-
ment. Based on these findings and the hypothesis that 
not all patients with BCR benefit from salvage treat-
ment, the EAU proposed a new BCR risk stratification 
that suggested that EAU low-risk BCR patients after 
RP (PSADT >  1 year and pathologic Gleason score 
<  8) might avoid salvage treatment[57]. Neverthe-
less, a recent validation showed that SRT was highly 
protective, with maximum effect in early delivery[58]. 
Therefore, risk group stratification after BCR remains 
inaccurate, and more research is needed to develop a 
molecular approach.

So far, only retrospective studies have been published 
regarding this topic. When the ART versus SRT debate 

comes to an end, selecting those patients who may 
benefit from SRT seems to be the next step. In this 
regard, RCTs are of the utmost importance for shed-
ding light on the hypotheses retrospective studies  
have raised[59,60].

Conclusions
Early SRT may be suggested as the standard of care 
for patients with PCa with high-risk features and 
undetectable postoperative PSA. Nevertheless, some 
aspects, such as the duration of ADT with SRT as well as 
a more accurate stratification of patients at risk of clinical 
progression, require further investigation. Therefore, 
some patients with undetectable PSA following RP may 
benefit from ART, while other patients can avoid SRT 
despite reaching serum PSA levels above 0.2 ng/mL.  
In conclusion, only improving patient selection for ART 
or SRT will lead to peace.

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