Highlights
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PSMA-PET/CT-guided sWPRT post-RP gave high 5-yr biochemical and metastasis-free survival (69.3% & 79.0%).
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Biochemical progression occurred in 25%; in-field nodal recurrences were rare.
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Treatment was associated with favourable toxicity.
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Supports PSMA-PET/CT-guided sWPRT with ADT as an effective salvage strategy for nodal recurrence post-RP.
Keywords: Prostate cancer, Salvage, Radiotherapy, Pelvic, Lymph nodes, PSMA-PET/CT-guided
Abstract
Background and purpose
In patients with biochemical recurrence (BCR) after radical prostatectomy (RP), prostate-specific membrane antigen (PSMA) PET/CT can detect early pelvic lymph node metastases, yet optimal management of these recurrences remains unclear. This study evaluates oncological outcomes of patients with BCR after RP and (confirmed or suspected) pelvic lymph node metastases who were treated with PSMA PET/CT-guided salvage whole pelvis radiotherapy (sWPRT) and Androgen Deprivation Therapy (ADT).
Materials and methods
This single-centre retrospective analysis included 149 patients undergoing sWPRT and 2–3 years ADT after PSMA PET/CT for BCR following RP ± ePLND (2018–2022). sWPRT was offered to BCR patients with ≤ 6 pelvic PSMA-positive nodes, or to PSMA-negative patients with prior pN1 disease. Outcomes included biochemical progression-free survival (bPFS), metastasis-free survival (MFS), treatment-free survival (TFS), overall survival (OS), and cancer-specific survival (CSS). Multivariate Cox regression identified predictors of biochemical progression. Recurrence locations on PSMA PET/CT were recorded and correlated with radiotherapy fields.
Results
After a median 54-month follow-up, 5-year bPFS, MFS, TFS, OS and CSS were; 69.3%, 79.0%, 78.5%, 91.7% and 97.5%. Outcomes did not differ between PSMA-negative and PSMA-positive subgroups. Biochemical progression occurred in 37 patients (25%), with rare in-field recurrences (1/37) and predominantly out-field nodal recurrences (29/37). Higher pre-sWPRT PSA (HR = 3.88, p = 0.021) and longer ADT duration (HR = 0.92, p < 0.001) independently predicted biochemical progression.
Conclusion
PSMA PET/CT-guided sWPRT with ADT provides good in-field tumour control and good 5-year oncological outcomes in patients with BCR following RP. PSA prior to sWPRT and ADT duration were significant predictors for bPFS.
Introduction
Radical prostatectomy (RP) is a standard treatment for localised prostate cancer (PCa) and is associated with favourable long-term outcomes [1]. However, 20–40% of patients develop biochemical recurrence (BCR), defined as a prostate-specific antigen (PSA) level of ≥ 0.2 ng/ml post-RP [2], which is linked to higher risks of metastasis and cancer-specific mortality, especially in patients with pathological lymph node metastases (pN1) [3].
Prostate specific membrane antigen (PSMA) positron emission tomography (PET) / computed tomography (CT) has improved the detection of recurrent PCa, demonstrating higher diagnostic accuracy for the detection of metastases than conventional imaging), even at low PSA levels [4], establishing it as the standard for restaging in BCR (5). PSMA PET/CT enables more tailored salvage therapy, changing management in about half of BCR patients [[5], [6]], though survival data following PSMA-PET/CT-guided salvage treatment remain limited.
Salvage whole-pelvic radiotherapy (sWPRT) with concurrent ADT is an option but yields variable outcomes [7]. The external beam radiotherapy targets both involved and elective nodal regions to provide high locoregional control, and ADT is known to improve survival in high-risk and node-positive patients [8]. In our clinic, sWPRT is offered either to patients with BCR and pelvic lymph node involvement on PSMA PET/CT, or to pN1 patients with BCR, but do not have visible metastases on PSMA PET/CT. Recently, the randomised PEACE V-STORM trial reported superior outcomes in favour of sWPRT compared with metastasis-directed therapy (MTD), though not all patients in that study were restaged using PSMA PET/CT [9]. Treatment approaches for recurrent PCa vary widely across institutions, reflecting the absence of clear evidence-based guidance. Against that background, we evaluated the oncological outcomes of PSMA PET/CT-guided sWPRT with concurrent ADT according to our institutional practice in patients with BCR following RP in this single-centre observational cohort study, contributing data to guide research and clinical decision-making for patients with recurrent PCa.
Methods
Study population
Using a prospectively maintained database from the Prostate Cancer Network Netherlands, we retrospectively identified consecutive patients treated with PSMA PET/CT-guided sWPRT for BCR following RP with or without extended pelvic lymph node dissection (ePLND), at the Netherlands Cancer Institute (NCI) between January 2018 and December 2022. Eligible patients had undergone RP ± ePLND for localised PCa and PSMA PET/CT at PSA ≥ 0.2 ng/ml before sWPRT. Exclusion criteria included systemic treatment within 12 months prior sWPRT or castration-resistant PCa. Minimum follow-up was 6 months after ADT discontinuation. The study was approved by the institutional review board (IRBd25-007).
Other management options for BCR following RP (e.g. observation, stereotactic ablative radiotherapy, salvage surgery or hormonal), were also discussed in multidisciplinary team meetings and offered depending on individual disease characteristics. sWPRT was offered to patients with BCR following RP and up to six pelvic lymph node metastases on PSMA PET/CT (PSMA-positive) or to pN1 patients with BCR and no (distant) metastases on PSMA PET/CT (PSMA-negative). In this context, patients with isolated local recurrence on imaging were treated with sWPRT due to their pN1 status and classified as PSMA-negative. Subgroups were defined accordingly. Data collected included age at sWPRT, PSA and testosterone levels pre-, during, and post-treatment, pathology results, PSMA PET/CT findings, previous and additional treatments, and toxicity. Testosterone recovery after ADT discontinuation was assessed when possible.
Objectives
The primary outcome was biochemical progression-free survival (bPFS), defined as the time from sWPRT completion (end of ADT) to PSA ≥ 0.2 ng/ml. Secondary outcomes were metastasis‑free survival (MFS; to first M1 lesion on PSMA‑PET/CT), treatment‑free survival (TFS; time to first subsequent PCa treatment), overall survival (OS), cancer‑specific survival (CSS; time to PCa‑related death), recurrence patterns (pelvic vs. extra‑pelvic; pelvic defined as local/nodal at or below the aortic bifurcation) and toxicity CTCAE v5.0 [10]. For patients developing castration‑resistant PCa during ADT, the ADT end date was set as the biochemical progression date; deaths with metastatic castration‑resistant disease and testosterone < 1.7 nmol/L were considered PCa‑related.
PSMA-PET/CT Imaging prior to sWPRT
PSMA PET/CT was performed to restage local, nodal, and distant disease. Although imaging protocols and tracers (68Ga-PSMA-11, 18F-DCFPyl, 18F-PSMA-1007, 18F-JK-PSMA-7) varied across referral centres, all met European Association of Nuclear Medicine standards [11]. Before sWPRT at the NCI, all scans were reviewed by experienced nuclear medicine physicians from the NCI. A scan was considered positive when PSMA expression exceeded background and was not due to physiological uptake, according to E-PSMA guidelines [12].
sWPRT treatment
Patients received either sWPRT alone or sWPRT combined with sRT to the prostatic fossa, based on the radiation oncologist’s discretion and factors such as prior irradiation, EAU high-risk features (positive surgical margins, pT ≥ 3, or ISUP grade ≥ 4) and patient preference [13]. Additional institutional radiotherapy protocol details are provided in Supplementary Table S1.
Follow-up
All patients were advised to undergo 3 years of adjuvant ADT, with PSA and testosterone monitored every 3–6 months from the start of sWPRT. Toxicity was assessed during routine consultations, alongside the lab tests, and only new or worsened toxicities were recorded. Upon biochemical progression (PSA ≥ 0.2 ng/ml), PSMA PET/CT was performed to identify recurrence. If negative, scans could be repeated after further PSA rises, typically following one or two PSA doublings. The first positive PET/CT was used for evaluation if a subsequent scan turned positive. In-field recurrences were defined as PSMA-PET/CT-positive lesions located within the anatomical boundaries of the previously delivered sWPRT field; lesions outside this volume were classified as out-field recurrences.
Statistical analysis
Continuous variables were reported as medians with interquartile ranges (IQR) and compared using the Mann-Whitney U test; categorical variables as counts and percentages, compared with Pearson’s Chi-square test. Due to the retrospective exploratory design, no correction for multiple testing was applied.
Survival outcomes (bPFS, MFS, TFS, OS and CCS) were estimated using Kaplan-Meier curves and compared with the log-rank test. Five-year survival outcomes were reported to facilitate comparison with prior literature, and Kaplan-Meier methods were used to account for censoring, allowing estimation even when follow-up durations varied across patients. Associations were examined using Cox proportional hazards models; PSA was dichotomised at 0.50 ng/mL and ADT duration at 24 months [14], [15]. Variables with a p ≤ 0.05 in univariate analysis entered multivariate models, while clinically relevant factors linked to PCa progression (pT3–4, ISUP 4–5, positive margins, pN1, number of positive pathological nodes, and biochemical persistence (BCP) (PSA ≥ 0.1 ng/ml post-RP)) were included in the multivariate model, irrespective of significance [16]. Analyses used IBM SPSS Statistics Version 30.0.0.0(171) or Rstudio (Version 4.2.2).
Results
Study population
Between January 2018 and December 2022, 180 patients received sWPRT for recurrent PCa. Of these, 31 patients were excluded; 4 without prior PSMA PET/CT, 13 lost to follow-up after referral outside the Prostate Cancer Network Netherlands and 14 had < 6 months follow-up post-ADT, leaving 149 sWPRT patients (Fig. 1).
Fig. 1.
Flowchart patient cohort. Abbreviations: sWPRT = salvage whole-pelvic radiation therapy, n = number of patients, PSMA = prostate specific membrane antigen, PET = positron emission tomography, CT = computed tomography, ADT = androgen deprivation therapy, m = months.
Patient characteristics
Baseline characteristics of the 149 included patients, stratified by PSMA PET/CT findings, are presented in Table 1. In total, 123 patients (82.6%) underwent ePLND at RP, of whom 95 (63.8%) had pN1 disease. BCP had occurred in 74 (49.7%) patients. Thirteen (8.7%) received local salvage treatment prior to sWPRT (10 fossa-only sRT, 4 sLND, 1 both). Median PSA prior to sWPRT was 0.44 ng/mL (IQR 0.26–0.85), median time from RP to sWPRT 14 months (IQR 6–25), median age 67 years (IQR 62–72) and median follow-up54 months (IQR 44–66).
Table 1.
Baseline characteristics.
| Total cohort (n = 149) |
PSMA- (n = 41) |
PSMA+ (n = 108) |
p-value | |
|---|---|---|---|---|
| Initial PSA, median (IQR) | 11.5 (7.3–19.0) | 14.6 (7.2–24.7) | 11.3 (7.3–17.2) | 0.176 |
Initial treatment, n (%)
|
25 (16.8)124 (83.2) |
1 (2)40 (98) |
25 (23)83 (77) |
0.002 |
pT-stage, n (%)
|
1 (0.7)38 (25.5)47 (32)61 (41)2 (1.3) |
−5 (12)10 (24)25 (61)1 (2) |
1 (1)33 (31)37 (34)36 (33)1 (1) |
0.024 |
pN-stage, n (%)
|
25 (17)29 (20)95 (64) |
− −41 (100) |
25 (23)29 (27)54 (50) |
<0.001 |
Number of positive pathological lymph nodes, n (%)
|
25 (17)29 (19)51 (34)44 (30) |
− −24 (59)17 (41) |
25 (23)29 (27)27 (25)27 (25) |
<0.001 |
ISUP of surgical specimen, n (%)
|
1 (0.7)28 (18.9)64 (43.2)15 (10.1)40 (27.0) |
−6 (15)23 (56)2 (5)10 (24) |
1 (1)22 (21)41 (38)13 (12)30 (28) |
0.309 |
| Positive surgical margin, n (%) | 84 (56.8) | 27 (66) | 57 (53) | 0.197 |
EAU recurrence risk group**, n (%)
|
14 (9)135 (91) |
−41 (100) |
14 (13)94 (87) |
0.236 |
| PSA density, median (IQR) | 0.21 (0.12–0.34) | 0.26 (0.17–0.44) | 0.27 (0.11–0.30) | 0.041 |
| Previous RT to the prostatic fossa, n (%) | 10 (7) | − | 10 (9) | 0.061 |
Previous therapy between RP and sWPRT, n (%)
|
136 (91)12 (8.1)1 (0.7) |
40 (98)1 (2) − |
96 (89)11 (10)1 (1) |
0.242 |
| BCP, n (%) | 74 (49.7) | 17 (42) | 57 (53) | 0.272 |
| Time RP – BCR in months, median (IQR) | 8 (3–19) | 12 (3–18) | 8 (3–19) | 0.668 |
| Time RP – sWPRT in months, median (IQR) | 14 (6–25) | 13 (6–22) | 15 (6–28) | 0.430 |
| PSA prior to sWPRT, median (IQR) | 0.44 (0.26–0.85) | 0.29 (0.23–0.45) | 0.58 (0.29–1.26) | <0.001 |
| Age at start of sWPRT, median (IQR) | 67 (62–72) | 65 (59–70) | 68 (62–72) | 0.057 |
Number of positive lymph nodes PSMA PET/CT, n (%)
|
41 (27)56 (38)30 (20)11 (7)8 (5)2 (1)1 (1) |
41 (100) − − − − − − |
−56 (52)30 (28)11 (10)8 (7)2 (2)1 (1) |
<0.001 |
| Local recurrence PSMA PET/CT, n (%) | 13 (9) | 5 (12) | 8 (7) | 0.347 |
| Concomitant sRT to prostatic fossa, n (%) | 133 (89.3) | 41 (100) | 92 (85) | 0.006 |
| Boost 60 Gy on positive lymph nodes, n (%) | 91 (61.1) | 2 (5) | 89 (82) | <0.001 |
| Duration adjuvant ADT (months), median (IQR) | 33 (18–37) | 31 (17–36) | 33 (19–37) | 0.307 |
| Median follow-up time (months), median (IQR) | 54 (44–66) | 55 (45–70) | 54 (44–65) | 0.514 |
| Biochemical progression after sWPRT, n (%) | 37 (25) | 11 (27) | 26 (24) | 0.832 |
| Median time to biochemical progression after sWPRT, months (IQR) | 21 (9–25) | 23 (0–38) | 19 (9–24) | 0.438 |
Abbreviations: PSMA-: no nodal recurrence on PSMA PET/CT prior to sWPRT; PSMA+: nodal recurrence on PSMA PET/CT prior to sWPRT; PSA: prostate specific antigen; RP: radical prostatectomy; ePLND: (extended) pelvic lymph node dissection; pT: pathological tumor stage; ISUP: international society of Urological Pathology grade; EAU: European Association of Urology; RT: radiation therapy; BCP: biochemical persistence; sWPRT: salvage whole-pelvic radiation therapy; BCR: biochemical recurrence; ADT: androgen deprivation therapy; NA: not applicable.
*Patient was treated with neoadjuvant hormone therapy before RP and ePLND (previously staged as mT3bN1)** High-risk characteristics for recurrence defined as any of the following: pN1, pT3-4, ISUP4-5, positive surgical margins (5).
Concomitant sRT to the prostatic fossa was given in 133 (89.3%). Median adjuvant ADT duration was 33 months (IQR 20–37); one patient with pre-existing testosterone deficiency discontinued testosterone supplementation as alternative to conventional ADT, and three declined ADT.
Significant differences between PSMA-negative and PSMA-positive subgroups were observed in initial treatment, pT-stage, pN-stage, number of positive pathological lymph nodes, PSA density, prior fossa RT, PSA prior to sWPRT, number of PET-positive nodes, concomitant prostatic fossa sRT, and receipt of 60 Gy boost (all p ≤ 0.05; Table 1). In the PSMA‑negative group, two boosts were given (one based on positive nano‑MRI, one undocumented).
Treatment outcomes
The 5‑year outcomes of the total cohort were bPFS 69.3% (95% CI 60.6–79.2), MFS 79.0% (95% CI 70.6–87.5), TFS 78.5% (95% CI 70.2–87.9), OS 91.7% (95% CI 86.8–96.8) and CSS 97.5% (95% CI 94.7–100.0) (Table 2 and Fig. 2). Corresponding subgroup rates are shown in Table 2 and Fig. 3.
Table 2.
Five‑year mean survival outcomes per PSMA PET/CT subgroup.
| Outcome | Total cohort (95% CI) | PSMA–negative (95% CI) | PSMA–positive (95% CI) | p–value |
|---|---|---|---|---|
| bPFS | 69.3 (60.6–79.2) | 67.5 (51.1–89.3) | 69.9 (60.1–81.2) | 0.756 |
| MFS | 79.0 (70.6–87.5) | 84.4 (70.7–100) | 76.2 (66.7–87.1) | 0.206 |
| TFS | 78.5 (70.2–87.9) | 89.7 (78.5–100) | 73.8 (63.1–86.2) | 0.094 |
| OS | 91.7 (86.8–96.8) | 96.9 (91.0–100) | 89.8 (83.6–96.4) | 0.212 |
| CSS | 97.5 (94.7–100) | 96.9 (91.0–100) | 97.7 (94.6–100) | 0.818 |
Abbreviations: bPFS = biochemical progression-free survival, MFS = Metastasis‑free survival, TFS = Treatment‑free survival, OS=Overall survival, CSS= Cancer‑specific survival.
Fig. 2.
Kaplan-Meier plot of biochemical progression-free survival at 5 years (A), metastasis-free survival at 5 years (B), treatment-free survival at 5 years (C), and overall survival at 5 years (D) by total cohort. Abbreviations: bPFS = biochemical progression-free survival, MFS = metastasis-free survival, TFS = treatment-free survival, OS = overall survival, sWPRT = salvage whole-pelvic radiation therapy.
Fig. 3.
Kaplan-Meier plot of 5-years biochemical progression-free survival (A), metastasis-free survival (B), treatment-free survival (C) and overall survival (D) by subgroups of treatment indication. Abbreviations: bPFS = biochemical progression-free survival, MFS = metastasis-free survival, TFS = treatment-free survival, OS = overall survival, sWPRT = salvage whole-pelvic radiation therapy, PSMA- = no nodal recurrence on PSMA PET/CT prior to sWPRT, PSMA+= nodal recurrence on PSMA PET/CT prior to sWPRT.
Biochemical progression occurred in 37 patients (25%), including 2 who declined ADT and 8 with testosterone < 1.7 nmol/L; 6 of these developed castration-resistant disease during ADT. In the remaining patients, testosterone recovery could not be evaluated due to missing testosterone measurements. Median time to biochemical progression after ADT discontinuation was 21 months (IQR 9–25) overall, 23 months (IQR 0–38) in the PSMA-negative group, and 19 months (IQR 9–24) in the PSMA-positive group. Recurrence patterns are summarised in Table 3. Most patients (29/37, 78%) had recurrences outside of the sWPRT field of which 6 had both in- and out-field recurrences and 3% had isolated in-field recurrences. Biochemical progression without radiographic recurrence was observed in 19%. Supplementary table S2 provides a detailed overview of recurrence locations per patient. Seven patients had nodal relapses close to the radiotherapy field border as their only sites of failure (Supplementary table S2 and supplementary figure S1).
Table 3.
Distribution of recurrence*.
| Total cohort (n = 37) | PSMA- (n = 11) |
PSMA+ (n = 26) |
|
|---|---|---|---|
| Biochemical progression only, n (%) | 7 (19) | 3 (27) | 4 (15) |
In-field recurrence only, n (%)
|
1 (3)
|
−- | 1 (4)
|
Out-field recurrence only, n (%)
|
23 (62)
|
6 (55) −
|
17 (65)
|
Both in- and out-field recurrences, n (%)
|
6 (16)
|
2 (18) −- −
|
4 (15) −
|
Abbreviations: PSMA-: no nodal recurrence on PSMA PET/CT; PSMA+: nodal recurrence on PSMA PET/CT, n = number of patients.
See Supplementary Table S2 for more detailed description of recurrence locations per patient.
Predictors of biochemical progression-free survival
In univariate analysis, higher PSA prior to sWPRT (HR 3.61, 95% CI 1.72–7.56, p < 0.001) and shorter adjuvant ADT duration (HR 0.96, 95% CI 0.92–0.97, p < 0.001) were linked to worse bPFS (Supplementary Table S3). Categorised analysis showed increased biochemical progression risk with PSA > 0.50 ng/mL (HR 2.24, 95% CI 1.13–4.42, p = 0.021) and decreased risk with ADT > 24 months (HR 0.42, 95% CI 0.22–0.81, p = 0.009). In multivariate analysis, PSA prior to sWPRT (HR 3.88, 95% CI 1.23–12.29, p = 0.021) and ADT duration (continuous variable) (HR 0.92, 95% CI 0.87–0.96, p < 0.001) remained independent predictors.
Toxicity
One patient discontinued sWPRT early due to severe gastro intestinal toxicity. No acute toxicity was reported in 77 patients (52%), with similar rates between PSMA- and PSMA + groups (p = 0.844). Acute toxicity was mostly grade 2 (69 patients, 46%), with grade 3 in 12 patients (8%) and no grade 4 events. Early toxicity grade distribution did not differ significantly PSMA- and PSMA+ (p = 0.380) (Supplementary Table S4).
Regarding late toxicity, 45 patients (30%) experienced none, with no significant differences between PSMA- and PSMA+ (p = 0.247). Grade 2 was most common (84 patients, 56%), followed by grade 3 (41 patients, 28%) and grade 4 (4 patients,7%). Late toxicity grade distribution did not differ significantly between PSMA- and PSMA+ (p = 0.623) (Supplementary Table S4). Detailed toxicities are listed in Supplementary Table S5.
Discussion
This retrospective study evaluated oncological outcomes of PSMA PET/CT-guided sWPRT as implemented in our institutional practice for patients with BCR following RP. Five-year survival rates exceeded expectations with bPFS, MFS and TFS around 75%, and OS and CSS above 90%. Few biochemical progression events occurred within three years, likely reflecting the planned three‑year ADT. Higher PSA before sWPRT and shorter ADT duration independently predicted progression. Although statistically significant, ADT duration was associated with only a modest positive effect in multivariate analysis (HR 0.92). Survival was similar between patients with PSMA‑ negative (microscopic) and PSMA‑positive (macroscopic) disease, suggesting a 60 Gy nodal boost effectively controls macroscopic lesions with no predefined limit of nodes boosted. However, given the retrospective, non-randomised, single-arm design, these finding should be interpreted cautiously, as selection bias and uncontrolled confounders may have influenced outcomes. Median follow-up was 4,5 years. Longer observation would be necessary to draw more definitive conclusions regarding long-term oncological outcomes. New late toxicities grade ≥ 2 occurred in over half of patients, without significant differences between PSMA subgroups.
The absence of significant differences in oncological outcomes between PSMA-negative and PSMA-positive patients may have several explanations. First, patients in the PSMA-negative group typically received sWPRT based on prior pathological nodal involvement, even in the absence of PSMA-avid lesions, reflecting consideration of historical nodal metastases as a high-risk feature. Previous evidence suggested that WPRT in patients with lymph node metastases at RP may improve survival compared with observation or ADT alone, supporting this treatment approach [16], [17]. Second, pre-treatment PSA values correspond to PSA levels at the time of PSMA PET/CT and initiation of sWPRT. Patients were monitored according to EAU guideline, with PSA measured at 3, 6, 12, 18 and 24 months post-RP, and PSMA-PET/CT typically performed when PSA reached 0.2–0.4 ng/mL. Thus, PSA at PSMA-PET/CT reflects the start of sWPRT rather that the initial BCR. This explains why PSA was higher in the PSMA-positive group compared with the PSMA-negative group: PSMA-negative patients received sWPRT at the time of BCR due to their pN1 status, whereas PSMA-positive patients often began salvage therapy only once nodal recurrence became detectable on PSMA PET/CT, generally at higher PSA levels, reflecting literature [18]. Third, patients with PSMA-positive pelvic lymph nodes received an additional targeted boost to macroscopic lesions, potentially enhancing local control and therefore contributing to comparable outcomes between both groups, despite their differing imaging results. Fourth, limitations in PSMA-PET/CT detection, particularly for small-volume or low-PSA recurrences, may have also influenced subgroup classification. Finally, pre-sWPRT PSA values were not consistently available for all patients, as some were referred from external centre; therefore, these measurements may not uniformly reflect PSA levels at BCR, which could affect interpretation of the observed differences.
Our results compare favourably with prior PSMA‑guided sWPRT studies. In PEACE V‑STORM, 4‑year MFS was 76%, which included patients with shorter ADT and less uniform imaging [9]. Other retrospective series reported bPFS rates between 50% and 60% [19], [20], likely reflecting older imaging, inclusion of only nodal‑recurrence cases, higher baseline PSA, and limited ADT. In contrast, all patients in our cohort underwent PSMA PET/CT, providing contemporary staging and allowing for targeted nodal treatment. Still, as a single-cohort respective study, direct comparisons remain limited.
Stereotactic body radiation therapy (SBRT) is a common alternative salvage radiotherapy (sRT) for nodal recurrence, targeting only detected nodes with high-dose radiation over few fractions to reduce toxicity and improve patients’ convenience. However, retrospective data show superior failure-free survival with sWPRT [21], [22]. The PEACE V-STORM trial reported improved 4-year metastasis-free survival with sWPRT versus MTD (76% vs. 63%) without significant differences in toxicity or quality of life [[9], [23]]. Nonetheless, sWPRT may represent overtreatment for some patients, particularly those with limited regional nodal metastases. In our cohort, over 50% of patients developed new late grade ≥ 2 toxicity, likely influenced by strict CTCAE grading, where minimal use of incontinence material qualifies as grade 2, possibly overestimating clinical impact. Severe urinary toxicity requiring cystectomy, such as for haematuria, remains rare and typically occurs in heavily pretreated, high-risk patients.
Another form of MTD for patients with imaging-proven nodal recurrence following RP is PSMA-radioguided sLND, which uses a radioactive PSMA-tracer and intraoperative gamma probe to localise nodal recurrences, improving oncological outcomes compared to standard template sLND [24]. A retrospective cohort study on PSMA-radioguided sLND reported a 2-year bPFS of 32% and TFS of 58% [25]. In comparison, the present analysis suggests more favourable survival outcomes for patients treated with sWPRT. The prospective randomised TRACE-II trial, will assess the added benefit of short-term ADT with PSMA-radioguided sLND versus ADT alone (NCT05555017).
An alternative treatment strategy patients with BCR following RP could be early intermittent ADT alone. The RADIOSA trial has already showed that adding ADT to SBRT, improved clinical progression-free survival compared to SBRT alone [26]. Similarly, the ongoing phase III OLIGOPELVIS 2-GETUG P12 trial will compare short-term ADT alone versus short-term ADT plus sWPRT (NCT03630666).
In this analysis, higher PSA before sWPRT predicted worse bPFS (HR 6.54), with PSA > 0.50 ng/mL increasing biochemical progression risk (HR 2.24). This aligns with studies showing better bPFS and MFS at PSA ≤ 0.5 ng/mL, and some suggesting a 0.2 ng/mL threshold [14], [27], [28], [29]. These results support early sRT, though the optimal PSA cut-off remains unclear and should be individualised.
Longer ADT duration was associated with improved bPFS. However, the optimal ADT duration is debated, given additional toxicities and the balance between efficacy and quality of life. As there was no control group without ADT, the true benefit remains uncertain. While SPPORT suggest short-course ADT with sWPRT [30], and RADICALS‑HD found improved MFS with long course ADT (24mo) but at the expense of increased side-effects [31], the ideal timing and duration remains unclear, particularly for patients starting salvage therapy at low PSA levels (<0.05–0.7 ng/ml). ADT may suppresses rather than eradicates disease, merely delaying recurrence until testosterone recovery, raising questions about its value in indolent or low-burden cases. Ongoing trials (LOBSTER, URONCOR 06‑24) aim to clarify short‑ vs. long‑course ADT [32], [33], though data specific to sWPRT remain scarce. Moderate dose escalation to macroscopic nodal lesions could be explored in future studies as a strategy to maintain local control while potentially allowing shorter ADT duration, which may reduce therapy-related toxicities. Notably, the limited protective effect of longer ADT duration observed within our cohort, together with results from PEACE V-STORM where patients received WPRT with only 6 months of ADT, suggest that the optimal duration of hormonal therapy in this setting remains uncertain [9]. Moreover, PEACE V-STORM demonstrated improved outcomes with sWPRT compared with MTD, supporting the potential benefit of comprehensive pelvic irradiation over SBRT in nodal recurrence. In this context, shorter ADT courses combined with effective WPRT may represent a strategy to maintain oncological control while reducing treatment-related toxicity. These findings have motivated the design of a prospective study at our institution evaluating WPRT with 6 months of ADT.
To our knowledge, this is the first study to present outcomes of PSMA-guided sWPRT plus ADT in patients with BCR and PSMA PET/CT-positive lymph nodes, including those with high-risk characteristics. Additionally, it addresses toxicities of this adjuvant treatment, a topic still unexplored in retrospective studies. A further strength is that PSMA PET/CT findings were evaluated by a dedicated multidisciplinary board, enhancing data standardisation and reliability.
Several limitations should be acknowledged. First, the retrospective design carries risks of selection bias, incomplete data, limited control of confounders and limits causal inference. Second, although other management options (e.g. observation, SBRT, salvage surgery) were discussed, inconsistent documentation of treatment decisions and patient preference meant that only patients receiving sWPRT were captured, introducing potential selection bias. Third, the inclusion of patients with prior pN1 disease who received sWPRT despite absence of PSMA-PET/CT-detected nodal disease, some of whom had previously undergone radiotherapy to the prostate bed, as well as the prolonged duration of concomitant ADT (median 33 months), may have favourably influenced survival outcomes, restricting direct comparability between subgroups and limiting attribution of oncological results to radiotherapy alone. Excluding patients with prior radiotherapy could have strengthened comparative analyses, but our relatively small cohort precluded such exclusion, and heterogeneity in prior treatments remains a limitation. Fourth, reporting 5-year survival outcomes in a cohort with variable follow-up durations may introduce uncertainty, as not all patients had reached this time point. Fifth, incomplete testosterone data limited assessment of prior ADT’s impact on survival. Sixth, non-standardised follow-up across centres may have delayed or inconsistently detected recurrences. Seventh, although a Cox regression identified predictors of bPFS, no model was developed to stratify individual biochemical progression risk. Finally, toxicity reporting were not standardised, and grade 1–2 toxicities might have been underreported.
Future studies should evaluate the toxicity and side effects of sWPRT and ADT, develop predictive models to identify patients most likely to benefit, and conduct prospective trials to further compare different treatment strategies for patients with BCR following RP.
Conclusion
Data from our institutional practice on PSMA‑guided sWPRT with concurrent ADT yielded 5‑year bPFS, MFS, and TFS rates of 70.4%, 78.6%, and 78.5%, respectively. While PSA before sWPRT predicted bPFS, the modest effect observed for ADT duration suggest that shorted courses may warrant further evaluation. Overall, these findings suggest that sWPRT plus ADT may provide benefit in patients with BCR and either high-risk characteristics or PSMA PET/CT-positive lymph nodes, with limited toxicity. These retrospective outcomes require confirmation in prospective studies.
CRediT authorship contribution statement
L.G. Zuur: Writing – review & editing, Writing – original draft, Resources, Project administration, Methodology, Investigation, Formal analysis, Data curation. A. Jansen: Writing – original draft, Resources, Methodology, Investigation, Formal analysis, Data curation. S.H. van der Graaf: . K.C.C. de Bie: Writing – review & editing. E.E. Schaake: Writing – review & editing, Data curation. F.J. Pos: Writing – review & editing, Data curation. A.N. Vis: Writing – review & editing, Conceptualization. H.G. van der Poel: . W.V. Vogel: Writing – review & editing, Supervision, Conceptualization. P.J. van Leeuwen: Writing – review & editing, Supervision, Methodology, Funding acquisition, Conceptualization.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.ctro.2026.101161.
Appendix A. Supplementary data
The following are the Supplementary data to this article:
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