# High-Dose-Rate brachytherapy for salvage treatment of prostate cancer recurrence post-prostatectomy and radiotherapy: A multicenter retrospective analysis (HDR-REPOPRA) by UroGEC

Adam Kluska, Artur J Chyrek, Benjamin Guix, Patricia Willisch, Tamer Soror, Mateusz Bilski, Ivan Garcia, Teresa Guix, Beatriz Vázquez, Wojciech Burchardt, et al.

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## To cite this version:

Adam Kluska, Artur J Chyrek, Benjamin Guix, Patricia Willisch, Tamer Soror, et al. High-Dose-Rate brachytherapy for salvage treatment of prostate cancer recurrence post-prostatectomy and radiotherapy: A multicenter retrospective analysis (HDR-REPOPRA) by UroGEC. Radiotherapy & Oncology, 2025, 212, pp.111145. 10.1016/j.radonc.2025.111145. inserm-05376711

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# High-Dose-Rate brachytherapy for salvage treatment of prostate cancer recurrence post-prostatectomy and radiotherapy: A multicenter retrospective analysis (HDR-REPOPRA) by UroGEC☆

Adam Kluska<sup>a</sup>, Artur J. Chyrek<sup>a,b,*</sup>, Benjamin Guix<sup>c</sup>, Patricia Willisch<sup>d</sup>, Tamer Soror<sup>e</sup>, Mateusz Bilski<sup>f,g</sup>, Ivan Garcia<sup>c</sup>, Teresa Guix<sup>c</sup>, Beatriz Vázquez<sup>d</sup>, Wojciech Burchardt<sup>a,b</sup>, Piotr Lelek<sup>h</sup>, Ricarda Merten<sup>i</sup>, Vratislav Strnad<sup>i,j</sup>, Iosif Strouthos<sup>k</sup>, Mario Terlizzi<sup>l</sup>, David Büchser<sup>m</sup>, Pierre Blanchard<sup>l</sup>, Alfonso Gomez- Iturriaga<sup>m,n</sup>, Piotr Wojcieszek<sup>h</sup>

ARTICLE INFO

Keywords:

Brachytherapy, High-Dose-Rate

Prostatic Neoplasms/recurrence

Prostatectomy

Radiotherapy, Adjuvant

Radiotherapy, Salvage

Re-Irradiation

A B S T R A C T

**Background:** Local recurrence of prostate cancer following radical prostatectomy (RP) and adjuvant or salvage external beam radiotherapy (a/sEBRT) presents a therapeutic challenge. Salvage high-dose-rate brachytherapy (HDR-BT) is a promising modality, though evidence remains limited.

**Materials and Methods:** We retrospectively analyzed 90 patients treated with salvage HDR-BT after RP and a/sEBRT across 10 UroGEC-ESTRO-affiliated European centers. Eligible patients had biopsy- or imaging-confirmed local recurrence and ECOG performance status 0–2. Primary endpoints were local recurrence-free survival (LRFS) and toxicity; secondary endpoints included biochemical failure-free survival (BFFS), metastasis-free survival (MFS), progression-free survival (PFS), and overall survival (OS).

**Results:** The median follow-up was 47 months. The 5-year LRFS was 81.1 %, BFFS 62 %, MFS 77.5 %, PFS 58.0 %, and OS 95.9 %. Biopsy-confirmed recurrence and use of androgen deprivation therapy (ADT) were associated with improved LRFS and PFS. Grade ≥3 genitourinary toxicity occurred in 5.5 % (acute) and 8.9 % (late) of patients; gastrointestinal grade 3 toxicity was observed in 1.1 %.

**Conclusion:** HDR-BT is a safe and effective salvage option for well-selected patients with local recurrence after RP and a/sEBRT. Our data support its feasibility, acceptable toxicity, and favorable oncologic outcomes. Biopsy confirmation and ADT use may improve results and should be considered in treatment planning. These findings warrant further prospective evaluation to optimize patient selection and refine salvage strategies.

<footnote><sup>a</sup> Brachytherapy Department, Greater Poland Cancer Centre, Poznań, Poland</footnote>

<footnote><sup>b</sup> Electroradiology Department, University of Medical Sciences, Poznań, Poland</footnote>

<footnote><sup>c</sup> Department of Radiation Oncology. Fundacion IMOR, Barcelona, Spain</footnote>

<footnote><sup>d</sup> Department of Radiation Oncology, Hospital Meixoeiro, Vigo, Spain</footnote>

<footnote><sup>e</sup> Radiation Oncology Department, University of Lübeck/UKSH-CL, 23562 Lübeck, Germany</footnote>

<footnote><sup>f</sup> Radiotherapy Department, Affidea Nu-med Center of Oncologic Diagnostics and Therapy, Zamość, Poland</footnote>

<footnote><sup>g</sup> Radiotherapy Department, Medical University of Lublin, Poland</footnote>

<footnote><sup>h</sup> Brachytherapy Department, Maria Skłodowska-Curie National Research Institute of Oncology Gliwice Branch, Gliwice, Poland</footnote>

<footnote><sup>i</sup> Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany</footnote>

<footnote><sup>j</sup> CCC Erlangen-EMN, Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany</footnote>

<footnote><sup>k</sup> Department of Radiation Oncology, German Oncology Center, European University Cyprus, Limassol, Cyprus</footnote>

<footnote><sup>l</sup> Department of Radiation Oncology/Brachytherapy, Paris Saclay University, INSERM U1018 Oncostat, Gustave Roussy, Villejuif, France</footnote>

<footnote><sup>m</sup> Radiation Oncology Department, Hospital Universitario Cruces, BioBizkaia, Basque Health Research, Baracaldo, Spain</footnote>

<footnote><sup>n</sup> University of the Basque Country, UPV/EHU, Bilbo, Spain</footnote>

<footnote>* This article is part of a special issue entitled: 'Reirradiation' published in Radiotherapy and Oncology.</footnote>

<footnote>* Corresponding author at: Plawno 31, 62-095 Plawno, Poland.</footnote>

<footnote>E-mail address: chyrek.artur@gmail.com (A.J. Chyrek).</footnote>
## Introduction

Patients with local recurrence (LR) of prostate cancer after radical prostatectomy (RP) followed by adjuvant or salvage external beam radiotherapy (a/sEBRT) present a significant clinical challenge. Although multiparametric MRI and PSMA PET-CT have improved the detection of isolated local failures, therapeutic options for salvage treatment in this setting remain limited and often exceed guidelines and recommendations [1]. Few retrospective reports or case series have presented the outcomes of different re-irradiation techniques based on the clinical experience of authors and small patient cohorts [2–6].

A wide array of patients with localized prostate cancer have RP as a standard treatment worldwide [7]. However, nearly one-third develop biochemical recurrence within 10 years of surgery [8]. The standard of care for patients experiencing biochemical failure is salvage radiotherapy (sRT) to the prostatic bed, which may be combined with androgen deprivation therapy (ADT) depending on recurrence-related risk factors [9]. Nevertheless, 30–60 % of patients who receive sRT have a significant probability of second biochemical failure [10,11].

Brachytherapy (BT) is an established salvage technique following radiotherapy failure [9,12]. While it offers comparable efficacy to salvage RP, cryoablation or stereotactic body radiation therapy, the risk of severe complication is among the lowest, below 10 % [13]. Some specialized cancer centers have adopted salvage brachytherapy for patients with recurrence after RP followed by a/sEBRT. Such treatment, however, is highly individualized and dependent on the skills and experience of the clinical team. There is also limited data to guide the selection of BT techniques in this setting. Recent studies on ultra-low-dose-rate BT (uLDR-BT) have demonstrated the technical feasibility and safety of salvage brachytherapy in cases of locally recurrent prostate cancer [3,4]. Data on oncologic outcomes following salvage uLDR-BT remain scarce and are based on small, heterogeneous patient cohorts, limiting the ability to draw firm conclusions. While some early reports suggest acceptable local control (LC) in selected cases, further evidence is needed. These limitations underscore the need for careful patient selection and the continued evaluation of alternative techniques, including high-dose-rate BT (HDR-BT), which may offer dosimetric advantages and improved treatment precision. Preliminary evidence suggests that it may be an effective salvage option, but comprehensive long-term oncologic outcome data are lacking [5,6].

The UroGEC-ESTRO working group posed a key question regarding the efficacy of salvage HDR reirradiation for prostate bed recurrence. To address this, we formed an international retrospective data collection initiative within the working group to evaluate the safety, efficacy, and outcomes of HDR-BT as salvage treatment in this challenging clinical scenario.

## Material and methods

UroGEC-ESTRO-affiliated cancer centers across Europe participated in this retrospective analysis. Anonymized data were collected using electronic data sheets with inclusion and exclusion criteria. Those criteria were: diagnosed prostate cancer initially treated with RP followed by a/sEBRT, with subsequent LR confirmed by imaging (multiparametric MRI, PSMA PET/CT) and/or biopsy, treated with salvage HDR-BT. Indication for adjuvant or salvage EBRT as well as regional lymph nodes irradiation were according to national guidelines and local protocols, so was prescription of ADT. The treatment was performed between 2003 and 2024. All patients had ECOG performance status 0–2. Exclusion criteria included the presence of distance metastases and prior salvage treatment using another modality. Distant metastases were ruled out with PET-PSMA or Computed Tomography of chest, abdomen and pelvis with bone scan.

Salvage brachytherapy was performed using HDR-BT. Fractionation schemes varied between centers and are summarized in Table 1. All HDR-BT applications were carried out under general anesthesia, guided

<table><caption>Table 1</caption><thead><tr><th colspan="2">Patients characteristics</th></tr></thead><tbody><tr><td>Age of patients</td><td></td></tr><tr><td>Median [IQR]</td><td>69 [64–73]</td></tr><tr><td>Initial PSA</td><td></td></tr><tr><td>Mean (ng/ml)</td><td>12,26</td></tr><tr><td>Prostatectomy pT (n)</td><td></td></tr><tr><td>pT1</td><td>2</td></tr><tr><td>pT2a</td><td>4</td></tr><tr><td>pT2b</td><td>9</td></tr><tr><td>pT2c</td><td>24</td></tr><tr><td>pT3a</td><td>31</td></tr><tr><td>PT3b</td><td>17</td></tr><tr><td>pT4</td><td>1</td></tr><tr><td>unknown</td><td>2</td></tr><tr><td>EBRT purpose (n)</td><td></td></tr><tr><td>Adjuvant</td><td>33</td></tr><tr><td>Salvage</td><td>57</td></tr><tr><td>EBRT dose</td><td></td></tr><tr><td>Median [IQR]</td><td>66 [64–70]</td></tr><tr><td>ADT after EBRT (n)</td><td></td></tr><tr><td>Yes</td><td>30</td></tr><tr><td>no</td><td>69</td></tr><tr><td>Unknown</td><td>1</td></tr><tr><td>PSA nadir after EBRT</td><td></td></tr><tr><td>Mean (ng/ml)</td><td>0,117</td></tr><tr><td>rPSA after EBRT</td><td></td></tr><tr><td>Mean (ng/ml)</td><td>2,51</td></tr><tr><td>Staging before salvage HDR-BT (n)</td><td></td></tr><tr><td>MRI</td><td>43</td></tr><tr><td>PET-choline</td><td>37</td></tr><tr><td>PET-PSMA</td><td>34</td></tr><tr><td>Not reported</td><td>11</td></tr><tr><td>Biopsy before salvage HDR-BT (n)</td><td></td></tr><tr><td>Yes</td><td>56</td></tr><tr><td>No</td><td>34</td></tr><tr><td>Gleason score (n)</td><td></td></tr><tr><td>7 (3 + 4)</td><td>6</td></tr><tr><td>7 (4 + 3)</td><td>15</td></tr><tr><td>8</td><td>18</td></tr><tr><td>9</td><td>12</td></tr><tr><td>10</td><td>3</td></tr><tr><td>salvage HDR-BT fractionation (n)</td><td></td></tr><tr><td>1x14 Gy</td><td>1</td></tr><tr><td>1x19 Gy</td><td>1</td></tr><tr><td>2x13 Gy</td><td>16</td></tr><tr><td>2x8,5 Gy</td><td>9</td></tr><tr><td>2x10 Gy</td><td>7</td></tr><tr><td>2x14 Gy</td><td>1</td></tr><tr><td>2x12 Gy</td><td>4</td></tr><tr><td>2x15 Gy</td><td>11</td></tr></tbody></table>

(continued on next page)
<table><caption>**Table 1 (continued)**</caption><thead><tr><th></th><th></th></tr></thead><tbody><tr><td>Patients characteristics</td><td></td></tr><tr><td>3x10 Gy</td><td>19</td></tr><tr><td>4x8 Gy</td><td>21</td></tr><tr><td>ADT after salvage HDR-BT</td><td></td></tr><tr><td>Yes</td><td>39</td></tr><tr><td>No</td><td>47</td></tr><tr><td>Unknown</td><td>4</td></tr><tr><td>PSA nadir after salvage HDR-BT</td><td></td></tr><tr><td>Mean (ng/ml)</td><td>0,456</td></tr><tr><td>Biochemical Failure (n)</td><td></td></tr><tr><td>Yes</td><td>33</td></tr><tr><td>No</td><td>57</td></tr><tr><td>rPSA after salvage HDR-BT</td><td></td></tr><tr><td>Mean (ng/ml)</td><td>3,733</td></tr></tbody></table>

by transrectal ultrasonography (TRUS) and planned using a TRUS-compatible BT planning system.

The primary endpoints were local recurrence-free survival (LRFS) and toxicity profiles. LR was defined as radiographic recurrence within the irradiation field. Toxicity was reported by physician during follow up using RTOG criteria. Secondary endpoints included biochemical failure-free survival (BFFS), metastasis-free survival (MFS), progression-free survival (PFS) and overall survival (OS). We defined BFFS as time from the end of salvage brachytherapy until Phoenix criterion (nadir +2 ng/mL) biochemical failure or subsequent unequivocal progression of prostate-specific antigen (PSA). The definition of MFS was time from the end of salvage brachytherapy until diagnosis of metastasis. MFS and PFS were defined as the time from treatment to the diagnosis of metastasis or any progression event (biochemical, nodal, local, metastatic, or death), respectively.

For survival analysis, we used the Kaplan-Meier method. Comparisons between two groups were conducted using the log-rank test, and a chi-square test was used to compare more than two groups. To evaluate the association between clinical variables and LC, univariable and multivariable Cox proportional hazards regression models were applied. P-values below 0.05 were considered statistically significant. Statistical tests and figures were made using Statistica v.13 (StatSoft, Tulsa, USA). The Poznan University of Medical Sciences issued a statement declaring no ethical approval requirement due to the study's retrospective nature.

## Results

We included 90 patients from 10 centres across Europe who were primarily treated with RP. All were initially treated with RP and subsequently underwent salvage HDR-BT following failure of a/sEBRT.

The median patient age was 69 years (interquartile range (IQR) 64–74). RP margin status was R0 in 45 patients (50 %), R1 in 37 (41.1 %), and R2 in 6 (6.6 %). Thirty-three (36.7 %) patients received aEBRT and 57 (63.3 %) sEBRT. The median dose to prostate bed was 66 Gy (IQR 64–70), delivered in a median of 33 fractions (IQR 30–35). Regional lymph nodes were irradiated in 26 (28.8 %) with a median dose of 50 Gy (IQR 46–50). Thirty patients (33.3 %) received adjuvant ADT. Mean post-EBRT PSA nadir was 0.12 ng/dl (range 0.004 – 0.95), and median PSA at recurrence (rPSA) was 2.51 ng/ml (range 0.19–55.0). Median time from a/sEBRT to biochemical failure was 58.89 months (IQR 32.93

– 81.41) and median time from a/sEBRT to salvage brachytherapy was 68.36 [IQR 37.27 – 96.55]. Biopsy was performed in 56 cases (62.2 %). Gleason scores were as follows: 3 + 4 in 6 cases (10.7 %), 4 + 3 in 15 (26.8 %), 4 + 4 in 18 (32.2 %), Gleason 9 in 12 (21.4 %), and Gleason 10 in 3 (5.3 %). Two cases lacked Gleason scoring (3.6 %). The mean volume of local recurrence was 12.74 ml (range 0.3 – 59.0). Median salvage HDR-BT dose was 30.0 Gy (IQR 26–30). Ten different fractionation schemes were used. Most patients (53.3 %) received a 2-fraction regimen. Table 1 presents patients' characteristics. ADT was prescribed after HDR in 33 patients (36.7 %), with a median duration of 36 months (IQR 21.6–36.1).

The median follow-up was 47 months (IQR 27.4–83.5). Acute genitourinary (GU) toxicity of grade 3 or more was observed in 5 (5.5 %) men, with no grade 5 toxicity reported. Eight patients (8.9 %) suffered from late GU toxicity grade 3. No grade 4 or 5 late GU toxicity was reported. Gastrointestinal (GI) toxicity, both acute and late, was reported in 11 men (12.2 %), with one grade 3 (1.1 %). The incidence of GI toxicity in group with previously pelvic lymph node sEBRT was 19.23 % and 9.38 % in group with sEBRT to prostate bed. Fig. 1 presents the overall occurrence of toxicity.

Sixteen patients (17.8 %) developed LR. The median time from sBRT to LR was 37.09 months [IQR 17.89–73.19]. The 5-year LRFS was 81.1 % (Fig. 2). ADT use significantly improved LRFS (p = 0.033), as did having a biopsy-confirmed recurrence prior to HDR (p = 0.040) (Fig. 3). The mean nadir PSA after treatment was 0.46 ng/ml (0.002 – 4.3).

Thirty-three (36.7 %) men experienced biochemical failure. The median time from sBRT to biochemical failure was 31.28 [IQR 16.48–69.31]. The mean PSA at post-HDR recurrence was 3.73 ng/ml (0.43 – 17.0). The 5-year BFFS was 62 % (Fig. 4a). Eighteen patients developed distant metastases, with a 5-year MFS of 77.46 % (Fig. 4b). The 5-year OS was 95.87 % (Fig. 4c). Neither ADT use nor pre-HDR biopsy status significantly impacted BFFS, MFS, or OS. The 5-year PFS was 57.96 % (Fig. 4d). No statistically significant differences existed in groups with and without ADT (p = 0.139). While ADT use did not affect PFS (p = 0.139), biopsy-confirmed recurrence was associated with significantly better PFS (p = 0.037). In the univariable Cox regression analysis, the addition of ADT was significantly associated with improved LC (HR 0.24; 95 % CI: 0.07–0.90). Other significant factors included PSA nadir (HR 1.82; 95 % CI: 1.21–2.75), BT dose (HR 0.84; 95 % CI: 0.77–0.92), and the number of fractions (HR 0.33; 95 % CI: 0.15–0.72). The change of Gleason score (primary versus at biopsy before salvage treatment) was not significant factor in univariable Cox regression analysis (p = 0.09), nor was volume of treated CTV (p = 0.12). In the multivariable analysis, total BT dose remained the only independent prognostic factor for LC (HR 0.87; 95 % CI: 0.78–0.98) (Fig. 5).

## Discussion

Advancements in imaging techniques, particularly multiparametric MRI and PET-CT, have improved the detection of isolated local failures and made staging more accurate [15]. With those diagnostic tools, local salvage reirradiation becomes available for patients experiencing failure in the prostate bed after a/sEBRT. LR affects significant numbers of these men, with 30–60 % experiencing biochemical failure [10,11]. In the absence of robust evidence supporting further local therapy, patients are commonly offered ADT monotherapy, even with clearly localized relapse [1,16]. The primary issue is the potentially higher toxicity of such treatment, as reported in trials concerning salvage reirradiation after primary radiotherapy [13].

Our study presents the largest reported cohort of patients treated with salvage HDR-BT following RP and a/sEBRT failure. Although our analysis is more detailed and includes additional endpoints, it confirms the initial findings from smaller series and case reports. Aghili et al. reported that after a median follow-up of 48 months, 13 (86.6 %) of 15 patients had no biochemical relapse. [5]. Soror et al. reported 3 and 4-year BFFS of 60 % in ten patients after a median follow-up of 34 months.
<figure><img src="image_4.png" /></figure>

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<figure><img src="image_6.png" /></figure>

<figure><img src="image_7.png" /><figcaption>**Fig. 1.** Distribution of genitourinary (GU) and gastrointestinal (GI) toxicity following salvage HDR BT. (a) GU acute toxicity; (b) GU late toxicity; (c) GI acute toxicity; (d) GI late toxicity.</figcaption></figure>

<figure><img src="image_8.png" /><figcaption>**Fig. 2.** Kaplan-Meier curve illustrating the cumulative probability of local recurrence-free survival (LRFS) in patients treated with salvage high-dose-rate brachytherapy (HDR-BT).</figcaption></figure>

[6]. Outcomes following salvage uLDR-BT have been more variable: Le Roy et al. achieved LC in 3 of 5 patients after 21 months of follow-up [3], while Losa et al. observed PSA stabilization or decline in 7 of 10 patients, but without robust long-term biochemical data [4]. Additionally, Schönle et al. reported on a subgroup of 24 patients treated with salvage pulsed-dose rate (PDR) BT following RP and EBRT, demonstrating a 5-year BRFS of 54 % and a LR rate of 16 % after a median follow-up of 4.1 years [14]. All studies concerning sBRT after RP and EBRT are

presented in Table 2. Taken together, these findings support the feasibility of various brachytherapy techniques for salvage reirradiation. Our analysis showed a 5-year BFFS of 62 %, confirming that HDR reirradiation is a viable option for selected group of patients.

In our cohort, ADT use was associated with improved LC but did not significantly affect other oncologic endpoints. This may reflect the complexity of salvage treatment settings, where prior RP and a/sEBRT may select for more resistant tumor clones and subclinical metastatic
<figure><img src="image_9.png" /><figcaption>Fig. 3. (a) Comparison of cumulative proportion of LRFS depending on the ADT treatment. Solid line presents ADT group and dashed line presents group without ADT; (b) Comparison of cumulative proportion of LRFS depending on the biopsy. Solid line presents no-biopsy group, dashed line presents group with ISUP 1–3, dotted line – ISUP 4 and higher.</figcaption></figure>

<figure><img src="image_10.png" /><figcaption>Fig. 4. (a) Kaplan-Meier graph showing the cumulative proportion of biochemical failure-free survival (BFFS) in patients after salvage HDR-BT; (b) Kaplan-Meier graph showing the cumulative proportion of metastasis-free survival (MFS) in patients after salvage HDR-BT; (c) Kaplan-Meier graph showing the cumulative proportion of overall survival (OS) in patients after salvage HDR-BT; (d) Kaplan-Meier graph showing the cumulative proportion of progression-free survival (PFS) in patients after salvage HDR-BT.</figcaption></figure>

Nevertheless, androgen deprivation has been shown to sensitize prostate cancer cells to radiotherapy by impairing DNA repair, inducing cell cycle arrest, and modifying the tumor microenvironment. A large individual patient data meta-analysis confirmed that the addition of ADT to definitive radiotherapy improves metastasis-free survival in patients with localized disease [17]. These radiosensitizing effects may contribute to the improved LC observed in our study. However, the oncologic benefits of ADT must be weighed against its potential risks [18].

Several factors were associated with improved local control, including higher HDR-BT dose and greater number of fractions. This is consistent with previous data demonstrating better tumor control with dose escalation in radiotherapy [19]. Additionally, patients with lower PSA nadir values after salvage treatment had a lower risk of recurrence, confirming previous findings in the definitive treatment setting [20,21]. All patients in our cohort were treated with conventionally fractionated a/sEBRT, which was standard at that time, however raising role of hypofractionation in that setting is bringing query whether sBRT would
<figure><img src="image_11.png" /><figcaption>**Fig. 5.** Forest plot of univariate and multivariate Cox regression analyses for local control. (a) Univariate Cox analysis. Factors associated with improved local control included biopsy confirmation prior to salvage, higher brachytherapy dose, and use of ADT. (b) Multivariate Cox analysis. In the adjusted model, brachytherapy dose remained the only independent predictor of improved local control. Hazard ratios (HRs) are presented with 95 % confidence intervals (CI). The dashed vertical line represents HR = 1.0. HR < 1 indicates reduced risk of local recurrence; HR > 1 indicates increased risk.</figcaption></figure>

<table><caption>**Table 2**
Reported outcomes of other studies on sBRT after RP and a/sEBRT.</caption><thead><tr><th>Study</th><th>Number of patients</th><th>Endpoint</th><th>Results</th><th>Median FU [months]</th></tr></thead><tbody><tr><td>Aghili et al [5]</td><td>15</td><td>BFF</td><td>86 %</td><td>48</td></tr><tr><td>Soror et al. [6]</td><td>10</td><td>4-year BFFS</td><td>60 %</td><td>34</td></tr><tr><td>Le Roy et al. [3]</td><td>10</td><td>PSA response</td><td>70 %</td><td>21</td></tr><tr><td>Schönle et al [14]</td><td>24</td><td>5-year BFFS LR rate</td><td>65 % (whole group) 17,7% (whole group)</td><td>49</td></tr></tbody></table>

be safe option after such treatment. Published data suggest no higher toxicity of hypofractionated s/aEBRT than with conventional fractionation [22,23,24]. Extrapolating possible toxicity of sBRT is however uncertain and reliable answer needs to be investigated, preferably in prospective studies.

Patient selection remains a crucial factor in optimizing salvage outcomes. In our cohort, patients with biopsy-confirmed recurrence prior to HDR-BT experienced better LC and PFS, likely due to accurate confirmation of true localized failure. Conversely, patients diagnosed exclusively through functional imaging—particularly those with low PSA levels—may have had undetected disseminated disease, contributing to distant progression [25]. Despite strong guideline recommendations for biopsy in patients eligible for salvage therapy and consideration of ADT, real-world practice varies considerably based on institutional protocols, physician judgment, and patient-specific factors. Definitive answers will require data from prospective clinical trials.

Existing data on salvage treatment after RP and EBRT report grade ≥ 3 genitourinary (GU) toxicity rates ranging from 0 % to 20 % [3–6,14].

In our cohort, the incidence of acute and late GU toxicity ≥grade 3 was below 9 %, which is comparable to rates reported in salvage HDR-BT trials following primary radiotherapy [13,26]. Le Roy et al. observed no late GU toxicity ≥grade 2 among 5 patients treated with salvage HDR-BT [3]. Losa et al. reported that all seven patients treated with salvage BT remained free of grade ≥2 GU or GI toxicity [4]. Aghili et al., in a series of 15 patients treated with salvage HDR-BT, reported two cases (13.3 %) of grade 3 GU toxicity – both related to urinary incontinence following transurethral resection of a post-treatment stricture [5]. Soror et al. reported grade 3 late GU toxicity in 2 of 10 patients (20 %), with no grade ≥3 GI events [6]. Notably, in the Schönle et al. PDR-BT subgroup no late GU toxicity ≥grade 2 was observed [14]. These findings, consistent with our own, reinforce the safety profile of salvage BT. Moreover, they suggest that patients who tolerated previous treatments without significant toxicity may be appropriate candidates for reirradiation. Careful selection based on prior tolerance and clinical risk remains essential [27].

This study has several limitations. Its retrospective design, heterogeneity in patient characteristics, and variability in total dose, variability of toxicity reporting during follow-up and fractionation schedules limit the ability to draw definitive conclusions regarding the most effective or safest treatment regimen. Nevertheless, it represents the largest reported cohort of patients treated with salvage HDR-BT following RP and a/sEBRT failure. Our findings are encouraging and demonstrate that this method is a feasible option for managing local relapse in the prostate bed after prior radiotherapy. In the multivariable analysis, the total BT dose was the only independent prognostic factor for LC. Based on these results, fractionation schedules such as 2 × 13 Gy or more, 3 × 10 Gy, or 4 × 8 Gy, as used in our cohort, appear to be the most preferable. This analysis provides a foundation for future prospective trials and supports the consideration of salvage HDR-BT in appropriately selected patients treated at experienced centers.

## Conclusion

Salvage HDR-BT for local recurrence after RP and a/sEBRT is a feasible and effective treatment with acceptable toxicity. Biopsy-confirmed relapse was associated with improved outcomes, supporting the role of histological verification and careful patient selection. Our findings also suggest that ADT may enhance LC. These results provide a rationale for prospective trials and further refinement of salvage strategies in experienced centers.

## CRediT authorship contribution statement

**Adam Kluska:** Writing – original draft, Visualization, Resources, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. **Artur J. Chyrek:** Writing – review & editing, Visualization, Validation, Supervision, Project administration, Methodology, Investigation, Data curation, Conceptualization. **Benjamin Guix:** Validation, Data curation. **Patricia Willisch:** Validation, Data curation. **Tamer Soror:** Validation, Data curation. **Mateusz Bilski:** Validation, Conceptualization. **Ivan Garcia:** Data curation. **Teresa Guix:** Data curation. **Beatriz Vázquez:** Data curation. **Wojciech Burchardt:** Methodology, Investigation, Formal analysis, Data curation, Validation. **Piotr Lelek:** Validation, Data curation. **Ricarda Merten:** Data curation. **Vratislav Strnad:** Writing – review & editing, Validation, Supervision. **Iosif Strouthos:** Validation, Data curation. **Mario Terlizzi:** Validation, Data curation. **David Büchser:** Validation, Data curation. **Pierre Blanchard:** Validation, Supervision. **Alfonso Gomez-Iturriaga:** Writing – review & editing, Validation, Supervision, Conceptualization. **Piotr Wojcieszek:** Writing – review & editing, Validation, Supervision, Resources, Project administration, Conceptualization.
## Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

## 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.

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