Balancing Efficacy and Toxicity in Salvage Brachytherapy and SBRT for Radio-Recurrent Prostate Cancer: Insights Beyond the UroGEC Review

Abstract

Salvage treatment for locally recurrent prostate cancer after primary radiotherapy remains a clinical challenge, with multiple modalities— including stereotactic body radiotherapy (SBRT), high-dose-rate (HDR) brachytherapy, and low-dose-rate (LDR) brachytherapy—competing for optimal use. The recent UroGEC expert review in Radiotherapy & Oncology provides a timely synthesis of available evidence and underscores the potential role of brachytherapy in this setting. Here, we contextualize these findings with recently published meta-analyses that expand the evidence base and refine our understanding of salvage outcomes. Updated analyses highlight significant differences across modalities: HDR brachytherapy achieves favorable disease control with low gastrointestinal toxicity, whereas LDR appears to offer superior relapse- free survival in selected subgroups at the cost of higher late genitourinary morbidity. By contrast, SBRT, although attractive for its non-invasiveness, demonstrates lower long-term relapse-free survival when scrutinized in broader pooled cohorts, despite acceptable toxicity. Collectively, these findings emphasize that the “one-size-fits-all” paradigm is inadequate. Clinical decision-making must instead be individualized, integrating oncologic efficacy, toxicity risks, patient comorbidities, and personal preferences. Looking forward, prospective trials and harmonized outcome reporting will be essential to strengthen the comparative evidence. Until then, a nuanced, patient-centered approach—anchored in multidisciplinary discussion—remains the cornerstone of salvage treatment planning. This perspective complements and extends the UroGEC review, underscoring the need to balance efficacy with quality of life in managing radio- recurrent prostate cancer.

Main Body

We read with great interest the recent review by Gomez-Iturriaga et al, published in Radiotherapy & Oncology, offering an expert-endorsed uroGEC perspective on salvage brachytherapy for locally recurrent prostate cancer. ¹ The authors are to be congratulated on their timely and comprehensive synthesis of existing evidence in this important clinical area.

As highlighted in the LEVIATHAN meta-analysis, local failure after primary radiotherapy—occurring most commonly within 2–4 years—is strongly associated with a “second wave” of metastatic spread and poorer outcomes in terms of overall survival (OS), cancer-specific survival (CSS), and distant metastasis-free survival (DMFS). ² Early identification and management of intraprostatic recurrence may thus offer meaningful oncologic benefit and mitigate treatment burden.

The 2021 MASTER meta-analysis demonstrated comparable 5-year relapse-free survival (RFS) rates across salvage stereotactic body radiotherapy (SBRT), high-dose-rate (HDR), and low-dose-rate (LDR) brachytherapy (60%, 56%, and 60%, respectively). However, conclusions for SBRT were based on a single eligible study with sufficient follow-up. ³ The authors of the uroGEC review noted minimal differences between brachytherapy modalities and limitations in cross-modal comparisons due to short follow-up durations.

However, several high-quality meta-analyses have since enriched the evidence base:

A 2024 update on SBRT outcomes included 36 studies (15 with survival curve reconstruction), encompassing 682 patients. ⁴ This analysis reported a median RFS of 36.2 months and a 5-year RFS of 40.6%, which is markedly lower than the MASTER estimate. The cumulative ≥ G3 genitourinary (GU) and gastrointestinal (GI) toxicity rates were 5.8% and 1.3%, respectively. Improved RFS was associated with whole-gland reirradiation (HR 1.83, p = 0.008) and higher biologically effective doses (BEDs) (HR 1.40, p = 0.015). ⁴ It should be noted that SBRT utilizes various modalities (eg, CyberKnife, Linac). Higher BED (>144 Gy) improves control. Notably, while most studies followed expert consensus favoring partial irradiation, whole-gland treatment proved more effective. Spatially Fractionated Radiation Therapy (SFRT) could therefore serve as a middle ground, combining whole-gland efficacy with the safety of focal approaches.

A recent meta-analysis on HDR brachytherapy reported outcomes from 26 studies (1447 patients), including survival reconstructions for 13 (761 patients). The pooled 5-year RFS was 52.3%, with a median RFS of 61.2 months. Favorable toxicity profiles were observed: cumulative acute and late ≥ G3 GU toxicities were 1% and 5%, respectively, while GI events remained <0.5%. ⁵ Whole-gland, multifraction regimens and longer time intervals from primary treatment to salvage were predictive of improved outcomes.

In parallel, new data comparing HDR to LDR brachytherapy (31 studies, 891 patients) suggested that LDR may confer superior 5-year RFS (63.5% vs 52.3%) and median RFS duration (131.6 vs 61.2 months). ⁶ Certain subgroups—including younger patients (≤70 years), those with longer intervals from primary treatment (≥70 months), and those with a pre-salvage PSA level of ≥ 5 ng/mL—benefited significantly from LDR. However, toxicity risks were higher: cumulative ≥ G3 GU (12.7% vs 5.8%) and GI (3.5% vs 0.3%) toxicity favored HDR.

A recent addition to the evidence base is the multicenter HDR-REPOPRA study by Kluska et al, which specifically examined patients with local recurrence following prostatectomy and subsequent external beam radiotherapy. This trial reported highly favorable outcomes, with a 5-year local relapse-free survival (LRFS) of 81.1%, metastasis-free survival (MFS) of 77.5%, and OS of 95.9%. Importantly, treatment-related morbidity remained acceptable, with grade ≥3 genitourinary toxicity observed in 5.5% (acute) and 8.9% (late), and grade 3 gastrointestinal events limited to 1.1%. ⁷ These results highlight that even in heavily pretreated patients, salvage HDR brachytherapy can achieve durable disease control while preserving a favorable balance between efficacy and safety, supporting its use as a feasible option in selected cases.

Taken together, recent data underscore the importance of individualized decision-making, balancing oncologic efficacy with toxicity. Patient-centered discussions should inform the final choice of salvage modality, incorporating clinical factors, patient preferences, and projections of long-term outcomes. (Table 1).

Table 1.

Summary of Efficacy and Toxicity Outcomes for Salvage Modalities in Radio-Recurrent Prostate Cancer Based on Recent Evidence.

Study/Reference	Modality	No. of Studies/Patients	Median RFS (months)	5-Year RFS	Cumulative ≥ G3 GU Toxicity	Cumulative ≥ G3 GI Toxicity
Meng et al, 2024  4	SBRT	36 studies/682 pts	36.2	40.6%	5.8%	1.3%
Shen et al, 2024  5	HDR-BT	26 studies/1447 pts	61.2	52.3%	Acute: 1% Late: 5%	<0.5%
Xie et al, 2025  6	LDR-BT	31 studies/891 pts*	131.6	63.5%	12.7%	3.5%
Xie et al, 2025  6	HDR-BT	(Comparative analysis)	61.2	52.3%	5.8%	0.3%
Kluska et al, 2025  7 †	HDR-BT	Multicenter/Retrospective	Not reported	81.1%‡	Acute: 5.5% Late: 8.9%	1.1%

Abbreviations: SBRT = Stereotactic Body Radiotherapy; HDR-BT = High-Dose-Rate Brachytherapy; LDR-BT = Low-Dose-Rate Brachytherapy; RFS = Relapse-Free Survival; GU = Genitourinary; GI = Gastrointestinal; pts = patients. Notes: * Comparison cohort size. ^† Study specifically examining patients with recurrence following prostatectomy and subsequent external beam radiotherapy (HDR-REPOPRA). ^‡ Reported as Local Relapse-Free Survival (LRFS).