When should salvage radiotherapy be combined with androgen deprivation therapy to improve biochemical control?
Executive summary
Salvage radiotherapy (SRT) improves biochemical control after local treatment failure, and randomized trials show that adding androgen deprivation therapy (ADT) further reduces biochemical and clinical progression—most clearly when disease carries high‑risk features such as high Gleason score, short PSA doubling time, or early/persistent PSA after prostatectomy (GETUG‑AFU 16, RTOG 9601) [1] [2]. Contemporary guidelines therefore recommend offering ADT with SRT for biochemical recurrence, but duration and patient selection must be individualized because benefit and harm vary by baseline risk and PSA level [3] [4].
1. The evidence base: randomized trials that changed practice
Two pivotal randomized trials underpin the practice of combining ADT with SRT: the GETUG‑AFU 16 trial demonstrated that 6 months of short‑term ADT given with salvage radiotherapy significantly reduced biochemical or clinical progression and improved metastasis‑free survival versus SRT alone with long follow‑up [1], and earlier randomized work including RTOG 9601 showed survival and metastasis benefits from adding endocrine therapy to radiation in the post‑operative setting [2]. Phase II series and subsequent trials support that combining hormonal manipulation with SRT produces more durable biochemical control than radiation alone [5] [6].
2. Who benefits most: clinical and pathological selectors
The benefit of adding ADT to SRT is concentrated in patients with higher‑risk features: those with high Gleason grade, short PSA doubling time, rapid recurrence after primary therapy, persistent detectable PSA after prostatectomy, or other pathological indicators of aggressive disease [7] [4]. Large multi‑institutional analyses found that only patients with more aggressive disease characteristics derive clear oncologic benefit from concomitant ADT during early SRT [4], and contemporary reviews emphasize stratifying patients by these risk factors before recommending systemic therapy [7].
3. Timing: early/“early salvage” SRT with ADT versus delayed approaches
Current data support offering ADT with early SRT—i.e., at the time of confirmed biochemical recurrence but before overt metastatic disease—especially when PSA is rising and risk markers are unfavorable [6] [3]. Guidelines advise confirming a rising PSA trend and obtaining PSMA‑PET or equivalent staging when appropriate, because accurate staging informs whether local SRT plus ADT is appropriate or whether systemic or metastasis‑directed strategies should be considered [3] [6].
4. Duration and agents: short‑term to intermediate courses
Trial data and guideline summaries suggest a typical ADT duration with SRT of roughly 6 months for many patients, with trials testing both short‑term (6 months) and longer regimens (up to 24 months) and some evidence of durable biochemical control with varied durations and agents [5] [8]. The GETUG‑AFU 16 result used 6 months of ADT [1], whereas other studies (and older trials) used longer anti‑androgen strategies and demonstrated survival signals but also raised questions about late harms in certain subgroups [2] [9].
5. Harm, nuance and open questions
Benefit is not universal: long‑term analyses highlighted heterogeneity, and secondary analyses have suggested that prolonged anti‑androgen therapy may increase non‑cancer mortality in selected men, so clinicians must weigh cardiovascular and metabolic harms against oncologic gains [9]. Imaging advances (PSMA‑PET) also change the calculus by revealing oligometastatic disease that may alter the benefit of prostate‑directed SRT plus ADT versus metastasis‑directed or systemic approaches [6] [3]. High‑risk settings after nonstandard primary treatments (for example HIFU) have retrospective data supporting feasibility and good biochemical control with combined SRT+ADT, but those series are small and nonrandomized [10].
6. Practical synthesis
For patients with biochemical recurrence after definitive local therapy, combine ADT with salvage radiotherapy when recurrent disease carries high‑risk features (high Gleason, short PSA doubling time, early or persistent PSA, nodal disease) or when randomized trial evidence supports improved metastasis‑free and biochemical outcomes; a 6‑month course is the clearest evidence‑backed starting point for many, with longer durations considered for very high‑risk disease but balanced against toxicity and competing mortality risks [1] [5] [9]. Before committing to combined therapy, restage with modern imaging as indicated, confirm a rising PSA trend, and discuss individualized tradeoffs in multidisciplinary care because unanswered questions about optimal agent, exact duration, and management after PSMA‑PET–detected oligorecurrence remain [3] [6].