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When is salvage radiation therapy indicated versus systemic hormone therapy for biochemical relapse?
Executive summary
Salvage radiotherapy (SRT) is the primary potentially curative option for biochemical recurrence after radical prostatectomy and is often recommended early when PSA is low; randomized trials (GETUG‑AFU‑16, RTOG 9601) show that adding short‑term androgen deprivation therapy (ADT) to SRT improves some outcomes but the benefit varies by pre‑SRT risk factors such as PSA level, PSA doubling time, and Grade Group [1] [2] [3]. Guideline panels therefore recommend SRT alone for lower‑risk biochemical recurrence and SRT plus ADT for patients with high‑risk features (e.g., PSA ≥0.7 ng/mL, Grade Group 4–5, PSADT ≤6 months) [4].
1. Why the choice matters: cure vs systemic control
Salvage radiotherapy after prostatectomy is the only intervention with curative intent for many men with isolated biochemical recurrence; it targets presumed local disease in the prostate bed, whereas systemic hormone therapy (ADT) treats micrometastatic disease but is not curative on its own in this setting. Multiple reviews and practice summaries emphasize SRT as “the sole curative option” after radical prostatectomy for biochemical relapse and note the trade‑offs between local control, systemic disease suppression, and side effects like hot flashes, sexual dysfunction, and metabolic effects [1] [5].
2. What randomized trials tell us: who benefits from adding ADT to SRT
Two randomized trials shaped current practice. GETUG‑AFU‑16 found that adding short‑term ADT to SRT improved metastasis‑free outcomes (long‑term follow up showed improved metastasis‑free survival) [3] [6]. RTOG 9601 tested antiandrogen given with SRT and demonstrated benefit in certain subsets but also later analyses suggested harms (e.g., increased other‑cause mortality) when antiandrogen was used broadly in lower‑risk men; this underlies the nuanced interpretation that benefit is not uniform and depends on baseline risk [2] [6].
3. Risk stratification — which patients should get SRT alone vs SRT+ADT
Guideline recommendations (AUA/ASTRO/SUO) explicitly endorse offering SRT plus ADT for patients with biochemical recurrence and any high‑risk features (examples: PSA ≥0.7 ng/mL, Gleason Grade Group 4–5, PSADT ≤6 months, persistently detectable post‑op PSA, seminal vesicle invasion). For men without high‑risk features, clinicians may offer radiation alone [4]. Systematic reviews and frameworks likewise conclude that ADT benefit varies with pre‑SRT PSA and other prognostic factors, supporting risk‑adapted use [7] [8].
4. Timing and PSA thresholds: earlier SRT often favored
Clinical trials and practice statements favor delivering SRT at low PSA levels (many trials included men with PSA <0.5–1.0 ng/mL) because earlier intervention is more likely to be curative for local recurrence; GETUG‑AFU‑16 and other studies enrolled patients with low rising PSA and used SRT as the primary approach [3] [9]. A randomized Japanese study (JCOG0401) directly compared early SRT versus hormone therapy in men with PSA increase to 0.4–1.0 ng/mL and supports consideration of SRT prior to systemic hormone therapy in that range [9].
5. Imaging and patient selection: finding who truly needs local therapy
Next‑generation imaging (PSMA‑PET) is now recommended to distinguish local from regional or distant recurrence before committing to prostate‑bed SRT; guidelines advise obtaining PSMA‑PET when considering salvage RT because up to two‑thirds of men may have disease outside the prostate bed and could be less likely to benefit from local SRT alone [10] [11] [4]. Available sources emphasize using advanced imaging to avoid “blind” radiation and to tailor fields or to add systemic therapy when distant disease is identified [11] [10].
6. Duration of ADT when combined with SRT — short vs long
Trials and guideline panels support short‑course ADT (4–6 months) with SRT for many patients and longer durations (18–24 months) for those with multiple high‑risk features; RADICALS and other studies have prospectively tested ADT durations in the postoperative setting and informed recommendations [12] [4]. Systematic reviews argue the incremental benefit of longer ADT must be weighed against toxicity and competing mortality [7] [6].
7. Real‑world practice and alternatives
Some clinicians and centers prioritize local salvage options (SRT, focal ablation such as cryo/HIFU) to postpone or avoid systemic ADT and its side effects, reserving hormones for men who progress systemically; contemporary reviews note this “middle ground” and the modest durable cure rates of salvage therapies (roughly 20–25% durable complete response in some series) [5]. This reflects a patient‑centered trade‑off between potential cure and quality‑of‑life impacts.
Bottom line and practical approach
For men with biochemical relapse after prostatectomy, pursue PSMA‑PET to localize recurrence and offer early SRT when disease appears confined to the prostate bed; reserve addition of ADT for men with high‑risk features (PSA ≥0.7 ng/mL, high Grade Group, short PSADT, persistent PSA) and tailor ADT duration (short course for many, longer for very high risk) in line with guidelines [4] [7] [3]. Where sources disagree — for example, optimal PSA cutoffs and duration of ADT — clinicians should individualize decisions and discuss trade‑offs with patients [8] [6].