In a man who has undergone radical prostatectomy and now has biochemical recurrence, which high‑risk features—post‑operative prostate‑specific antigen ≥0.2 ng/mL confirmed on two measurements, PSA doubling time ≤6 months, Gleason grade group ≥4 (Gleason score ≥8), positive surgical margins, extracapsular extension or seminal‑vesicle invasion, estimated life expectancy ≥10 years, and ability to tolerate hormonal therapy—indicate that a 24‑month androgen‑deprivation therapy should be administered together with salvage external‑beam radiotherapy?

Criteria for 24-Month ADT with Salvage Radiotherapy After Radical Prostatectomy

Men with biochemical recurrence after radical prostatectomy should receive 24-month androgen-deprivation therapy combined with salvage radiotherapy when they have MULTIPLE high-risk features or specifically Grade Group 4-5 (Gleason score ≥8) disease, particularly when accompanied by PSA doubling time ≤6 months, persistently detectable post-operative PSA, or seminal vesicle invasion. 1

Minimum ADT Duration: 4-6 Months for ANY High-Risk Feature

The baseline recommendation is that any patient with at least ONE high-risk feature should receive a minimum of 4-6 months of ADT with salvage radiotherapy. 1 High-risk features include:

• PSA ≥0.7 ng/mL at time of biochemical recurrence 1, 2
• Grade Group 4-5 (Gleason score ≥8) 1, 3
• PSA doubling time ≤6 months 1, 4
• Persistently detectable post-operative PSA (≥0.2 ng/mL confirmed on two measurements) 1, 5
• Seminal vesicle invasion 1, 3
• Node-positive disease 1

This 4-6 month minimum is based on three landmark randomized trials (RTOG 9601, GETUG AFU-16, and NRG/RTOG 0534 SPPORT) that demonstrated 40-60% improvement in freedom from clinical progression, with RTOG 9601 specifically showing overall survival benefits. 1

Extended Duration: 18-24 Months for Highest-Risk Disease

The decision to extend ADT from 4-6 months to 18-24 months hinges on the presence of MULTIPLE high-risk features or specifically Grade Group 4-5 disease. 1 The stratified analysis from RTOG 9601 demonstrated that longer-term ADT (24 months of bicalutamide in that trial) was associated with lower likelihood of progression and death specifically in patients with multiple high-risk factors. 1

Specific Indications for 24-Month ADT:

Primary indication: Grade Group 4-5 (Gleason score ≥8) combined with any of the following:

• PSA doubling time ≤6 months 1, 4
• Persistently detectable post-operative PSA 1
• Seminal vesicle invasion 1, 3
• Pre-salvage PSA ≥0.7 ng/mL 1, 2

Secondary indication: Multiple high-risk features present simultaneously, even if Grade Group is 3 (Gleason 4+3=7), particularly when combined with:

• Positive surgical margins 1
• Extracapsular extension 3, 6
• Short PSA doubling time ≤6 months 5, 4

Critical Nuances and Caveats

PSA Threshold Considerations

For patients with PSA <0.7 ng/mL, PSA level alone should NOT determine ADT use—other high-risk features must be present to justify ADT. 1 The RTOG 9601 trial showed that the overall survival benefit from extended ADT was restricted to patients with pre-salvage PSA ≥0.7 ng/mL. 2 However, patients with PSA <0.7 ng/mL but with Grade Group 4-5 or PSA doubling time ≤6 months still warrant consideration for extended ADT. 1

Surgical Margin Status: An Inconsistent Predictor

Positive surgical margins are listed as a high-risk feature, but this is one of the more inconsistent risk indicators for ADT benefit. 1 Paradoxically, some retrospective analyses suggest that patients with negative surgical margins and pre-radiation PSA ≥0.5 ng/mL may derive MORE benefit from ADT than those with positive margins. 7, 8 This counterintuitive finding suggests that negative margins with rising PSA may indicate more aggressive systemic disease that benefits from hormonal therapy.

Life Expectancy and Tolerability

Patients must have estimated life expectancy ≥10 years and ability to tolerate hormonal therapy to justify 24-month ADT, as the toxicity burden increases with duration. 1 ADT increases acute grade 2 adverse events, hot flashes, hypertension, gynecomastia, and sexual dysfunction, but these quality-of-life impacts must be weighed against mortality and metastasis benefits. 1

Algorithmic Approach to ADT Duration

Step 1: Confirm Biochemical Recurrence

• PSA ≥0.2 ng/mL with second confirmatory level ≥0.2 ng/mL 5

Step 2: Assess for ANY High-Risk Feature

If ANY of the following present → Minimum 4-6 months ADT:

• PSA ≥0.7 ng/mL 1
• Grade Group 4-5 1
• PSA doubling time ≤6 months 1
• Persistently detectable post-operative PSA 1
• Seminal vesicle invasion 1
• Node-positive disease 1

Step 3: Identify Criteria for Extended 18-24 Month ADT

Extend to 18-24 months if:

• Grade Group 4-5 (Gleason ≥8) PLUS any other high-risk feature 1, 3
• OR Multiple (≥2) high-risk features present simultaneously 1
• OR Grade Group 4-5 with PSA doubling time ≤6 months (highest-risk combination) 1, 4

Step 4: Consider Omitting ADT in Select Low-Risk Patients

ADT may be safely omitted in patients with ALL of the following favorable features:

• Pre-salvage PSA <0.45 ng/mL 9
• PSA doubling time >8 months 9
• Positive surgical margins 8
• Grade Group ≤3 7

These highly selected patients treated with prostate bed salvage radiotherapy alone showed 100% metastasis-free survival and excellent ADT-free survival. 9

Timing of ADT Initiation

ADT can be initiated either concurrently with salvage radiotherapy or up to 2 months prior to starting radiation, based on trial protocols. 1 Shorter durations than 4 months have not been demonstrated to improve patient outcomes. 1

Common Pitfalls to Avoid

1. Do not use ADT alone without radiotherapy in node-negative post-prostatectomy patients—ADT monotherapy has no therapeutic role in this setting. 3

2. Do not delay salvage radiotherapy waiting for PSA to rise further—effectiveness is greatest when administered at lower PSA levels, ideally <0.5 ng/mL. 5

3. Do not assume all positive margins require extended ADT—margin status is an inconsistent predictor, and negative margins with rising PSA may actually indicate higher-risk disease. 1, 7, 8

4. Do not overlook PSA doubling time—this is one of the most powerful predictors of benefit from both salvage radiotherapy and extended ADT, with PSA doubling time <6 months identifying patients who derive the greatest mortality benefit. 5, 1, 4