What is the best management for biochemical relapse after prostatectomy?

Management of Biochemical Relapse After Prostatectomy

Salvage radiotherapy should be offered to all patients with biochemical recurrence after radical prostatectomy who have no evidence of distant metastatic disease, with treatment initiated at the earliest sign of PSA recurrence and at the lowest possible PSA level (preferably <0.5 ng/mL) to maximize disease control. 1, 2

Definition of Biochemical Recurrence

• Biochemical recurrence is defined as a detectable PSA ≥0.2 ng/mL with a second confirmatory level ≥0.2 ng/mL 1, 2
• This threshold represents the most widely accepted definition and should be used for clinical decision-making 3
• PSA should be monitored regularly after radical prostatectomy to enable early administration of salvage therapies 1

Restaging Evaluation

• A restaging evaluation should be considered to determine if recurrence is local versus metastatic, as this guides salvage strategy selection 1, 2
• PSMA-PET/CT is the preferred imaging modality for restaging at PSA levels below 10 ng/mL, as it can detect occult metastatic disease at PSA levels as low as 0.2 ng/mL 4
• Conventional imaging (bone scan, CT) has extremely low yield until PSA >10 ng/mL 2, 3
• Pelvic imaging should be obtained unless the disease is low-volume and low-risk (PSA <1.0, Gleason score <7, and PSA doubling time >15 months) 2

Salvage Radiotherapy: The Primary Treatment

Salvage radiotherapy is the only potentially curative treatment for biochemical failure after prostatectomy and should be offered as the primary intervention. 1, 5

Timing of Salvage Radiotherapy

• Treatment effectiveness is greatest when administered at lower PSA levels, with patients receiving radiotherapy at PSA <0.5 ng/mL achieving 6-year biochemical progression-free survival of 48%, compared to only 18% when PSA is >1.5 ng/mL 2
• Early salvage radiotherapy provides better metastasis-free survival in selected patient groups, particularly those with clinically significant but not yet systemic recurrence 6
• Outcomes are superior when PSA is <2.0 ng/mL at treatment initiation 3

Radiation Dose and Technique

• A minimum dose of 64-66 Gy should be delivered to the prostatic bed 1, 2
• Radiation doses ≥60 Gy result in superior biochemical outcomes even in patients with pre-radiotherapy PSA ≤0.50 ng/mL 7
• Modern techniques (3D-CRT or IMRT) should be used when available 1

Addition of Androgen Deprivation Therapy (ADT)

The decision to add ADT to salvage radiotherapy depends on specific risk factors and PSA levels:

When to Add ADT

• For patients with PSA ≥0.7 ng/mL before salvage radiotherapy, the addition of ADT improves overall survival based on the RTOG 9601 trial showing benefit after 13 years of follow-up 8
• For patients with high-risk features (Grade Group 4-5, stage pT3b-4, node-positive disease, short PSA doubling time <6 months, or Gleason score 8-10), ADT should be considered with salvage radiotherapy 1, 8
• The GETUG-AFU 16 trial demonstrated that 6 months of goserelin added to salvage radiotherapy improved progression-free survival 8

When ADT May Not Be Necessary

• For patients with PSA <0.7 ng/mL without high-risk features, radiation alone may be offered, as the benefit of ADT is less well defined in this population 1, 8
• PSA level alone should not determine ADT use when PSA <0.7 ng/mL; other risk factors must be considered 1

Duration of ADT

• When ADT is indicated, 6 months of treatment appears effective based on GETUG-AFU 16 8
• Two years of ADT was used in RTOG 9601, though this involved bicalutamide which is not commonly used today 1, 8

Risk Stratification for Treatment Planning

High-Risk Features Requiring Aggressive Management

The following features predict worse outcomes and should prompt consideration of ADT with salvage radiotherapy 1:

• Grade Group 4-5 (Gleason score 8-10)
• Stage pT3b-4 (seminal vesicle invasion)
• Node-positive disease
• PSA doubling time <6-10 months
• Pre-salvage radiotherapy PSA >2 ng/mL
• Positive surgical margins (though this is an inconsistent risk indicator)

Optimal Candidates for Early Salvage Radiotherapy

Based on regression tree analysis, early salvage radiotherapy provides the greatest benefit in three specific groups 6:

1. Low risk: Undetectable PSA after radical prostatectomy, Gleason score ≤7, and tumor stage ≥pT3b
2. Intermediate risk: Undetectable PSA after radical prostatectomy with Gleason score ≥8
3. High risk: PSA persistence after radical prostatectomy with Gleason score ≤7

Management After Salvage Radiotherapy Failure

If biochemical recurrence occurs after both radical prostatectomy and salvage radiotherapy:

• Systemic therapy with ADT or newer agents (enzalutamide) should be considered, particularly if PSA doubling time is <3 months indicating aggressive disease 4
• Continuous ADT with GnRH analog is first-line hormonal therapy 4
• Intermittent ADT is preferred over continuous ADT based on the PR.7 trial showing non-inferior overall survival with superior quality of life 2
• However, routine early ADT is not recommended unless patients have symptomatic local disease progression, proven metastases, or PSA doubling time <3 months, as early ADT delays time to metastases but does not improve overall survival 2

Patient Counseling and Side Effects

• Patients should be informed of possible short- and long-term urinary, bowel, and sexual adverse effects of radiotherapy 1
• When considering ADT, discuss treatment side effects and impact of medical comorbidities using shared decision-making 1
• ADT is associated with increased risk of cardiovascular events, dementia, fracture risk, and metabolic syndrome 1
• The risk-benefit ratio must be evaluated for each patient, including medical comorbidities, life expectancy, and quality of life considerations 1

Common Pitfalls to Avoid

• Do not delay salvage radiotherapy while waiting for PSA to rise further, as outcomes are significantly better at lower PSA levels 2, 7
• Do not reflexively initiate ADT based solely on rising PSA after both prostatectomy and radiotherapy have been completed without considering high-risk features 2
• Do not use conventional imaging (bone scan, CT) for restaging when PSA is <10 ng/mL; use PSMA-PET/CT instead 2, 4
• Do not treat with radiation doses <64 Gy, as higher doses improve biochemical outcomes 1, 7
• Patient anxiety about rising PSA should not drive treatment decisions in the absence of high-risk features or rapid PSA doubling time 2