Salvage Radiotherapy for Recurrent Prostate Cancer After Radical Prostatectomy
Primary Recommendation
Salvage radiotherapy (SRT) should be offered to all patients with biochemical recurrence (BCR) after radical prostatectomy who have no evidence of distant metastatic disease, and treatment must be initiated at the earliest sign of PSA recurrence—ideally when PSA is ≤0.5 ng/mL—to maximize disease control and reduce prostate cancer-specific mortality. 1, 2, 3
Defining Biochemical Recurrence
- BCR is defined as a confirmed PSA ≥0.2 ng/mL with a second confirmatory level ≥0.2 ng/mL 1, 2
- Regular PSA monitoring after radical prostatectomy is mandatory to enable early detection and administration of salvage therapy 1
Pre-Treatment Imaging and Staging
PSMA-PET/CT Imaging
- Next-generation molecular PET imaging (PSMA-PET/CT) should be performed in all patients being considered for salvage radiotherapy 1, 3
- PSMA-PET/CT is the most sensitive imaging modality for detecting biochemically recurrent prostate cancer and should be performed instead of or after negative conventional imaging 1
- If PSMA-PET/CT is unavailable or shows PSMA-negative disease, 18F-fluciclovine-PET/CT is the preferred alternative over conventional imaging alone 1
- Conventional imaging (bone scan, CT) has extremely low yield when PSA is <10 ng/mL and should not be relied upon for BCR with PSA <5 ng/mL 1, 3
Treatment Planning Based on PET Findings
- If PET/CT shows pelvic nodal disease, these positive findings must be incorporated into the radiation treatment plan 1
- Proceed with salvage prostate bed radiotherapy even if PET/CT is negative, as detection rates are not high enough to exclude benefit from SRT, and delaying treatment may miss the optimal therapeutic window 1
- If elective pelvic nodal irradiation is being considered, PET/CT findings should guide this decision 1
Optimal Timing of Salvage Radiotherapy
PSA Level at Treatment Initiation
- The effectiveness of salvage radiotherapy is greatest when administered at PSA levels ≤0.5 ng/mL 1, 2, 3
- Patients receiving SRT at PSA <0.5 ng/mL achieve 6-year biochemical progression-free survival of 48%, compared to only 18% when PSA is >1.5 ng/mL 2
- Initiation of SRT at PSA ≤0.5 ng/mL is associated with improved metastasis-free survival independent of pathologic risk status and ADT use 4
- Treatment efficacy drops dramatically as PSA rises above 0.5 ng/mL—do not delay salvage radiation when indicated 3
Radiation Dose
- A minimum dose of 64-66 Gy should be delivered to the prostatic bed 2, 3
- Higher radiation doses are associated with improved PSA relapse-free rates 5
Addition of Androgen Deprivation Therapy (ADT)
High-Risk Features Requiring ADT
ADT should be added to salvage radiotherapy for patients with any of the following high-risk features: 1, 3
- PSA ≥0.7 ng/mL at time of SRT
- Gleason Grade Group 4-5 (Gleason score 8-10)
- PSA doubling time (PSADT) ≤6 months
- Persistently detectable post-operative PSA
- Seminal vesicle involvement
This recommendation is supported by three randomized trials (GETUG-AFU 16, RTOG 9601, and NRG/RTOG 0534 SPPORT) comparing salvage RT plus ADT versus salvage RT alone 1
Low-Risk Features Not Requiring Immediate ADT
- PSADT >12 months
- Gleason score <8
- Longer time to recurrence (>3 years post-surgery)
- Pathological stage ≤pT3a N0 3
Prognostic Factors and Expected Outcomes
Adverse Prognostic Features
Key factors predicting poor response to salvage therapy include: 2, 6, 7
- Gleason score 8-10
- Pre-salvage PSA >2.0 ng/mL
- Negative surgical margins
- PSA doubling time <10 months
- Seminal vesicle invasion
Expected Outcomes
- Patients without adverse features achieve 6-year progression-free survival of 69% with salvage radiotherapy 2
- Patients with no adverse features have a 4-year progression-free probability of 77% 6
- Achieving undetectable PSA after salvage radiotherapy is an independent predictor of favorable outcome 2
- Nearly half of patients treated with SRT at the earliest sign of recurrence have long-term PSA response 7
Toxicity and Side Effects
Acute Toxicity (During Treatment)
- Genitourinary: Grade 1-2 in 10.5-26%, Grade 3-4 in 2.0-8.0% 1, 8
- Gastrointestinal: Grade 1-2 in 22.0-25.0%, Grade 3-4 in 0.0-2.0% 1, 8
Late Toxicity (Long-term)
- Genitourinary: Grade 1-2 in 2.0-22.0%, Grade 3-4 in 0.0-10.6% 8
- Gastrointestinal: Grade 1-2 in 1.0-12.7%, Grade 3-4 in 0.0-6.7% 8
Urinary Incontinence and Sexual Function
- Rates and severity of urinary incontinence in patients receiving salvage RT after radical prostatectomy are generally similar to rates for patients who had radical prostatectomy only 1
- The impact of RT on erectile function in men post-radical prostatectomy is unclear, as the majority of men presenting for RT already have compromised erectile function 1
- Patients must be informed of possible short-term and long-term urinary, bowel, and sexual side effects as well as potential benefits of controlling disease recurrence 1
Critical Pitfalls to Avoid
- Do not delay salvage radiation when indicated—efficacy drops dramatically as PSA rises above 0.5 ng/mL 3, 4
- Do not rely on conventional imaging for BCR with PSA <5 ng/mL—use PSMA-PET instead 1, 3
- Do not withhold salvage prostate bed RT based on negative PET/CT alone—proceed with treatment to avoid missing the therapeutic window 1
- Do not initiate ADT reflexively for all patients—reserve for those with high-risk features as defined above 1, 3