PSA Biochemical Recurrence After Prostatectomy and Radiotherapy
For PSA biochemical recurrence after prostatectomy without distant metastases, salvage radiotherapy should be offered as the primary treatment, ideally initiated at the earliest sign of PSA recurrence and at the lowest possible PSA level (preferably <0.5 ng/mL) to maximize disease control and reduce prostate cancer-specific mortality. 1
After Radical Prostatectomy
Defining Biochemical Recurrence
- Biochemical recurrence is defined as a confirmed PSA ≥0.2 ng/mL with a second confirmatory level ≥0.2 ng/mL 1
- In the era of ultrasensitive PSA assays, a detectable PSA that is confirmed and rising may trigger salvage therapy, particularly in high-risk patients 1
Re-staging Evaluation
- Re-staging should be considered to determine if recurrence is local versus metastatic, as this guides salvage strategy selection 1
- Important caveat: Imaging yield is extremely low when PSA is <10 ng/mL, particularly for bone scans 1
- For patients being evaluated for salvage radiotherapy, 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) 1
Primary Treatment: Salvage Radiotherapy
Salvage radiotherapy should be offered to all patients with PSA or local recurrence after radical prostatectomy who have no evidence of distant metastatic disease. 1
Timing and PSA Thresholds
- Critical principle: More favorable biochemical outcomes are associated with very low PSA values at the time radiotherapy is initiated 1
- Patients receiving radiotherapy 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 1
- Radiotherapy should be administered at the earliest sign of PSA recurrence 1
- Evidence suggests salvage radiotherapy may reduce prostate cancer-specific mortality, with greatest benefit in patients with PSA doubling time <6 months 1
Radiation Dose
- A minimum dose of 64-66 Gy should be delivered to the prostatic bed 1
- For salvage radiotherapy treating only biochemical evidence of disease, at least 66 Gy is recommended 1
Evidence Supporting Salvage Radiotherapy
- SWOG 8794 demonstrated that salvage radiotherapy significantly reduced metastatic recurrence rates among patients with detectable PSA post-prostatectomy 1
- EORTC 22911 showed salvage radiotherapy significantly reduced biochemical failure rates in patients with detectable PSA post-prostatectomy 1
- Observational studies demonstrate salvage radiotherapy reduces local recurrence risk by almost 90%, systemic progression by 75%, and delays need for androgen deprivation therapy 1
- At median 9-year follow-up, 22% of men receiving no salvage therapy died from prostate cancer versus 11% who received salvage radiotherapy 1
Important Caveats
- A small percentage (8.8%) of patients with biochemical recurrence may have detectable but stable PSA for 10+ years without clinical failure 1
- The decision to initiate salvage therapy requires full knowledge of pathology findings, risk factors, family history, and patient preferences 1
- Achieving undetectable PSA after salvage radiotherapy is an independent predictor of favorable outcome 1
Counseling on Side Effects
- Patients must be informed of potential short-term and long-term urinary, bowel, and sexual side effects 1
- Acute genitourinary toxicity (Grade 3-4): 0-6% 1
- Acute gastrointestinal toxicity (Grade 3-4): 0-2.2% 1
- Evidence for toxicity is based mostly on older radiotherapy techniques; newer techniques appear to have lower toxicity 1
After Primary Radiotherapy
Defining Biochemical Recurrence
- Biochemical recurrence after radiotherapy is defined as nadir PSA plus 2 ng/mL (Phoenix definition) 1
- The date of failure should be determined "at call" and not backdated 1
Management Approach
The optimal treatment of biochemical relapse after radical radiotherapy is not well-established, and radical local salvage treatments may induce considerable toxicity. 1
Workup Requirements
- Further workup is indicated for patients who are candidates for local therapy: original clinical stage T1-T2, life expectancy >10 years, and current PSA <10 ng/mL 1
- Workup includes prostate biopsy, bone scan, and additional imaging as clinically indicated (CT, MRI) 1
Treatment Options for Positive Biopsy
- Salvage prostatectomy in highly selected cases, though morbidity (incontinence, erectile dysfunction, bladder neck contracture) remains significantly higher than primary radical prostatectomy 1
- Alternative local therapies: cryotherapy or brachytherapy may be considered 1
- Observation remains acceptable for select patients 1
- Treatment must be individualized based on risk of progression, likelihood of success, and therapy-related risks 1
Role of Androgen Deprivation Therapy
- Early hormonal therapy is not routinely advised for PSA relapse after local treatments 1
- Exception: ADT is an option for patients with short PSA doubling time (<12 months) 1
- Intermittent androgen deprivation can be offered to patients starting salvage ADT for rising PSA >1 year following radiotherapy 1
High-Risk Biochemical Recurrence (After Exhaustion of Local Options)
For patients with high-risk biochemical recurrence (PSA doubling time ≤9 months) after exhaustion of all local treatment options:
- Combination therapy with enzalutamide plus leuprolide significantly improves metastasis-free survival compared to leuprolide alone, while maintaining quality of life 2
- This represents the concept of anticipation and intensification of therapy in the high-risk setting 2
- Low-risk biochemical recurrence cases should be actively observed without early systemic therapies to avoid development of castration resistance before metastases appear 2
Prognostic Factors
Key factors predicting poor response to salvage therapy include: 1
- Gleason score 8-10
- Pre-salvage PSA >2 ng/mL
- Negative surgical margins (paradoxically suggests systemic disease)
- PSA doubling time <10 months
- Seminal vesicle invasion
Patients without these adverse features achieve 6-year progression-free survival of 69% with salvage radiotherapy 1