What is the preferred adjuvant therapy, radiotherapy (RT) or hormonal therapy, for a patient with prostate cancer?

Adjuvant Radiotherapy Should Be Offered Over Hormonal Therapy Alone for High-Risk Pathologic Features After Prostatectomy

For patients with adverse pathologic findings (positive surgical margins, extraprostatic extension, or seminal vesicle invasion) after radical prostatectomy, adjuvant radiotherapy is the evidence-based standard that reduces biochemical recurrence, local recurrence, and clinical progression, while adjuvant hormonal therapy alone lacks high-quality evidence for this indication. 1

The Evidence Base for Adjuvant Radiotherapy

Three landmark randomized controlled trials with over 10 years of follow-up (SWOG 8794, EORTC 22911, and ARO 96-02) consistently demonstrate that adjuvant radiotherapy significantly improves outcomes compared to observation alone in patients with adverse pathologic features 1:

• Biochemical recurrence-free survival is significantly improved across all three trials 1
• Local recurrence is reduced (16% vs 33% at 4 years in combination with hormonal therapy) 2
• Clinical progression is decreased 1
• Overall survival benefit was demonstrated in SWOG 8794, though the other two trials were not powered to detect this endpoint 1

The recommended radiation dose is 64-65 Gy minimum to the prostate bed, with decisions regarding higher doses made based on patient tolerance and functional status 1.

When Hormonal Therapy Has a Role

Hormonal therapy is not recommended as adjuvant monotherapy after prostatectomy for patients with adverse pathologic features 1. However, hormonal therapy does have specific evidence-based indications:

For Salvage Radiotherapy (Not Adjuvant)

When PSA rises after surgery (≥0.2 ng/mL confirmed), hormonal therapy should be offered in combination with salvage radiotherapy 1:

• RTOG 9601 demonstrated that 24 months of bicalutamide (150 mg daily) with salvage radiotherapy improved overall survival at 12 years, reduced distant metastases, and decreased prostate cancer-specific mortality 1
• GETUG-AFU 16 showed improved progression-free survival with hormonal therapy added to salvage radiotherapy 1
• This represents a Standard recommendation with Grade A evidence 1

For Primary Radiotherapy (Not Post-Prostatectomy)

If a patient receives primary radiotherapy instead of surgery for high-risk disease, then hormonal therapy is indicated 1:

• Neoadjuvant and concurrent ADT for 4-6 months is recommended for high-risk disease receiving radical radiotherapy 1
• Adjuvant ADT for 2-3 years is recommended for men at high risk of prostate cancer mortality who receive neoadjuvant hormonal therapy and radical radiotherapy 1

For Node-Positive Disease

If positive lymph nodes are found at surgery, immediate adjuvant ADT is recommended as a category 1 option, though observation is acceptable for very low-risk or low-risk patients 1:

• One small randomized trial (n=98) showed improved overall survival (76% vs 53% at 12 years) with immediate versus deferred ADT in pN1 patients 1
• Radiotherapy may be added to ADT for pN1 patients, though this is category 2B evidence 1

The Critical Distinction: Adjuvant vs. Salvage

Adjuvant radiotherapy is delivered when PSA is undetectable (<0.2 ng/mL) after surgery in patients with adverse pathologic features 1. This is the scenario where radiotherapy alone (without hormonal therapy) is the evidence-based standard 1.

Salvage radiotherapy is delivered when PSA rises after surgery (≥0.2 ng/mL confirmed) 1. This is the scenario where adding hormonal therapy to radiotherapy has proven survival benefit 1.

Algorithm for Post-Prostatectomy Management

Step 1: Assess pathology and PSA

• Positive surgical margins, extraprostatic extension, or seminal vesicle invasion present? 1
• PSA undetectable (<0.2 ng/mL)? 1

Step 2: If adverse pathology + undetectable PSA

• Offer adjuvant radiotherapy (64-65 Gy minimum to prostate bed) 1
• Timing: within 1 year after surgery, typically after recovery (12-16 weeks) 1, 3
• Do not add hormonal therapy in this adjuvant setting (no evidence for benefit) 1

Step 3: If PSA rises (≥0.2 ng/mL confirmed)

• Offer salvage radiotherapy PLUS hormonal therapy 1
• Start early when PSA <0.5 ng/mL for best outcomes 1
• Hormonal therapy duration: 24 months of bicalutamide 150 mg daily (based on RTOG 9601) 1

Step 4: If node-positive (pN1)

• Offer immediate ADT (category 1) 1
• Consider adding pelvic radiotherapy (category 2B) 1

Common Pitfalls to Avoid

Pitfall 1: Using hormonal therapy alone as adjuvant treatment after prostatectomy

• One older study (1989) directly compared radiotherapy versus hormonal therapy for locally recurrent prostate cancer and found radiotherapy superior for local control (14/16 vs 7/16, p<0.05) and disease-free survival (8/16 vs 1/16, p<0.05) 4
• Hormonal therapy alone is not recommended as standard initial treatment of non-metastatic disease 1

Pitfall 2: Delaying salvage radiotherapy until PSA is high

• Salvage radiotherapy is most effective when PSA <0.5 ng/mL 1
• Waiting until PSA exceeds 1.5 ng/mL significantly reduces effectiveness 1

Pitfall 3: Adding hormonal therapy to adjuvant radiotherapy in the post-prostatectomy setting

• The three major RCTs of adjuvant radiotherapy did not include hormonal therapy 1
• Evidence for hormonal therapy exists only in the salvage setting (PSA ≥0.2 ng/mL), not the adjuvant setting (undetectable PSA) 1

Pitfall 4: Confusing primary radiotherapy protocols with post-prostatectomy protocols

• Hormonal therapy combined with radiotherapy is standard for primary treatment of high-risk localized disease 1, 2
• This does not translate to the post-prostatectomy adjuvant setting where radiotherapy alone is the standard 1

Quality of Life Considerations

Adjuvant radiotherapy after prostatectomy has been generally well tolerated 3, though complications occur more frequently than with hormonal therapy alone 4. However, the superior disease control with radiotherapy outweighs this consideration for patients with adverse pathologic features 1, 4.

Hormonal therapy carries significant side effects including osteoporosis, metabolic syndrome, hot flashes, and sexual dysfunction 1. When hormonal therapy is used (in the salvage setting), patients should be counseled about these risks and offered supportive measures including calcium/vitamin D supplementation and bisphosphonates for bone health 1.