What are the treatment options for prostate cancer at different stages?

Treatment of Prostate Cancer by Stage

Treatment selection for prostate cancer depends primarily on risk stratification (very low, low, intermediate, high, and very high/locally advanced) combined with life expectancy, with active surveillance preferred for low-risk disease, radical prostatectomy or radiation therapy for intermediate-risk disease, and radiation therapy plus long-term androgen deprivation therapy for high-risk and locally advanced disease. 1

Risk Stratification Framework

Risk stratification is essential before selecting treatment, as it determines prognosis and guides therapeutic decisions 2:

• Very low risk: Gleason score ≤6, PSA <10 ng/mL, <3 positive biopsy cores, ≤50% cancer in any core, PSA density <0.15 ng/mL/g 3
• Low risk: Gleason score ≤6 and PSA <10 ng/mL 2, 3
• Intermediate risk: Gleason score 7, or PSA 10-20 ng/mL 1, 3
• High risk: Gleason score 8-10, or PSA >20 ng/mL 1, 3
• Very high risk/locally advanced: Clinical stage T3b-T4 1, 3

Staging Workup Requirements

For intermediate and high-risk disease, obtain cross-sectional imaging (CT or MRI of abdomen and pelvis) and bone scan to evaluate for metastases before treatment decisions. 1, 2

• Low-risk patients do not require staging imaging 1
• Chest CT should be added for high-risk patients 1

Treatment by Risk Category

Very Low and Low Risk Disease

For patients with life expectancy <10 years, observation (watchful waiting) is recommended, involving monitoring without immediate curative intent, with delayed hormone therapy only if symptomatic progression occurs. 2, 3

For patients with life expectancy ≥10 years, active surveillance is the preferred option, which includes 2:

• PSA measurement every 6 months 1, 2
• Digital rectal examination every 12 months 1, 2
• Repeat prostate biopsy every 12 months 1, 2
• Intervention triggered by Gleason score progression or increased tumor volume 1

Alternative curative options for low-risk disease include 1:

• Radical prostatectomy 1
• External beam radiation therapy (minimum 70 Gy) 3
• Brachytherapy 1, 4

A critical caveat: Despite low-risk classification, approximately 20% of patients who choose observation may die from prostate cancer over 20 years, though prostate cancer-specific mortality at 10 years remains only 2.4%. 1

Intermediate Risk Disease

For intermediate-risk disease, radical prostatectomy or radiation therapy plus androgen deprivation therapy (ADT) are the standard treatment options. 1

Treatment options stratified by favorable vs. unfavorable intermediate risk 1:

Favorable intermediate risk (single intermediate-risk factor):

• Radical prostatectomy 1
• Radiation therapy alone (though evidence is less robust than RT + ADT) 1
• Brachytherapy 1
• Active surveillance may be offered to select patients, though this carries higher risk of developing metastases compared to definitive treatment 1

Unfavorable intermediate risk (multiple intermediate-risk factors):

• Radical prostatectomy 1
• Radiation therapy (70-78 Gy) plus 4-6 months of ADT (preferred based on survival benefit demonstrated in randomized trials) 1
• EBRT plus brachytherapy boost 1

Key evidence: Two randomized trials (RTOG 9408 and D'Amico trial) demonstrated 10-year overall survival improvement with ADT added to radiation therapy (54% to 61%, p=0.03), though these used lower radiation doses than current standards. 1

High Risk Disease

For high-risk localized disease, long-term ADT (2-3 years) plus radical radiation therapy is the preferred treatment based on survival benefit demonstrated in randomized controlled trials. 1

Standard treatment options 1:

• Radiation therapy (minimum 78 Gy) plus 2-3 years of ADT (Category 1 recommendation) 1
• EBRT plus brachytherapy boost with or without 2-3 years of ADT 1
• Radical prostatectomy plus pelvic lymph node dissection (for select patients) 1

Critical point: Radical prostatectomy compared to watchful waiting reduces prostate cancer-specific mortality (20.4% vs 31.6% at 29 years) and overall mortality, though this data comes from pre-PSA screening era patients. 1

Very High Risk/Locally Advanced Disease (T3b-T4)

For locally advanced disease, neoadjuvant ADT plus radical radiation therapy plus adjuvant ADT is the standard approach. 1

Treatment options 1:

• Radiation therapy plus long-term ADT (Category 1 recommendation) 1
• EBRT plus brachytherapy with or without long-term ADT 1
• Radical prostatectomy plus pelvic lymph node dissection (only for selected patients with no fixation to adjacent organs) 1
• Neoadjuvant docetaxel may be considered 1

Metastatic Disease

Hormone-Naïve Metastatic Disease

For metastatic hormone-naïve prostate cancer, ADT combined with novel androgen receptor pathway inhibitors (abiraterone, enzalutamide, apalutamide, or darolutamide) is the standard first-line treatment. 1, 2

Treatment options 1:

• ADT plus abiraterone (improved median overall survival from 36.5 to 53.3 months, HR 0.66) 1, 5
• ADT plus enzalutamide 1
• ADT plus apalutamide 1
• ADT plus darolutamide 1
• ADT plus docetaxel (for patients fit enough for chemotherapy) 1, 2
• Radiation therapy for low-volume disease 1
• ADT alone only for frail patients who cannot tolerate combination therapy 1
• Bone health agents 1

Castration-Resistant Metastatic Disease

First-line options for metastatic castration-resistant prostate cancer 1:

• Abiraterone 1
• Docetaxel 1
• Enzalutamide 1
• Radium-223 (only for patients unfit for above treatments with bone-only metastases) 1

Second-line or post-docetaxel options 1:

• Abiraterone 1
• Cabazitaxel 1
• Enzalutamide 1
• Radium-223 1

Non-Metastatic Castration-Resistant (M0 CRPC)

For high-risk M0 CRPC, add second-generation androgen receptor pathway inhibitors to ongoing ADT 1:

• ADT plus apalutamide 1
• ADT plus darolutamide 1
• ADT plus enzalutamide 1

Post-Treatment Surveillance

After radical prostatectomy, PSA should be undetectable (<0.2 ng/mL) within 2 months 2, 3:

• Measure PSA every 6-12 months for first 5 years, then annually 1
• PSA every 3 months may be required for high-risk patients 1
• Digital rectal examination is optional if PSA remains undetectable 2

After external beam radiation therapy, PSA should reach ≤1.0 ng/mL within 16 months 3:

• Follow same PSA monitoring schedule as post-prostatectomy 1

For biochemical recurrence (rising PSA), salvage radiation therapy to the prostate bed should be initiated early (PSA <0.5 ng/mL) for improved outcomes. 2

Critical Pitfalls to Avoid

Common errors that compromise outcomes 2, 3:

• Using cryotherapy, HIFU, or focal therapy as standard initial treatments for localized prostate cancer (these are not standard care options due to lack of comparative outcome evidence) 1, 2, 3
• Prescribing primary ADT alone for localized prostate cancer (does not improve survival) 3
• Offering brachytherapy to patients with obstructive urinary symptoms (can exacerbate symptoms) 2, 3
• Denying radical local treatment solely because metastatic lesions are identified on novel imaging techniques like PSMA-PET in patients with localized disease on routine imaging 1

Shared Decision-Making Considerations

Patients must be counseled about treatment-related adverse effects 1:

• Radical prostatectomy: Higher rates of urinary incontinence (49% vs 21%) and erectile dysfunction (80% vs 45%) compared to observation 1, 4
• Radiation therapy: Bowel dysfunction and sexual dysfunction 1
• ADT: Osteoporosis, metabolic syndrome, fatigue (recommend regular exercise to all men on ADT) 2
• Older men experience higher rates of permanent erectile dysfunction and urinary incontinence after prostatectomy 3

Patients should consult with both a urologist and radiation oncologist before making treatment decisions for localized disease. 1