What are the recommended treatment options for prostate cancer at each clinical stage and their common side effects?

Treatment of Prostate Cancer by Stage and Side Effects

Risk Stratification Framework

Treatment decisions for prostate cancer depend primarily on risk stratification using PSA level, Gleason score, and clinical stage, with management ranging from active surveillance for low-risk disease to multimodal therapy for high-risk and metastatic disease. 1

Risk Categories

• Low-risk disease: T1-2a, Gleason ≤6, PSA <10 ng/mL 1, 2
• Intermediate-risk disease: Gleason 7 OR PSA 10-20 ng/mL 1, 3
• High-risk disease: T3-4 OR Gleason 8-10 OR PSA >20 ng/mL 1, 2
• Metastatic disease: Presence of distant metastases, associated with 5-year survival of 37% 4

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Treatment by Stage

Low-Risk Localized Disease (T1-2a, Gleason ≤6, PSA <10)

Active surveillance is the preferred approach for low-risk disease with life expectancy >10 years, achieving 99% disease-specific survival at 8 years. 5, 1

Active surveillance protocol:

• PSA measurement every 6 months 1
• Digital rectal examination every 12 months 1
• Repeat prostate biopsy within 12 months 1, 3
• Intervention triggered by Gleason score increase or tumor stage progression 4

Alternative definitive treatment options (for patients preferring immediate intervention):

• Radical prostatectomy 1, 2
• External beam radiotherapy (minimum 70 Gy in 2.0 Gy fractions) 5, 1
• Brachytherapy (≈120 Gy palladium or ≈140 Gy I-125) 1

Intermediate-Risk Localized Disease (Gleason 7 OR PSA 10-20)

For intermediate-risk disease, radical prostatectomy or external beam radiotherapy with 4-6 months of androgen deprivation therapy are equally effective options. 1, 3

Treatment options:

• Radical prostatectomy with pelvic lymph node dissection 1, 3
• External beam radiotherapy (minimum 70 Gy) with androgen suppression for 6 months 5, 1
• Brachytherapy as monotherapy (for Gleason 3+4=7 with PSA <10 ng/mL) or combined with EBRT 3

Selection considerations:

• Patients with >17% positive biopsy cores have higher risk of extracapsular extension and should receive more aggressive treatment 6
• Gleason 4+3 disease carries higher risk than 3+4 and warrants consideration of combined modality therapy 3, 7

High-Risk Localized Disease (T3-4 OR Gleason 8-10 OR PSA >20)

High-risk localized prostate cancer requires multimodal therapy: external beam radiotherapy plus long-term (2-3 years) androgen deprivation therapy, or radical prostatectomy with extended pelvic lymph node dissection. 5, 1, 8

Standard treatment options:

• Radiation therapy plus ADT for 2-3 years (preferred for most patients) 5, 1, 8
• Radical prostatectomy with extended pelvic lymph node dissection (for surgical candidates) 1, 3
• EBRT plus brachytherapy boost with or without long-term ADT 1

Critical points:

• Dose escalation above 70 Gy provides additional benefit for high-grade tumors 1
• Extended lymph node dissection detects nodal metastases twice as often as limited dissection 1
• Primary ADT alone should NOT be used as it does not improve survival 1, 2

Metastatic Disease

First-line treatment for metastatic prostate cancer is androgen deprivation therapy (bilateral orchidectomy or LHRH agonist) combined with androgen receptor pathway inhibitors such as abiraterone or darolutamide. 5, 4

Treatment sequence:

• Initial therapy: LHRH agonist with short-course antiandrogen to prevent disease flare 5
• Addition of novel agents: Abiraterone improves median overall survival from 36.5 to 53.3 months (HR 0.66) 4
• Chemotherapy: Docetaxel (3-weekly schedule) for symptomatic castration-refractory disease 5, 4

Castration-refractory disease management:

• Continue androgen suppression 5
• Second-line hormonal therapy (antiandrogen, corticosteroid) 5
• External beam radiotherapy for painful bone metastases (1×8 Gy or 10×3 Gy) 5
• Radioisotope therapy (strontium-89 or samarium-153) for bone pain 5
• Intravenous bisphosphonates for resistant bone pain 5

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Side Effects by Treatment Modality

Radical Prostatectomy

Radical prostatectomy causes erectile dysfunction in 80% of patients and urinary incontinence in 49% of patients, though rates vary by surgical volume and technique. 5

Common complications:

• Erectile dysfunction: 80% (vs 45% with watchful waiting) 5
• Urinary leakage/incontinence: 49% (vs 21% with watchful waiting) 5
• Severe incontinence (>2 pads daily): <5% at one year 1
• Infertility: Universal 5

Risk factors for worse outcomes:

• Older age associated with higher rates of permanent erectile dysfunction and incontinence 1, 3
• Lower-volume surgical centers have inferior outcomes 1

External Beam Radiotherapy

External beam radiotherapy causes less urinary incontinence than surgery but has higher rates of bowel dysfunction and delayed erectile dysfunction. 5

Common complications:

• Erectile dysfunction: Develops gradually; 4 out of 5 patients maintain erections initially 5
• Bowel dysfunction: Diarrhea and rectal symptoms 5
• Urinary symptoms: Pain on urination, less incontinence than surgery 5
• Chronic urinary symptoms: Less common than with surgery 5

Brachytherapy

Brachytherapy results in similar long-term survival to radical prostatectomy with less chronic urinary symptoms and erectile dysfunction, but can exacerbate obstructive urinary symptoms. 5, 3

Specific considerations:

• Better preservation of erectile function (4 out of 5 patients maintain erections) 5
• Can worsen pre-existing urinary obstructive symptoms 1, 3
• Contraindicated in patients with significant lower urinary tract symptoms 3

Androgen Deprivation Therapy

Androgen deprivation therapy increases cardiovascular risk including myocardial infarction, sudden cardiac death, and stroke, in addition to causing sexual dysfunction and metabolic complications. 2

Major side effects:

• Cardiovascular events: Increased risk of MI, sudden cardiac death, stroke 2
• Sexual dysfunction: Universal loss of libido and erectile function 5
• Metabolic effects: Weight gain, osteoporosis, diabetes risk 5
• Gynaecomastia: Preventable with breast bud irradiation (8-10 Gy) when using bicalutamide 5
• Hot flashes: Common with LHRH agonists 5

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Critical Warnings and Common Pitfalls

Avoid primary ADT alone for localized prostate cancer—it does not improve survival and should only be used for metastatic disease or combined with radiation. 1, 2

Key caveats:

• Patients with obstructive urinary symptoms are better candidates for surgery than brachytherapy 1
• Adjuvant radiotherapy immediately following radical prostatectomy has not been shown to improve survival 3
• Salvage radiotherapy after prostatectomy is most effective when PSA <0.5 ng/mL 2
• Cryotherapy, HIFU, and focal therapy are NOT recommended as standard initial treatments 5, 1
• PSA should be undetectable (<0.1 ng/mL) within 2 months after radical prostatectomy 2
• PSA should reach ≤1 ng/mL within 16 months after external beam radiotherapy 2