What are the recommended treatment options for prostate cancer based on disease stage, Gleason score, prostate-specific antigen level, patient age, comorbidities, and patient preferences?

Prostate Cancer Treatment

Treatment for prostate cancer must be stratified by risk category using Gleason score, PSA level, and clinical stage, with active surveillance preferred for low-risk disease, definitive local therapy (radical prostatectomy or radiation) for intermediate-risk disease, and combined-modality treatment for high-risk disease.

Risk Stratification Framework

The foundation of treatment selection depends on accurate risk classification 1:

• Very low risk: Gleason ≤6, PSA <10 ng/mL, <3 positive cores, ≤50% cancer per core, PSA density <0.15 ng/mL/g 1
• Low risk: Gleason ≤6, PSA <10 ng/mL 1
• Intermediate risk: Gleason 7 OR PSA 10-20 ng/mL 1, 2
• High risk: Gleason 8-10 OR PSA >20 ng/mL 1
• Very high risk: Locally advanced disease (T3b-T4) 1

Life expectancy is critical—patients with <10 years should generally pursue observation rather than aggressive treatment 3, 1.

Treatment by Risk Category

Very Low and Low Risk Disease

Active surveillance is the preferred management approach for patients with low-risk disease (Gleason ≤6, PSA <10 ng/mL) rather than immediate intervention 3. This recommendation reflects that many tumors will not progress during a patient's lifetime 4.

The structured monitoring protocol includes 3, 1:

• PSA measurement every 6 months
• Digital rectal examination every 12 months
• Repeat prostate biopsy every 12 months
• First follow-up visit at 3 months to establish baseline

Triggers to switch from surveillance to active treatment 3:

• Gleason score upgrades to ≥7 on repeat biopsy
• PSA velocity >2.0 ng/mL/year
• Increased tumor volume (>3 cores positive or >50% involvement per core)

For patients with life expectancy <10 years, observation (watchful waiting) without curative intent is more appropriate than active surveillance 3, 1.

Intermediate Risk Disease (Gleason 7)

For Gleason 7 disease, definitive local therapy is recommended for patients with life expectancy >10 years, with choice between surgery and radiation based on patient factors 2.

Radical Prostatectomy

• Standard option for intermediate-risk disease with life expectancy >10 years 2
• Benefits include complete removal with accurate pathological staging 2
• Expected complications: erectile dysfunction in up to 80% and urinary incontinence in up to 49% of patients 2
• Pelvic lymph node dissection should be performed unless nomograms predict <2% probability of nodal metastasis 1
• Extended lymph node dissection detects metastases twice as often as limited dissection 1

External Beam Radiation Therapy (EBRT)

• Minimum target dose of 70 Gy in 2.0 Gy fractions using conformal techniques 1, 2
• Consider adding androgen deprivation therapy (ADT) for 4-6 months for intermediate-risk disease 2
• Patients must be informed that ADT with radiation increases adverse effects on sexual function 1

Brachytherapy

• Can be used as monotherapy for low-intermediate risk (Gleason 3+4=7, PSA <10 ng/mL) 2
• Permanent seed implants should achieve ≥90% of prostate volume receiving ≥100% of prescribed dose 1
• Caution: Can exacerbate urinary obstructive symptoms 2

Special consideration for Gleason 3+4=7: Active surveillance may be considered for selected patients with comorbidities or limited life expectancy, particularly those with favorable characteristics 2, 5. However, Gleason 4+3=7 patients have significantly worse outcomes and should proceed to definitive treatment 5.

High Risk Disease (Gleason 8-10 or PSA >20 ng/mL)

Combined-modality treatment is standard for high-risk localized disease 1:

Option 1: Radiation Plus Long-Term ADT

• External beam radiation (minimum 70 Gy) combined with ADT for 2-3 years 1
• Dose escalation above 70 Gy provides additional benefit for high-grade tumors 1
• This combination improves survival compared to radiation alone 1

Option 2: Radical Prostatectomy with Extended Lymph Node Dissection

• Extended pelvic lymph node dissection is mandatory for high-risk disease 1
• High-volume surgeons at high-volume centers achieve superior outcomes 1
• Preserving urethral length beyond the apex reduces postoperative incontinence risk 1

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

Treatment options include 1:

• Radiation therapy with long-term ADT (preferred for most patients)
• EBRT plus brachytherapy boost with or without long-term ADT
• Radical prostatectomy with extended pelvic lymph node dissection (selected cases)

Metastatic Disease

For newly diagnosed metastatic prostate cancer, androgen deprivation therapy combined with androgen receptor pathway inhibitors is first-line treatment 6, 4.

• Abiraterone plus medical castration improved median overall survival from 36.5 to 53.3 months (HR 0.66) compared to castration alone 6
• Other options include darolutamide 6
• Chemotherapy with docetaxel should be considered, especially for extensive disease, as initial treatment with chemotherapy extends survival compared to ADT alone 4
• The 5-year survival rate for metastatic disease is 37% 6

Staging Requirements

Essential Staging Studies

All patients 7:

• Digital rectal examination
• Systematic biopsies (minimum 6 cores, though 12 cores detect 31% more cancers) 7
• PSA determination
• Histopathologic assessment with Gleason score

For stage T3 disease 7:

• Renal ultrasound
• CT scan

For T2a or higher, PSA >15 ng/mL, AND Gleason ≥7 7:

• Abdominal and pelvic CT scan

Bone scan indicated for 7:

• Bone pain
• Locally advanced tumor (≥T3Nx or T1-4N1-3)
• Gleason grade 4 or 5 AND PSA ≥10 ng/mL

Optional Advanced Imaging

• Pelvic or endorectal coil MRI if radical prostatectomy or radiotherapy is planned and extraprostatic extension is suspected 7
• Seminal vesicle biopsies if digital rectal exam, imaging, or PSA suggest periprostatic involvement 7

Post-Treatment Surveillance

After radical prostatectomy 1:

• Serum PSA should be below detection level after 2 months
• First follow-up at 3 months with PSA, digital rectal exam, and symptom assessment

After external beam radiotherapy 1:

• Serum PSA should reach ≤1 ng/mL within 16 months
• First follow-up at 3 months

Salvage radiotherapy is indicated for biochemical recurrence and is most effective when pre-salvage PSA is <1 ng/mL 1.

Critical Pitfalls to Avoid

• Do not use primary ADT alone for localized prostate cancer—it does not improve survival 1, 2
• Do not perform adjuvant radiotherapy immediately following radical prostatectomy—it has not been shown to improve survival 2
• Avoid brachytherapy in patients with significant lower urinary tract symptoms as it can exacerbate obstruction 2
• Do not omit lymph node dissection in high-risk patients or when nomograms predict >2% probability of nodal involvement 1
• Cryotherapy, HIFU, and focal therapy are not recommended as standard initial treatments 1
• Older men experience higher rates of permanent erectile dysfunction and urinary incontinence after prostatectomy 1, 2

Pathologic Upgrading Risk

Clinicians must counsel patients about the substantial risk of Gleason score upgrading at prostatectomy 8:

• For biopsy Gleason 6 with PSA <10 ng/mL: 43% upgraded
• For biopsy Gleason 6 with PSA 20-29.9 ng/mL: 61% upgraded
• For biopsy Gleason 3+4=7: approximately one-third have pathologically advanced disease
• For biopsy Gleason 4+3=7: two-thirds have pathologically advanced disease

Higher PSA and older age are independently associated with upgrading and pathologically advanced disease 8.