What are the treatment options for prostate adenocarcinoma?

Treatment Options for Prostate Adenocarcinoma

Treatment for prostate adenocarcinoma must be stratified by risk category and disease stage, with localized disease managed through active surveillance (for low-risk), radical prostatectomy or radiation therapy (for intermediate/high-risk), and metastatic disease requiring androgen deprivation therapy combined with additional systemic agents. 1, 2

Risk Stratification Framework

Risk stratification is the essential first step that determines all subsequent treatment decisions 1, 2:

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

Staging workup for intermediate and high-risk disease requires bone scintigraphy and cross-sectional imaging (CT or MRI) to evaluate for metastases 1

Treatment by Risk Category

Very Low and Low Risk Disease

For patients with life expectancy <10 years, observation (watchful waiting) is the recommended approach, involving monitoring without immediate curative intent, with delayed hormone therapy only if symptomatic progression occurs 1, 2

For patients with life expectancy ≥10 years, active surveillance is the preferred option 1, 2:

• PSA measurement every 6 months 1, 2
• Digital rectal examination every 12 months 1, 2
• Repeat prostate biopsy every 12 months 1, 2

Alternative curative options include radical prostatectomy, external beam radiation therapy (EBRT), or brachytherapy, though active surveillance avoids treatment-related morbidity while maintaining the option for curative intervention if disease progresses 1

Intermediate Risk Disease

Both radical prostatectomy and external beam radiotherapy are equally effective treatment options for intermediate-risk disease 1:

Radical prostatectomy with pelvic lymph node dissection offers:

• Comparable oncologic outcomes with shorter hospital stays and less blood loss 1
• Expected 15-year prostate cancer-specific mortality of approximately 12% 1
• Risk of lymph node metastasis approximately 5-10%, which should inform discussion of lymph node dissection 1

External beam radiation therapy:

• Requires minimum dose of 66-70 Gy given in 2.0 Gy fractions or equivalent using conformal techniques 1, 2
• Short-course androgen deprivation therapy for 4-6 months significantly improves local control, reduces disease progression, and improves overall survival 1
• Patients should be informed that ADT with radiation increases adverse effects on sexual function 2

Brachytherapy is also an option but can exacerbate urinary obstructive symptoms 2

High Risk and Locally Advanced Disease

Long-term ADT combined with radical radiation therapy is the standard treatment for high-risk localized and locally advanced disease 3, 2:

• Radiation therapy plus long-term ADT (neoadjuvant, concurrent, and adjuvant) 3, 2
• Radical prostatectomy with pelvic lymphadenectomy is an alternative for select patients 3, 2
• Neoadjuvant docetaxel can be considered in addition to standard approaches 3

Metastatic Disease

Hormone-Naive Metastatic Disease

Continuous ADT is the foundation of treatment for metastatic hormone-naïve prostate cancer, achieved through bilateral orchiectomy (surgical castration) or LHRH agonists (medical castration) 1:

For patients fit enough for chemotherapy, adding docetaxel to ADT at initial diagnosis provides survival benefit, representing a paradigm shift from sequential therapy 1, 4

Additional first-line combination options for metastatic hormone-naive disease 3:

• ADT + abiraterone 3
• ADT + enzalutamide 3
• ADT + apalutamide 3
• Radiation therapy for low-volume disease 3
• ADT alone only for frail patients who cannot tolerate combination treatments 3
• Bone health agents should be added 3

Castration-Resistant Metastatic Disease

First-line options for metastatic castration-resistant prostate cancer (mCRPC) 3:

• Abiraterone 3
• Enzalutamide 3
• Docetaxel 3
• Radium-223 for patients unfit for above treatments with bone-only metastases 3

Second-line or post-docetaxel options 3:

• Cabazitaxel 3
• Abiraterone (if not previously used) 3
• Enzalutamide (if not previously used) 3
• Radium-223 3

Recent real-world data demonstrates that both abiraterone and enzalutamide provide comparable efficacy, with median time to progression of 19 months for abiraterone versus 18 months for enzalutamide, and median overall survival of 67 months for the entire cohort 5

Non-Metastatic Castration-Resistant Disease (M0 CRPC)

For high-risk M0 CRPC, add one of the following to continued ADT 3:

• ADT + apalutamide 3
• ADT + darolutamide 3
• ADT + enzalutamide 3

Post-Treatment Surveillance

After Radical Prostatectomy

• PSA should be undetectable (<0.2 ng/mL) within 2 months after surgery 1, 2
• Follow-up includes PSA measurement every 3 months during year 1, then every 6 months for 7 years 1, 2
• Biochemical recurrence is defined as confirmed PSA >0.2 ng/mL 1
• For biochemical recurrence, salvage radiation therapy to the prostate bed should be initiated early (PSA <0.5 ng/mL), which improves outcomes compared to delayed treatment 1

After External Beam Radiotherapy

• PSA should reach nadir ≤1 ng/mL within 16 months after completing radiotherapy 1, 2
• Biochemical recurrence is defined as nadir PSA plus 2 ng/mL 1

Critical Pitfalls to Avoid

Common errors that compromise outcomes 1, 2:

• Do not use cryotherapy, HIFU, or focal therapy as standard initial treatments for localized prostate cancer 1, 2
• Do not use primary ADT alone for localized prostate cancer as it does not improve survival 2
• Do not rely solely on PSA for monitoring in patients with neuroendocrine features 1
• Recognize that brachytherapy can exacerbate urinary obstructive symptoms 1, 2
• Patients with obstructive urinary symptoms may be better candidates for surgical approaches rather than radiation 2

For patients on long-term ADT 1:

• Monitor for osteoporosis and metabolic syndrome 1
• Recommend regular exercise to all men on ADT to reduce fatigue and improve quality of life 1

Special Considerations

Older men experience higher rates of permanent erectile dysfunction and urinary incontinence after prostatectomy compared to younger men 2

Genetic counseling should be considered for high-risk patients with strong family history of specific cancers (breast, ovarian, pancreatic) 2

Abiraterone must be taken on an empty stomach (at least 2 hours after and 1 hour before food), as systemic exposure increases 5-fold with low-fat meals and 10-fold with high-fat meals 6