In an older man (>65 years) with advanced castration‑resistant prostate cancer presenting with brain metastases, what is the recommended diagnostic work‑up and treatment strategy?

Brain Metastases from Prostate Cancer: Diagnostic and Treatment Approach

In older men with advanced castration-resistant prostate cancer (CRPC) presenting with brain metastases, immediate brain MRI with gadolinium contrast is mandatory for diagnosis, followed by stereotactic radiosurgery (SRS) or whole-brain radiotherapy (WBRT) combined with continuation or escalation of systemic therapy, as this approach improves survival compared to systemic therapy alone.

Diagnostic Work-Up

Immediate Neuroimaging

• Brain MRI with gadolinium contrast is the diagnostic standard when brain metastases are suspected, as non-contrast CT may miss parenchymal lesions 1, 2
• Obtain urgent MRI for any patient with vertebral metastases who develops neurological symptoms to rule out concurrent spinal cord compression 3, 4
• Brain metastases from prostate cancer are rare (occurring in <1% of cases) but present late in disease course, typically 70-82 months after initial diagnosis 2, 5

Clinical Presentation Pitfalls

• Headache is the most common presenting symptom and should trigger immediate brain imaging in CRPC patients, even with normal or low PSA levels 6, 1
• Neurological symptoms may be non-specific (headache, altered consciousness, focal deficits), and serum PSA may be normal, contributing to delayed diagnosis 2
• Approximately 62% of patients present with multiple lesions, while 38% have solitary lesions 5

Systemic Staging

• Perform complete restaging with bone scan and cross-sectional imaging (CT chest/abdomen/pelvis or PET) to assess extent of extracranial disease 5
• Document current systemic therapy status, PSA trajectory, and Gleason score at diagnosis 5

Treatment Strategy

Local Brain-Directed Therapy (Priority Intervention)

Stereotactic radiosurgery is the preferred modality for patients with 1-4 brain lesions:

• SRS controls brain metastases in 100% of treated lesions with functional improvement (typically 1-grade Karnofsky performance score increase) 7
• Median survival after SRS is 10+ months, with some patients surviving >20 months 7
• SRS combined with systemic therapy demonstrates superior overall survival compared to systemic therapy alone (HR 0.37,95% CI 0.16-0.86, p=0.022) 5

Whole-brain radiotherapy is indicated for:

• Multiple (>4) brain metastases 6, 2
• Leptomeningeal involvement 2
• Patients with rapidly progressive neurological symptoms requiring urgent treatment 1
• WBRT combined with systemic therapy also shows improved survival versus systemic therapy alone 5

Surgical resection followed by WBRT should be considered for:

• Single, large (>3 cm), accessible lesions causing mass effect 7, 2
• Symptomatic lesions requiring immediate decompression 2
• Histological confirmation when diagnosis is uncertain 6, 2

Systemic Therapy Management

Continue or escalate systemic therapy based on CRPC treatment sequence:

For chemotherapy-naïve CRPC with brain metastases:

• Docetaxel 75 mg/m² every 3 weeks remains the backbone chemotherapy, with growth factor support strongly recommended in patients ≥65 years 3
• Abiraterone or enzalutamide can be used, but enzalutamide should be avoided or suspended due to epileptogenic potential in patients with brain lesions 6

For post-docetaxel progression:

• Cabazitaxel is indicated after docetaxel failure, though brain metastases may develop during cabazitaxel therapy 3, 6, 1
• Consider switching between abiraterone and enzalutamide (acknowledging cross-resistance), with preference for abiraterone in brain metastasis setting 8

Supportive Care Measures

Mandatory interventions:

• Initiate corticosteroids (dexamethasone) for symptomatic brain metastases to reduce cerebral edema 1
• Prescribe anti-epileptic prophylaxis for supratentorial lesions or if using medications that lower seizure threshold 6
• Continue bone-protective therapy (denosumab 120 mg SC every 4 weeks or zoledronic acid 4 mg IV every 3-4 weeks) for existing bone metastases 3, 8, 4
• Implement palliative care consultation, as brain metastases typically indicate terminal-stage disease with median survival <12 months 3, 5

Critical Monitoring Requirements

• Repeat brain MRI every 2-3 months to assess local control and detect new lesions 2
• Monitor PSA and systemic disease burden every 3 months 8
• Assess performance status and neurological function at each visit 7
• Screen for treatment-related complications: radiation necrosis (post-SRS/WBRT), neurocognitive decline (post-WBRT), and chemotherapy toxicity 7, 5

Common Pitfalls to Avoid

Do not delay brain imaging when CRPC patients report headache, even if non-contrast CT is negative—gadolinium-enhanced MRI is required 1, 2

Do not withhold local brain therapy based on poor prognosis alone—combined local and systemic treatment improves survival and quality of life compared to systemic therapy alone 7, 5

Do not continue enzalutamide in patients with brain metastases without careful consideration of seizure risk—switch to abiraterone or chemotherapy if local therapy is planned 6

Do not assume normal PSA excludes brain metastases—neurological symptoms warrant imaging regardless of PSA level 2

Prognosis

• Median survival after brain metastasis diagnosis is 2-10 months, with 76.5% mortality within the first year 5
• Patients treated with SRS or WBRT plus systemic therapy survive significantly longer than those receiving systemic therapy alone 7, 5
• Death typically results from systemic disease progression rather than neurological causes when local brain control is achieved 7, 2
• Five-year survival is exceptional but possible with aggressive multimodal therapy in selected patients 2