What is the treatment for extramammary Paget's disease (EMPD) of the perianal region with vertebral metastases, including systemic therapy options?

Treatment of Metastatic Extramammary Paget's Disease with Vertebral Involvement

For metastatic extramammary Paget's disease (EMPD) of the perianal region with vertebral metastases, immediate management should include corticosteroids (dexamethasone 16 mg/day minimum) for spinal cord compression risk, followed by radiation therapy to the spine for local control, and systemic chemotherapy with carboplatin/paclitaxel or targeted therapy based on HER2 status. 1, 2, 3

Immediate Management of Vertebral Metastases

Corticosteroid Administration

• Dexamethasone should be administered immediately upon diagnosis at a minimum dose of 4 mg every 6 hours (16 mg/day), with doses ranging from 10-100 mg depending on severity of spinal cord compression. 1
• Gradual reduction over 2 weeks after definitive treatment is initiated. 1

Imaging and Assessment

• MRI of the entire spine with contrast (T1 and T2) is the gold standard and should be performed within 12 hours if epidural metastatic spinal cord compression (MESCC) is suspected. 1
• Assess for spinal instability, neurological deficits, and degree of cord compression to guide treatment selection. 4

Definitive Local Treatment for Vertebral Metastases

Radiation Therapy (First-Line)

• Radiation therapy is the preferred treatment for symptomatic spinal metastases, providing pain relief in 50-58% of cases with complete pain disappearance in 30-35%. 1
• Hypofractionated regimens are the standard approach (single fraction 8 Gy or 5×4 Gy, 10×3 Gy for longer life expectancy). 1
• Stereotactic body radiation therapy (SBRT) achieves local tumor control and pain relief >80% with faster relief compared to conventional radiation. 4, 1

Surgical Intervention

• Surgery followed by radiation therapy is indicated only if life expectancy ≥3 months and specific criteria are met: 1
  • Spinal instability requiring fixation
  • Recurrence or progression after radiation therapy
  • Neurological deterioration during radiation and corticosteroids
• Contraindications include paraplegia >24 hours and life expectancy <3 months. 1

Percutaneous Procedures

• Vertebroplasty or kyphoplasty can provide pain relief within 1-3 days for vertebral fractures and has additive effects when combined with radiation therapy. 1
• Can be combined with radiofrequency ablation or cryoablation to reduce tumor mass. 1
• Note: One case report documented vertebral fractures during systemic treatment requiring percutaneous vertebroplasty, highlighting the need for bone-directed therapy. 5

Systemic Therapy Options for Metastatic EMPD

HER2-Targeted Therapy (If HER2-Positive)

• HER2 overexpression occurs in 30-40% of EMPD cases and should be tested via molecular profiling. 6
• Single-agent trastuzumab has demonstrated complete response in HER2-positive metastatic EMPD and should be the first-line systemic therapy when HER2 is overexpressed. 6
• Trastuzumab can be safely used even in hemodialysis patients. 6

Chemotherapy Regimens

• For HER2-negative disease or after HER2-targeted therapy failure, carboplatin and paclitaxel is the recommended chemotherapy regimen based on Mayo Clinic experience. 3
• Alternative option: irinotecan-based regimens. 3
• Historical regimen with documented partial response: mitomycin C (3.5 mg/m²) + epirubicin (50 mg/m²) on day 1, vincristine (0.6 mg/m²) on days 1 and 7, cisplatin (30 mg/m²) days 1-3, and 5-fluorouracil (350 mg/m²) days 3-7. 7

Immunotherapy and Targeted Combinations

• Anlotinib (anti-angiogenic) combined with tislelizumab (anti-PD-1) achieved partial response with significant SUV reduction (18.9 to 5.3) and CEA normalization in one case report. 5
• Molecular profiling frequently reveals PD-1, PD-L1, PTEN overexpression/loss, AR expression, and PIK3CA mutations, suggesting potential therapeutic targets. 6
• Consider immunotherapy particularly if PD-L1 positive or microsatellite instability is present. 6

Bone-Targeted Therapy

• Zoledronic acid, denosumab, or pamidronate should be administered to delay skeletal-related events (SREs) in patients with bone metastases. 1
• Dental preventive measures are mandatory before initiation to prevent osteonecrosis of the jaw. 1
• These agents should not replace analgesic treatment but are complementary. 1

Treatment Sequencing Algorithm

1. Immediate: Dexamethasone 16 mg/day minimum for spinal cord compression risk 1
2. Within 24 hours: Initiate radiation therapy to spine (SBRT preferred if available) 1
3. Concurrent/Sequential: Obtain HER2 testing and molecular profiling 2, 6
4. Systemic therapy selection:
   • If HER2-positive: Trastuzumab 6
   • If HER2-negative: Carboplatin/paclitaxel 3
   • Consider anlotinib/tislelizumab for AMER1 mutations or PD-L1 expression 5
5. Add bone-targeted therapy: Zoledronic acid or denosumab 1
6. Consider vertebroplasty: If pathologic fractures develop 1, 5

Multidisciplinary Coordination

• Urgent multidisciplinary consultation including medical oncology, radiation oncology, and spinal surgery is required within 24 hours of MESCC diagnosis. 1
• Treatment should be initiated within 24 hours after diagnosis. 1
• A designated responsible physician should coordinate all aspects of care, with palliative care team involvement for symptom management. 8

Prognosis and Monitoring

• Metastatic EMPD has a poor prognosis with median overall survival of 9 months in reported cases. 5
• Close follow-up for at least 5 years is recommended to monitor for recurrence. 2
• Common pitfall: Delaying spinal imaging or radiation therapy can result in irreversible neurological damage; proactive management is essential. 4

4, 1, 5, 7, 2, 3, 6