What is the optimal management for a patient with stage IV metastatic melanoma, a history of brain metastasis in the left temporal lobe, and a current diagnosis of pulmonary embolism, with increased bleeding and clot in the Superior Sagittal Sinus on MRI, requiring oxygen (O2) therapy and having an Eastern Cooperative Oncology Group (ECOG) performance status of 2-3?

Management of Stage IV Metastatic Melanoma with Brain Hemorrhage, Pulmonary Embolism, and Cerebral Venous Sinus Thrombosis

Immediate Life-Threatening Priorities

This patient requires urgent multidisciplinary neurosurgical evaluation for potential resection of the hemorrhagic brain metastasis, with continuation of anticoagulation for the dual thrombotic complications (pulmonary embolism and superior sagittal sinus thrombosis), as anticoagulation does not significantly increase intracranial hemorrhage risk in melanoma brain metastases and the thrombotic burden poses greater mortality risk. 1, 2

Critical Decision Point: Anticoagulation Management

Continue therapeutic anticoagulation despite the intracranial hemorrhage. 2

• Melanoma patients with brain metastases who receive systemic anticoagulation for venous thromboembolism have only a 4% risk of intracranial hemorrhage, which is not statistically different from those not anticoagulated (0%, p=1.00). 2
• The dual thrombotic complications (pulmonary embolism plus superior sagittal sinus thrombosis) create substantially higher mortality risk than the bleeding risk from anticoagulation. 2
• Patients receiving anticoagulation showed a trend toward longer overall survival (4.2 vs 1.2 months, p=0.06) compared to those not anticoagulated. 2
• Common pitfall to avoid: Do not withhold anticoagulation due to fear of hemorrhage progression—the thrombosis poses greater mortality risk. 1

Neurosurgical Intervention

Surgical resection should be strongly considered as first-line therapy for this solitary symptomatic hemorrhagic brain metastasis. 1

• Complete (R0) resection is the surgical goal, as incomplete resection fundamentally changes the treatment paradigm. 1
• Surgery provides immediate symptom relief, local disease control, and potential for long-term survival when followed by adjuvant immunotherapy. 1
• The hemorrhagic nature and symptomatic presentation (requiring oxygen, ECOG 2-3) make this an urgent neurosurgical indication. 1
• All decisions must be made in an interdisciplinary tumor board with neurosurgery, medical oncology, radiation oncology, and neuroradiology representation. 1

Post-Surgical Systemic Therapy

Following complete resection, initiate adjuvant anti-PD-1 monotherapy with nivolumab or pembrolizumab. 1, 3

• Anti-PD-1 monotherapy is the preferred approach based on guidelines, demonstrating superior efficacy compared to ipilimumab alone. 1, 3
• Checkpoint inhibitors can be safely used in patients with symptomatic brain metastases and hemorrhage. 1, 4
• Perform BRAF mutation testing on the resected tumor specimen immediately, as this will guide future treatment decisions if disease progresses. 1, 3

If BRAF-Mutated Disease

• For BRAF-mutated melanoma with ECOG 2-3, dabrafenib plus trametinib may be offered as it provides rapid response, which is critical in poor performance status patients. 3
• BRAF/MEK inhibitor combinations are options after immunotherapy failure. 1

If BRAF Wild-Type Disease

• Anti-PD-1 monotherapy (pembrolizumab or nivolumab) remains the standard first-line option. 3, 5
• Anti-PD-1 therapy is effective regardless of other mutation status (NRAS, c-KIT, or NF1 wild-type). 5

Prognosis and Performance Status Considerations

The ECOG performance status of 2-3 is a critical negative prognostic factor that substantially limits treatment options and expected survival. 6, 1, 7

• Performance status of 2 is associated with significantly shorter median overall survival (2.0 months). 7
• Good performance status (ECOG 0-1) is essential for aggressive treatment and improved outcomes. 1
• Solitary brain metastasis has better prognosis than multiple lesions, which is favorable in this case. 1
• Control of extracranial disease with systemic therapy is critical for overall survival. 1

Monitoring Requirements

Brain MRI should be performed every 3 months for the first 2 years, then every 6 months for years 3-5. 1

• Monitor closely for immune-related adverse events including colitis, hepatitis, pneumonitis, endocrinopathies, and severe infections. 1, 3
• Pembrolizumab and nivolumab significantly increase susceptibility to severe infections, particularly tuberculosis and bacterial infections. 5
• Monitor anticoagulation parameters according to FDA labeling: APTT should be 1.5 to 2 times normal, with periodic platelet counts, hematocrits, and tests for occult blood in stool. 8

Treatment Algorithm if Incomplete Resection or Progression

If Incomplete Resection

• Treat as disseminated disease with systemic therapy. 6
• Consider stereotactic radiosurgery for residual disease, as it is preferred over whole-brain radiotherapy. 1, 3

If Progression on Anti-PD-1 Monotherapy

Switch to ipilimumab plus nivolumab combination. 1, 3

• This combination produces a 21% response rate and 55% 12-month survival after anti-PD-1 monotherapy failure. 1, 3
• The combination is associated with significantly higher toxicity compared to monotherapy. 5

If Progression After Immunotherapy

• For BRAF-mutated melanoma, BRAF/MEK inhibitor combinations are options. 1
• If clinical trials are unavailable, cytotoxic chemotherapy options include dacarbazine, temozolomide, taxanes, fotemustine, or platinum derivatives. 5

Critical Management Pitfalls to Avoid

Do not delay neurosurgical consultation, as hemorrhagic brain metastases can deteriorate rapidly and require urgent intervention. 1

Do not use whole-brain radiotherapy as initial treatment, as it compromises neurocognitive function without survival benefit and should be reserved for multiple unresectable lesions. 1, 3

Do not discontinue anticoagulation based on the intracranial hemorrhage alone—the data support safety of continued anticoagulation in this population. 2

Palliative Care Considerations

Given the ECOG 2-3 status and stage IV disease with multiple life-threatening complications, concurrent palliative care consultation is appropriate. 6

• Best supportive care should be discussed as part of the treatment plan. 6
• Treatment at centers with extensive melanoma brain metastasis experience is strongly recommended. 1
• The median overall survival for patients with brain metastases receiving temozolomide is 3.6 months, and performance status of 2 is associated with 2.0 months median survival. 7