What is the best treatment approach for a patient with stage IV metastatic melanoma, a history of brain metastasis, pulmonary embolism, and cerebral venous sinus thrombosis, with an Eastern Cooperative Oncology Group (ECOG) performance status of 2-3, and not a candidate for surgery?

Treatment of Stage IV Metastatic Melanoma with Brain Metastasis, Thrombotic Complications, and Poor Performance Status (ECOG 2-3)

Given this patient's poor performance status (ECOG 2-3), history of brain metastasis with hemorrhage, and dual thrombotic complications (pulmonary embolism and cerebral venous sinus thrombosis), the priority is urgent neurosurgical evaluation for resection of the hemorrhagic brain metastasis, followed by anti-PD-1 immunotherapy (nivolumab or pembrolizumab), while continuing anticoagulation for the thrombotic complications. 1

Immediate Life-Threatening Priorities

The hemorrhagic brain metastasis requires urgent multidisciplinary neurosurgical evaluation for potential resection. 1 This takes precedence over systemic therapy because:

• Hemorrhagic brain metastases can deteriorate rapidly and require urgent intervention 2
• Surgical resection provides immediate symptom relief, local disease control, and potential for long-term survival when followed by adjuvant immunotherapy 1, 2
• Complete (R0) resection should be the surgical goal, as incomplete resection fundamentally changes the treatment paradigm 1, 2

Critical Anticoagulation Decision

Continue anticoagulation for the pulmonary embolism and cerebral venous sinus thrombosis despite the brain hemorrhage. 1 This recommendation is based on evidence that:

• Anticoagulation does not significantly increase intracranial hemorrhage risk in melanoma brain metastases 3
• The thrombotic burden poses greater mortality risk than the hemorrhage risk 1
• In a retrospective study of 74 melanoma patients with brain metastases and VTE, only 2 of 57 (4%) patients on anticoagulation developed intracranial hemorrhage, with no statistical difference compared to those not anticoagulated 3

Post-Surgical Systemic Therapy

Following complete resection, initiate adjuvant anti-PD-1 monotherapy with nivolumab or pembrolizumab. 1, 4, 2 This is the preferred approach because:

• Anti-PD-1 monotherapy demonstrates superior efficacy compared to ipilimumab alone 1, 4
• Checkpoint inhibitors can be safely used in patients with brain metastases and hemorrhage 2
• Nivolumab is administered at 240 mg IV every 2 weeks or 480 mg IV every 4 weeks 5

Perform BRAF mutation testing on the resected tumor specimen immediately. 1, 4, 2 This will guide future treatment decisions if disease progresses, as BRAF-mutated melanoma has additional targeted therapy options (dabrafenib/trametinib, vemurafenib/cobimetinib, or encorafenib/binimetinib) 4

Alternative Approach if Surgery Not Feasible

If neurosurgical resection is deemed not feasible due to location, patient instability, or other factors:

For BRAF-Mutated Melanoma with ECOG 2-3:

Consider BRAF/MEK inhibitor combination (dabrafenib plus trametinib) as first-line therapy. 6, 2 The rationale is:

• BRAF inhibitors provide rapid response, which is critical in poor performance status patients 2
• The 2013 Society for Immunotherapy of Cancer consensus recommends BRAF inhibitors for patients with BRAF-mutated melanoma with poor performance status and untreated CNS disease 6

For BRAF Wild-Type Melanoma:

Initiate anti-PD-1 monotherapy (nivolumab or pembrolizumab) with concurrent stereotactic radiosurgery for the brain metastasis. 4, 2 This approach is supported because:

• Anti-PD-1 therapy is the only recommended first-line option for BRAF wild-type melanoma 4
• Stereotactic radiosurgery is preferred over whole-brain radiotherapy as it preserves cognitive function 2, 6
• For asymptomatic brain metastases, systemic therapy can be initiated first with local therapy deferred until intracranial progression 2

Performance Status Considerations and Prognosis

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

• Good performance status (ECOG 0-1) is essential for aggressive treatment and improved outcomes 1, 6
• High-dose IL-2 is contraindicated in this patient due to poor performance status, as it requires ECOG 0-1 6
• The combination of stage IV disease, brain metastases, and ECOG 2-3 portends poor prognosis with median survival measured in months 6

Palliative Chemotherapy Options (If Immunotherapy Fails or Contraindicated)

If the patient is not a candidate for immunotherapy or progresses on anti-PD-1 therapy, palliative chemotherapy options include well-tolerated single agents: 6

• Dacarbazine (DTIC) - considered the reference drug for stage IV melanoma 6
• Taxanes (paclitaxel) 6
• Temozolomide 6
• Fotemustine 6

For aggressive metastatic disease, multi-agent polychemotherapy containing paclitaxel and carboplatin or cisplatin, vindesine and dacarbazine produces partial response and stabilizations in a meaningful number of patients. 6 However, the overall impact of systemic chemotherapy on survival in advanced melanoma patients is questionable 6

Palliative Radiotherapy

Palliative radiotherapy should be considered for symptomatic brain or localized and painful bone metastases. 6 Evidence shows:

• Radiation therapy achieves 39% symptom relief for CNS metastases and 68-84% for non-CNS metastases 6
• Brain metastases response rate is 54% 6
• Stereotactic radiosurgery is preferred over whole-brain radiotherapy for limited brain metastases 2, 6

Monitoring Requirements

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

Monitor closely for immune-related adverse events including: 1, 2, 5

• Colitis
• Hepatitis
• Pneumonitis
• Endocrinopathies
• Severe infections

The FDA label for nivolumab emphasizes that severe and fatal immune-mediated adverse reactions can occur 5

Second-Line Treatment Options if Disease Progresses

If progression occurs on anti-PD-1 monotherapy, switch to ipilimumab plus nivolumab combination. 4, 2 This yields:

• 21% overall response rate 4, 2
• 55% 12-month overall survival 4, 2
• Approximately 70% response rate for symptomatic, bulky, or rapidly progressive disease 4

For BRAF-mutated melanoma, BRAF/MEK inhibitor combinations are options after immunotherapy failure. 4, 2

Clinical trial enrollment should be strongly considered after immunotherapy failure. 4

Multidisciplinary Management Requirements

All decisions must be made in an interdisciplinary tumor board with neurosurgery, medical oncology, radiation oncology, and neuroradiology representation. 2 Stage IV melanoma patients need to be treated and discussed at centers with broad experience in this disease 6, 4, 2

Concurrent Palliative Care

Given the ECOG 2-3 status and stage IV disease with multiple life-threatening complications, concurrent palliative care consultation is appropriate. 1 Best supportive care should be discussed as part of the treatment plan 1

Common Pitfalls to Avoid

• Do not delay neurosurgical consultation - hemorrhagic brain metastases can deteriorate rapidly 2
• Do not withhold anticoagulation due to fear of hemorrhage - the thrombosis poses greater mortality risk 1, 3
• Do not use whole-brain radiotherapy as initial treatment - it compromises neurocognitive function without survival benefit and should be reserved for multiple unresectable lesions 2
• Do not discontinue heparin prophylaxis prematurely - 25% of VTE in stage IV melanoma are asymptomatic and 17 of 24 thrombotic events in one study occurred at home after stopping heparin prophylaxis 7