What is the best initial treatment for a patient with metastatic melanoma confined to two right axillary lymph nodes?

Treatment of Metastatic Melanoma in Two Right Axillary Lymph Nodes

Complete surgical resection via axillary lymph node dissection (levels I-III) is the primary treatment, followed by adjuvant anti-PD-1 immunotherapy (nivolumab or pembrolizumab) to reduce recurrence risk and improve survival. 1, 2

Initial Diagnostic and Staging Workup

Before proceeding with definitive treatment, confirm the diagnosis pathologically and complete comprehensive staging:

• Obtain tissue confirmation via fine needle aspiration (preferred) or core biopsy of the axillary nodes 1
• Perform baseline imaging with CT chest/abdomen/pelvis and brain MRI to exclude distant metastases and confirm disease is truly limited to regional nodes 1, 2
• Test for BRAF V600 mutation status on the metastatic tissue, as this guides adjuvant therapy selection 2

This staging is critical because the treatment algorithm differs dramatically between isolated regional nodal disease (Stage III) versus systemic metastatic disease (Stage IV). 2

Surgical Management: Complete Axillary Lymph Node Dissection

For resectable disease confined to two axillary nodes, complete lymph node dissection (CLND) is the standard of care:

• Perform levels I-III axillary dissection rather than removing only the involved nodes, as level III nodes are positive in approximately 17% of patients with palpable axillary disease 3
• The goal is R0 resection (complete removal with negative margins) 2
• Surgery should be performed by an experienced surgical team at a center with melanoma expertise 1, 4

The rationale for complete dissection rather than observation stems from the fact that this represents clinically apparent nodal disease (not just sentinel node positivity). While the MSLT-2 trial showed no survival benefit of immediate CLND after positive sentinel node biopsy, that trial specifically excluded patients with palpable or clinically apparent disease. 5 Your scenario with two identifiable axillary nodes likely represents more advanced Stage III disease where complete surgical clearance provides both therapeutic benefit and accurate staging information. 4, 3

Common surgical pitfall: Incomplete dissection (levels I-II only) misses level III disease in nearly 1 in 6 patients with palpable nodes and provides inadequate prognostic information. 3

Adjuvant Systemic Therapy After Complete Resection

Following complete surgical resection, initiate adjuvant immunotherapy within 13 weeks of surgery:

For BRAF Wild-Type Disease:

• Anti-PD-1 monotherapy is the preferred adjuvant treatment 2
• Nivolumab 240 mg IV every 2 weeks or 480 mg IV every 4 weeks for up to 1 year, OR
• Pembrolizumab 200 mg IV every 3 weeks for up to 1 year 2

For BRAF V600 Mutation-Positive Disease:

• Either anti-PD-1 monotherapy (as above) OR combination BRAF/MEK inhibitor therapy (dabrafenib/trametinib, vemurafenib/cobimetinib, or encorafenib/binimetinib) 2
• The choice depends on patient tolerance for toxicity and preference, as both approaches improve recurrence-free survival 6

Critical point: Adjuvant interferon-alfa is now obsolete and should NOT be used, as it has been replaced by anti-PD-1 therapy which demonstrates superior efficacy with better tolerability. 6, 2 The 2016 NCCN guidelines mentioning interferon 1 are outdated—current 2023-2025 evidence strongly favors checkpoint inhibitors. 2

What NOT to Do: Outdated Approaches

Avoid these historically used but now-discredited treatments:

• Do NOT use adjuvant chemotherapy (dacarbazine, temozolomide)—it provides no survival benefit 6, 2
• Do NOT use adjuvant hormone therapy—it has demonstrated no survival advantage 6
• Do NOT use high-dose interferon-alfa—it has inconsistent results, considerable toxicity, and has been superseded by checkpoint inhibitors 6, 2
• Do NOT perform routine adjuvant radiotherapy after complete resection with negative margins 6

Exception for radiotherapy: Consider adjuvant RT to the axillary basin only if there are high-risk features such as ≥2 involved nodes AND/OR ≥4 cm tumor within a node AND/OR extranodal extension. 1 However, this does not improve overall survival and must be weighed against toxicity. 1

Monitoring for Treatment-Related Toxicity

During adjuvant immunotherapy, monitor closely for immune-related adverse events:

• Colitis, hepatitis, pneumonitis, endocrinopathies (thyroid, adrenal, pituitary), and dermatologic toxicities are the most common 2
• Increased susceptibility to severe infections, particularly tuberculosis and bacterial infections 2
• Baseline and periodic monitoring of liver function, thyroid function, and pulmonary symptoms is essential 2

Follow-Up Strategy

After completing treatment, implement risk-appropriate surveillance:

• History and physical examination every 3-6 months for 2 years, then every 3-12 months for 3 years, then annually 1
• Consider CT and/or PET/CT scans every 6-12 months to screen for recurrent/metastatic disease (category 2B recommendation) 1
• Consider brain MRI annually given the propensity for melanoma to metastasize to the CNS 1
• Educate the patient on monthly self-examination of skin and lymph nodes 1

If Disease is Unresectable or Systemic at Presentation

If staging reveals distant metastases (Stage IV) or the axillary disease is unresectable:

• First-line treatment is systemic therapy, NOT surgery 2, 7
• Anti-PD-1 monotherapy (nivolumab or pembrolizumab) is preferred for most patients 2, 7
• Combination nivolumab plus ipilimumab offers higher response rates but significantly increased toxicity—reserve for carefully selected patients 2, 7
• For BRAF V600-mutated disease with symptomatic, bulky metastases, combination BRAF/MEK inhibitor therapy is a valid first-line option due to rapid response rates 2

Surgical resection can still be considered for isolated, resectable metastases in good performance status patients, followed by adjuvant immunotherapy. 2, 8