What is the best treatment approach for a patient with stage III D melanoma (T4 N3 disease) after resection?

Adjuvant Treatment for Stage IIID Melanoma (T4 N3) After Resection

For patients with resected stage IIID melanoma (T4 N3 disease), adjuvant immunotherapy with either nivolumab or pembrolizumab for 52 weeks is the recommended treatment, with dabrafenib plus trametinib as an equally effective alternative if the tumor harbors a BRAF V600E/K mutation. 1, 2

Primary Treatment Algorithm

Step 1: Confirm BRAF Mutation Status

• Test for BRAF V600E/K mutations immediately to determine all available treatment options 1, 2
• Testing should be completed before initiating adjuvant therapy to avoid delays 2

Step 2: Select Adjuvant Therapy Based on BRAF Status

For BRAF Wild-Type Disease:

• Nivolumab 240 mg IV every 2 weeks OR 480 mg IV every 4 weeks for 52 weeks 1, 2
• Pembrolizumab 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks for 52 weeks 1, 2
• Both options demonstrate equivalent efficacy with 12-month recurrence-free survival of approximately 70-75% 3, 2

For BRAF V600E/K Mutant Disease (choose one):

• Nivolumab or pembrolizumab (same dosing as above) 1, 2
• Dabrafenib 150 mg PO twice daily plus trametinib 2 mg PO once daily for 52 weeks 1, 2
• All three options show similar 3-year recurrence-free survival rates around 60% 2

Step 3: Consider Adjuvant Radiation Therapy

• Strongly consider adjuvant radiation to the nodal basin for stage IIID disease with N3 involvement (≥4 positive nodes), as this represents high-risk nodal disease 1, 2
• Radiation is particularly important if there is macroscopic extranodal soft tissue extension or large nodes 1, 2

Critical Decision Points Between Treatment Options

Immunotherapy vs. Targeted Therapy for BRAF-Mutant Disease

Choose immunotherapy (nivolumab or pembrolizumab) when:

• Patient can tolerate potential immune-related adverse events 2
• Desire for durable long-term disease control beyond 12 months 2
• Patient has autoimmune disease history that is well-controlled (relative consideration) 4

Choose targeted therapy (dabrafenib plus trametinib) when:

• Rapid disease control is prioritized in the first 6-12 months 2
• Patient has significant autoimmune disease contraindications to immunotherapy 2
• Patient preference after discussing toxicity profiles 2

Toxicity Comparison

• Immunotherapy: Grade 3-4 adverse events occur in 14-29% of patients, with treatment discontinuation in 9-14% 3, 4
• Targeted therapy: Grade 3-4 adverse events occur in 35-45% of patients, predominantly pyrexia, rash, and liver dysfunction 5, 2

Timing Considerations

• Initiate adjuvant therapy within 13 weeks post-surgery, as this was the maximum allowed in pivotal trials 2
• Complete surgical resection with negative margins is mandatory before starting adjuvant therapy 2
• Ensure adequate recovery from surgery before initiating systemic therapy 2

Treatments NOT Recommended

Do NOT use the following for routine adjuvant therapy:

• High-dose ipilimumab monotherapy - inferior efficacy and significantly higher toxicity (45.9% grade 3-4 adverse events, 42.6% treatment discontinuation rate) compared to anti-PD-1 agents 1, 3
• High-dose interferon - inconsistent overall survival benefit and substantial toxicity 1
• Biochemotherapy - limited benefit restricted to recurrence-free survival without overall survival improvement, with excessive toxicity 1

Common Pitfalls to Avoid

• Do NOT delay BRAF testing - this creates unnecessary delays in treatment initiation and limits patient options 2
• Do NOT use BRAF/MEK inhibitors for non-V600E/K mutations - efficacy data are lacking for other BRAF mutations 1, 2
• Do NOT omit consideration of adjuvant radiation - stage IIID with N3 disease represents high-risk nodal disease where radiation significantly improves local control 1, 2
• Do NOT continue treatment beyond 52 weeks unless in the context of a clinical trial - standard duration is 12 months 1, 2

Monitoring During Adjuvant Therapy

For immunotherapy (nivolumab/pembrolizumab):

• Monitor for immune-related adverse events including colitis, hepatitis, pneumonitis, endocrinopathies (hypothyroidism, hyperthyroidism, adrenal insufficiency), and dermatologic toxicities 4, 2
• Baseline and periodic thyroid function tests, liver function tests, and assessment for respiratory symptoms 4
• Critical warning: Pembrolizumab significantly increases susceptibility to severe infections, particularly tuberculosis and bacterial infections 6

For targeted therapy (dabrafenib/trametinib):

• Monitor for pyrexia (most common adverse event), skin rash, liver dysfunction, and cardiac toxicity 5, 2
• Regular ophthalmologic examinations for retinal vein occlusion with trametinib 2

Expected Outcomes

• Stage IIID melanoma has a 5-year survival rate of approximately 30-40% without adjuvant therapy 7
• With modern adjuvant immunotherapy, 3-year recurrence-free survival approaches 60% 2, 8
• Despite adjuvant therapy, recurrence rates remain approximately 30-35% at median follow-up of 22 months in real-world studies 8

Management of Recurrence After Adjuvant Therapy

• Patients who relapse during or after adjuvant targeted therapy respond well to subsequent anti-PD-1 therapy with excellent response rates 2
• Oligometastatic recurrence (1-3 lesions) should be considered for surgical resection or stereotactic radiation combined with systemic therapy 2, 6
• Treat unresectable recurrence as metastatic disease with combination immunotherapy or targeted therapy depending on BRAF status 1, 2