What is the best treatment approach for a 55-year-old female with Stage 3 melanoma of the right submandibular mass?

Treatment of Stage 3 Melanoma with Right Submandibular Mass in a 55-Year-Old Female

For this 55-year-old female with Stage III melanoma involving the right submandibular region, the optimal treatment consists of complete surgical resection (wide excision of primary if present plus complete lymph node dissection of the submandibular/cervical basin) followed by adjuvant immunotherapy with either nivolumab or pembrolizumab for 52 weeks, with adjuvant radiation therapy strongly considered given the head and neck location. 1

Surgical Management

Complete lymph node dissection of the involved nodal basin is the standard surgical approach for clinically positive (palpable or imaging-detected) Stage III melanoma. 2

• The submandibular mass represents regional lymph node metastasis, classifying this as Stage III disease requiring therapeutic lymph node dissection 3
• If a primary melanoma site is identified on the head/neck, perform wide excision with 1 cm clinical margins (conservative approach acceptable in Stage III context to facilitate primary closure and avoid complex reconstruction) 2
• Facial nerve preservation should be attempted unless the nerve is grossly involved or preoperative dysfunction exists 3
• Complete surgical resection is mandatory before initiating any adjuvant therapy 1

Important Surgical Consideration

• Recent trials (MSLT-2, DeCOG-SLT) showed no survival benefit for completion lymph node dissection in sentinel node-positive disease, but these findings do not apply to clinically positive (palpable/imaging-detected) nodes like this submandibular mass 2, 4, 5
• For clinically detected nodal disease, complete lymph node dissection remains standard of care 2

Adjuvant Radiation Therapy

Adjuvant radiation therapy to the cervical/submandibular nodal basin should be strongly considered in this case. 2, 1

• RT is recommended for high-risk features including: multiple positive nodes, large nodes, or macroscopic extranodal extension 2
• The head and neck location has a lower threshold for using adjuvant RT compared to other anatomic sites 1
• RT should be administered regardless of whether adjuvant systemic therapy is given 2

Adjuvant Systemic Therapy

Adjuvant immunotherapy with anti-PD-1 agents (nivolumab or pembrolizumab) for 52 weeks is the preferred treatment approach. 1, 6

First-Line Options (in order of preference):

1. Nivolumab 240 mg IV every 2 weeks OR 480 mg IV every 4 weeks for 52 weeks 1, 6, 7

   • CheckMate 238 demonstrated 12-month recurrence-free survival of 70.5% vs 60.8% with ipilimumab (HR 0.65, P<0.001) 6
   • Grade 3-4 adverse events occur in only 14.4% of patients (vs 45.9% with ipilimumab) 6

2. Pembrolizumab 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks for 52 weeks 1, 6, 8

   • KEYNOTE-054 showed 12-month recurrence-free survival of 75% vs 61% for placebo (HR 0.57, P<0.001) 6
   • Discontinuation due to adverse events occurred in 14% of patients 8

3. For BRAF V600E/K mutant disease only: Dabrafenib 150 mg PO twice daily plus trametinib 2 mg PO once daily for 52 weeks 1, 6

   • Equivalent efficacy to immunotherapy in BRAF-mutant disease 1
   • Provides faster disease control in first 6-12 months but requires BRAF V600E/K mutation 1

Critical Pre-Treatment Requirements

• BRAF mutation testing is mandatory to determine eligibility for targeted therapy 2, 1, 6
• PD-L1 testing is NOT required as benefit occurs regardless of PD-L1 status 6
• Adjuvant therapy should begin within 13 weeks post-surgery (maximum allowed in pivotal trials) 1

Baseline Staging Workup

Complete staging evaluation before treatment decisions: 2, 3

• Chest/abdomen/pelvic CT scan 2
• Brain MRI with contrast (optimal for head/neck melanoma assessment) 3
• Consider PET scan 2
• Serum LDH (independent predictor of poor outcome) 3
• Complete skin examination of entire head/neck/scalp, conjunctivae, and oral mucosa to identify potential primary site 3

Treatments NOT Recommended

The following should NOT be used: 1, 6

• High-dose interferon alfa-2b (inferior efficacy and higher toxicity compared to anti-PD-1 agents) 1, 6
• Ipilimumab monotherapy (45.9% grade 3-4 adverse events vs 14.4% with nivolumab, with inferior efficacy) 6
• Pegylated interferon (only modest benefit in low tumor burden N1a disease, not applicable here) 2
• BRAF/MEK inhibitors for non-V600E/K mutations (no efficacy data) 1

Expected Outcomes

• Stage III melanoma has 5-year survival rates ranging from 30-70% depending on nodal tumor burden 2
• With modern adjuvant immunotherapy, 3-year recurrence-free survival approaches 60% 1
• Multiple positive nodes or extranodal extension confers worse prognosis, reinforcing need for adjuvant RT 2

Common Pitfalls to Avoid

• Do NOT delay adjuvant therapy beyond 13 weeks post-surgery 1
• Do NOT use BRAF/MEK inhibitors without confirmed V600E/K mutation 1
• Do NOT omit radiation therapy consideration in head/neck Stage III disease with high-risk features 1
• Do NOT use observation alone in this clinically node-positive patient - adjuvant therapy substantially improves outcomes 1, 6
• Do NOT assume sentinel node trial data applies to clinically positive nodes - complete dissection remains standard for palpable disease 2, 4