What are the treatment options for melanoma?

Treatment Options for Melanoma

The treatment of melanoma depends on the stage of disease, with surgical excision as the primary approach for early stages, while advanced melanoma requires systemic therapies including immunotherapy (anti-PD-1 antibodies, ipilimumab) and targeted therapy (BRAF/MEK inhibitors) for patients with BRAF mutations. 1

Diagnosis and Staging

• Diagnosis should be based on a full-thickness excisional biopsy with a small side margin 1
• The histology report should include melanoma type, actinic damage, maximum thickness in millimeters (Breslow), mitotic rate, presence of ulceration, regression, and surgical margin clearance 1
• Mutation testing for actionable mutations (particularly BRAF) is mandatory in patients with resectable or unresectable stage III or IV and highly recommended in high-risk stage IIC disease 1
• Physical examination should focus on suspicious pigmented lesions, tumor satellites, in-transit metastases, regional lymph nodes, and distant metastases 1
• In higher tumor stages, ultrasound, CT, and/or PET scans are recommended for proper tumor assessment 1

Treatment of Localized Disease (Stages 0-II)

• Wide local excision of primary tumors with safety margins of:

  • 0.5 cm for in situ melanomas 1
  • 1 cm for tumors with thickness up to 2 mm 1
  • 2 cm for thicker tumors 1

• Sentinel lymph node biopsy (SNB) is recommended for all patients with pT1b or higher according to the AJCC 8th edition TNM staging system 1

• For stage IIB-C melanoma, adjuvant anti-PD-1 therapy with nivolumab or pembrolizumab significantly improves recurrence-free survival 2

Treatment of Regional Disease (Stage III)

• Complete lymph node dissection (CLND) is not recommended for sentinel node-positive patients but is indicated for clinically detectable lymph node metastases 1

• Adjuvant therapy options for resected stage III melanoma:

  • Anti-PD-1 therapy: nivolumab or pembrolizumab 1
  • For BRAF-mutated melanoma: dabrafenib/trametinib combination 1

• Adjuvant radiotherapy for local tumor control can be considered in cases of inadequate resection margins, R1 resections, or after resection of bulky disease 1

Treatment of Advanced/Metastatic Disease (Stage IV)

• Surgical removal or stereotactic irradiation of locoregional recurrence or single distant metastasis should be considered in fit patients 1

• All patients with metastatic melanoma should be tested for BRAF V600 mutation 1

• First-line systemic therapy options:

  • PD-1 blockade (pembrolizumab, nivolumab) or PD-1 and ipilimumab combination is standard of care for all patients regardless of BRAF status 1, 3
  • For BRAF-mutated melanoma: BRAF/MEK inhibitor combinations (dabrafenib/trametinib, encorafenib/binimetinib, or vemurafenib/cobimetinib) 1

• For unresectable stage IIIB/C, IVM1a, talimogene laherparepvec (T-VEC) is also an option 1

• Second-line options:

  • For BRAF wild-type disease: if first-line was anti-PD-1 alone, ipilimumab or ipilimumab/nivolumab combination 1
  • For BRAF-mutated disease: all options available for wild-type melanoma plus BRAF/MEK inhibitors if not used in first-line 1

• For NRAS-mutated melanoma: first-line immunotherapy options identical to those of wild-type melanoma 1

• If clinical trials or approved compounds are not available, cytotoxic drugs such as dacarbazine or temozolomide may be administered, with modest activity 1

Management of Brain Metastases

• Ipilimumab/nivolumab combination therapy is the preferred first-line treatment, even in BRAF-mutated asymptomatic patients 1

• For patients with a small number of asymptomatic metastases (<5-10), non-bulky disease (<3 cm), stereotactic radiosurgery (SRS) upfront is an option 1

• Other patients should receive systemic treatment first, keeping SRS for non-responding lesions 1

Special Considerations for Specific Melanoma Types

• Lentigo maligna melanoma (LMM) on the face has a higher risk of recurrence compared to other in situ melanomas 4

• For facial LMM, careful assessment of margins is critical due to the "field effect" where atypical melanocytes extend laterally but are not clinically detectable 4

Follow-up Recommendations

• Melanoma patients should be instructed in:

  • Avoidance of sunburns and extended unprotected solar or artificial UV exposure 1
  • Lifelong regular self-examinations of the skin and peripheral lymph nodes 1
  • Awareness that family members have an increased melanoma risk 1

• There is no consensus on optimal follow-up schedule or frequency of imaging and blood tests 1

• Sentinel node-positive patients should be followed by regular ultrasound examinations 1

• Rising levels of serum S100 protein is the most accurate blood test in melanoma follow-up, if any blood test is recommended at all 1

Treatment Efficacy and Survival

• In metastatic melanoma, the combination of ipilimumab and nivolumab has shown significant improvement in overall survival compared to ipilimumab alone (hazard ratio 0.55,95% CI: 0.44-0.69) 3

• In 2024, patients with distant metastatic or unresectable melanoma treated with ipilimumab and nivolumab had a 10-year overall survival rate of 43% 2