Melanoma - Surgical and Local Treatment

Treatment of Melanoma Introduction The treatment of melanoma is highly dependent on the disease stage and extent. For localized primary tumors, surgery is the foundation of care. For advanced disease, the treatment landscape has been transformed by immunotherapy and targeted agents. This section covers the key treatment modalities: surgical excision, lymph node management, and systemic therapies. Surgical Management of Primary Melanoma Wide local excision is the standard surgical treatment for primary cutaneous melanoma. The goal is to remove the tumor completely while preserving function and cosmetic appearance. The defining principle is that margin width should be tailored to the Breslow depth of the tumor. Margin Guidelines Based on Tumor Thickness For tumors with greater thickness (higher Breslow depth), wider surgical margins are required because deeper melanomas have a higher risk of harboring microscopic disease in the surrounding tissue. The standard recommendations are: Melanoma in situ and lentigo maligna: margins of 0.2–0.5 cm are sufficient Breslow depth < 1 mm: margins of 5–10 mm Breslow depth 1–2 mm: margins of 1 cm Breslow depth > 2 mm: margins of 1–2 cm The principle behind this approach is that thicker tumors have already demonstrated more aggressive behavior, and the risk of regional spread increases with depth. Therefore, more extensive surgical removal of surrounding tissue reduces the likelihood of leaving behind microscopic disease. <extrainfo> Mohs Micrographic Surgery is a specialized technique that uses histologic examination of tissue margins during surgery to guide complete tumor removal. It achieves cure rates greater than 95% for melanoma in situ and selected lentigo maligna cases. This technique is particularly useful on the face where margin-sparing is important for cosmetic and functional outcomes. </extrainfo> Lymph Node Management One of the most important recent shifts in melanoma treatment involves lymph node dissection. Historically, removing regional lymph nodes after the primary tumor was removed seemed logical—eliminating potential sites of disease spread. However, completion lymph node dissection does not improve overall survival and is associated with increased morbidity, including infection, seroma formation, and lymphedema. This finding is counterintuitive but demonstrates an important principle: removing lymph nodes that may contain microscopic disease does not translate into survival benefit. Current practice therefore reserves lymph node dissection for patients with clinically evident lymph node involvement (palpable or imaging-detected disease), not as a routine adjuvant procedure. For patients with clinically negative lymph nodes, sentinel lymph node biopsy may be considered in high-risk primary tumors to identify occult regional disease, which can guide staging and further treatment decisions—but this is distinct from therapeutic dissection. Systemic Therapies for Metastatic and High-Risk Disease The treatment of advanced melanoma has been revolutionized by the development of immunotherapy and targeted therapies. The choice of therapy depends on disease stage, BRAF mutation status, and other clinical factors. Immune Checkpoint Inhibitors Checkpoint inhibitors are the most important class of immunotherapy for melanoma. These drugs work by blocking proteins that normally suppress the immune system, thereby unleashing T cells to attack melanoma cells. PD-1 inhibitors (nivolumab and pembrolizumab) target the programmed cell death-1 pathway. These are used for advanced and metastatic disease and have become standard adjuvant therapy for high-risk resected melanoma. CTLA-4 inhibitors (ipilimumab) block cytotoxic T-lymphocyte-associated antigen 4, another immune checkpoint. While effective, CTLA-4 inhibition is often associated with more immune-related adverse events. Combination checkpoint inhibition (nivolumab plus ipilimumab) produces higher response rates than either agent alone in metastatic disease, though with increased toxicity. Recently, nivolumab combined with relatlimab (a LAG-3-targeting antibody) received FDA approval for unresectable or metastatic melanoma. This represents a next-generation checkpoint inhibitor combination targeting additional immune pathways. Targeted Therapy for BRAF-Mutant Melanoma Approximately 50% of melanomas harbor mutations in the BRAF gene, which encodes a protein in the mitogen-activated protein kinase (MAPK) signaling pathway. For patients with BRAF-mutant tumors, targeted therapy offers an alternative to immunotherapy. BRAF inhibitors (vemurafenib and dabrafenib) directly inhibit the mutant BRAF protein. However, resistance develops relatively quickly when BRAF inhibitors are used alone. The solution is combination therapy with MEK inhibitors (trametinib and cobimetinib), which target a downstream effector of BRAF. This combination approach significantly improves response rates and progression-free survival compared to BRAF inhibition alone. Key distinction: Targeted therapy provides rapid response rates but may have shorter duration of response compared to immunotherapy. Many oncologists use targeted therapy for rapid tumor burden reduction and immunotherapy for durable long-term control, sometimes sequencing them strategically. <extrainfo> High-dose interferon-α2b was historically used as adjuvant therapy for high-risk melanoma but provides only modest survival benefits and is associated with significant toxicity (fever, fatigue, and rarely, serious autoimmune complications). It has been largely replaced by checkpoint inhibitors. Adoptive cell transfer using expanded tumor-infiltrating lymphocytes is an emerging therapy that can produce durable complete responses in selected patients, but it is more resource-intensive and not yet standard care. </extrainfo> Adjuvant Therapy for High-Risk Resected Melanoma Patients who have had their primary melanoma surgically removed but face high risk of recurrence may benefit from adjuvant systemic therapy given for up to one year following surgery. Immune checkpoint inhibitors (primarily PD-1 inhibitors) are now the most common adjuvant regimen. These are indicated for stage III (regionally involved) and select stage IIIB/IIIC patients. The rationale is that adjuvant immunotherapy can eliminate micrometastatic disease before it becomes clinically evident, reducing recurrence risk. Targeted therapy with BRAF and MEK inhibitors is also used as adjuvant therapy for BRAF-mutant high-risk melanomas, providing an alternative for patients who cannot tolerate or do not respond to immunotherapy. The decision to use adjuvant therapy must balance the reduction in recurrence risk against treatment toxicity. This is individualized based on specific features of the primary tumor and patient factors. Radiation Therapy <extrainfo> Radiation therapy plays a limited but specific role in melanoma management. Post-surgical radiation is employed for locally or regionally advanced melanoma (stage III disease) and can reduce local recurrence rates in the operative bed or regional lymph node basin. However, radiation does not extend overall survival. Radiotherapy for palliation is used to treat symptomatic metastatic melanoma, such as bone or brain metastases causing pain or neurologic symptoms. The goal is symptom relief rather than cure. Because melanoma is considered relatively radioresistant compared to other cancers, higher doses per fraction are sometimes used, though clinical evidence for this approach is evolving. </extrainfo>