Surgery (Wide Excision)

A wide excision is the standard surgery for primary melanoma. Your surgeon will use a surgical knife to take out the tumor and a margin of normal skin around it. The margin of normal tissue depends on the thickness of the tumor. Thinner tumors require less of a margin, and may require stitches and leave a scar. Thicker tumors require a larger margin. Thicker tumors, and those located in areas of the body where there is insufficient skin to close together after wide excision may require repair with a local tissue flap or skin graft. Skin graft involves replacing the skin that was removed with healthy skin from a different part of the body. Your doctor will discuss the extent of normal skin to be removed and reconstructions options with you.

Sentinel Lymph Node Biopsy

This specialized lymph node biopsy is performed to find out whether the melanoma has spread to the lymph nodes. Surgeons are able to pinpoint which lymph nodes the melanoma is most likely to spread to first (called sentinel lymph nodes). The surgeon then removes these sentinel nodes then sends them to a pathologist for examination under a microscope to determine if they contain melanoma cells. If they do not, then the melanoma is much less likely to have spread to other lymph nodes or other areas of the body. The principal reason to consider sentinel lymph node biopsy is to get more information about the stage of the tumor, and the risk or recurrence after complete excision. For the most part, sentinel lymph node biopsy should be considered a staging test, with little, if any, impact on survival. Your doctor should discuss the pro’s and con’s of sentinel lymph node biopsy with you if your primary melanoma is over 0.8 mm thick, or has other features associated with an increased risk of metastasizing (i.e. primary tumor ulceration), and your regional lymph nodes are not enlarged.

Surgery (Lymph Node Dissection)

Lymph nodes in your body are arranged in groups, called basins. The lymph node basins that receive direct lymphatic drainage from the primary melanoma tumor are called regional lymph nodes. With melanoma, spread to the regional lymph nodes is the most common type of spread. The melanoma cells may be confined to the lymph nodes, and if so, removal of all the lymph nodes in a particular basin, may be curative. This type of surgery is called a lymph node dissection.

Surgery (distant sites)

When melanoma has spread to distant organ sites, surgery may be performed, particularly when the amount of disease is limited to only a few sites, it can be completely removed, and/or if it is causing symptoms such as pain or bleeding.

The intent of surgical resection of distant metastatic disease may be to remove all of the tumor, with the hope that it will not return ("curative intent"), or to remove less than all of the tumor with the goal or relieving some identifiable symptom ("palliative intent").  Generally, even with complete surgical removal of all distant metastatic disease, it is more likely than not that the tumor will return.  With the advent of newer systemic treatment options, including targeted therapy and immunotherapy, decisions about the appropriate integration of systemic therapy and surgery are quite complex, and are often discussed in multidisciplinary tumor conferences. You should discuss all of these concepts with your doctor.

Adjuvant Therapy

If your melanoma has been completely removed, and you are at risk for tumor recurrence, your doctor may talk to you about additional treatment after surgery. This type of treatment is called adjuvant therapy, and is used to try to prevent recurrence at distant sites and increase the chance for long-term survival or cure. While surgery can remove all of the known sites of disease, individual or small clusters of melanoma cells may have already escaped and spread to other sites before the surgery was performed, but not detected by you, your doctor, or x-rays. It is this microscopic spread of cells that can be the source of subsequent recurrence and what adjuvant therapy is intended to treat. The risk of microscopic spread is increased with more advanced stage disease. Your oncologist is more likely to recommend this type of treatment for Stage II and Stage III disease. Currently approved adjuvant therapy options for completely resected Stage III melanoma, include dabrafenib/trametinib, pembrolizumab, and nivilumab.  Pembrolizumab is also an approved adjuvant therapy option for completely resected Stage IIB or IIC melanoma. Each of these options is associated with a risk of significant side effects. Although each option has been shown to delay melanoma recurrence, the impact of these treatments on long-term cure is not well defined. These risks and benefits must be carefully discussed with each individual patient before a final decision is made. Additional adjuvant therapies are  are currently being evaluated in clinical trials.

Neoadjuvant Therapy

An emerging approach for the treatment of surgically resectable regionally metastatic disease (Stage III disease) is neoadjuvant therapy.  Neoadjuvant therapy refers to treatment that is given before a planned surgery.  One of the potential benefits of neoadjuvant therapy includes reducing the size of tumor or tumors to be resected, which can make surgery less complicated and lower the risk of side effects from the surgery.  Another potential benefit is that by using the systemic therapy before surgery, there is an opportunity to determine whether or not the treatment is working.  This information can help predict what the risk is of the cancer returning subsequently- and may help to inform decision-making about whether the same treatment should be given after surgery or if treatment should be changed.  Finally, both laboratory experiements and recent clinical trials have suggested that immunotherapies may be more effective if they are given both before (neoadjuvant) and after (adjuvant) surgery compared to giving them after surgery alone.  A number of neoadjuvant treatments are currently being evaluated in clinical trials.

Immunotherapy for Melanoma

Overview

• Immunotherapy stimulates the immune system to fight cancer cells.
• Commonly used for advanced-stage melanoma.
• Multiple types of immunotherapy drugs exist.

Immune Checkpoint Inhibitors

• Monoclonal antibodies target proteins (CTLA-4, PD-1, LAG-3) that prevent immune system activity.
• Blocking these proteins activates the immune system to attack melanoma cells.
• Long-lasting responses often occur after treatment stops.

Approved Single-Agent Drugs:

• Pembrolizumab (blocks PD-1).
• Nivolumab (blocks PD-1).
• Ipilimumab (blocks CTLA-4) – less effective and more side effects compared to PD-1 blockers.

Approved Combinations:

• Nivolumab (anti-PD-1) + Ipilimumab (anti-CTLA-4).
• Nivolumab + Relatlimab (anti-LAG-3).

Side Effects

• Side effects result from immune system attacks on normal organs.
• Managed with short-term immunosuppressants (e.g., steroids).
• Risks vary:
  • Lowest risk: Single-agent anti-PD-1 (nivolumab, pembrolizumab).
  • Highest risk: Nivolumab + Ipilimumab combination.
• Administered via intravenous infusion.

TVEC (Talimogene laherparepvec)

• Directly injected into accessible tumors.
• Primarily affects injected tumors, occasionally non-injected ones.
• Side effects:
  • Common: Injection site redness, tenderness.
  • Rare: Whole-body effects.

Uveal Melanoma and Tebentafusp

• Uveal melanoma responds poorly to immune checkpoint inhibitors.
• Tebentafusp approved for metastatic uveal melanoma.
  • Bi-specific antibody connects tumor cells and immune cells.
  • Requires HLA-A*02:01 genotype (blood test).
  • Not approved for other melanoma types.
• Ongoing clinical trials for new bispecific antibodies.

Adoptive Cell Transfer (ACT)

• Uses patient immune cells to fight tumors.
• Effective in some patients resistant to other therapies.
• Not yet FDA-approved but studied in clinical trials for over 20 years.

Key Considerations

• All immunotherapies can cause serious side effects.
• Treatments should only be administered by experienced medical teams.

Targeted Therapy

What is Targeted Therapy?

• Uses medications to block specific mutations in cancer cells.
• Requires genetic testing to identify mutations, typically performed on tumor tissue or occasionally a blood sample.

BRAF Mutations

• Found in 50% of cutaneous melanomas.
• Known as "BRAF V600" mutations, causing overactivity of the BRAF protein.
• Presence of this mutation predicts effectiveness of BRAF inhibitors.
• Combining BRAF inhibitors with MEK inhibitors improves results and reduces side effects.

Approved Therapies for BRAF Mutations

• Dabrafenib + Trametinib.
• Vemurafenib + Cobimetinib.
• Encorafenib + Binimetinib.

Administration

• All medications are taken as pills at home.

Side Effects

• Common but manageable with dose adjustments or treatment breaks ("holidays").

c-KIT Mutations

• Rare in most melanomas (~1%) but more common in:
• Acral melanomas (10-20%).
• Mucosal melanomas (20-30%).
• c-KIT inhibitors, like imatinib, are used when other treatments fail.

Uveal Melanomas

• Do not have BRAF or c-KIT mutations.
• ~80% have GNAQ or GNA11 mutations.
• Clinical trials for targeted therapies are ongoing.

Biochemotherapy

Biochemotherapy is a combination of chemotherapy and immunotherapy that can be used to treat advanced cases of melanoma. Combining these two treatments is associated with a higher response rate at the expense of significantly higher toxicity, and with no improvement in survival when compared to more standard chemotherapy options. This treatment is very uncommonly used.