Metastatic Melanoma Treatment Options

A Guide to Stage III and IV Melanoma Treatment

Like other cancers, melanoma is staged by severity. Staging cancer helps healthcare providers establish an appropriate treatment plan. Metastatic melanoma is when cancer has spread from its original location.

Stage III melanoma means cancer has spread to nearby lymph nodes or small areas of nearby skin cells. Stage IV is the most advanced stage—it is when cancer has metastasized, or spread from the skin to distant lymph nodes or to other organs in the body. Treatment at these stages is more complex than in earlier stages because it involves systemic (body-wide) therapies.

This article explains the various treatment options for stage III and IV melanoma.


Regardless of the stage of melanoma, the first step is surgical tumor removal. In stage III melanoma, this involves excision (removal) of the primary tumor and usually some lymph nodes.

Stage IV melanoma is more challenging to treat since it has already spread to distant lymph nodes or other organs. So, in addition to removing the original tumor, a surgeon may also remove lymph nodes and tumors on other organs.

Your surgeon may do a skin graft, which involves replacing the damaged skin with healthy skin, usually from elsewhere on your body.


Immunotherapy is a biologic therapy that stimulates your immune system to fight cancer. There are several types of immunotherapy used for melanoma, including immune checkpoint inhibitors, interleukin-2 (IL-2), and interferon (INF) therapy.

Immune Checkpoint Inhibitor Therapy

These drugs block proteins called checkpoints made by T cells and some cancer cells. When these checkpoints are blocked, T cells can more readily attack cancer cells. There are two types of immune checkpoint inhibitors:

  • CTLA-4 inhibitor therapy, including Yervoy (ipilimumab): A drug that binds to the CTLA-4 protein found on T cells, so they are better able to kill cancer cells
  • PD-1 and PD-L1 inhibitor therapy, including Opdivo (nivolumab), Keytruda (pembrolizumab), and Tecentriq (atezolizumab): Drugs that block the protein PD-1 from binding to PD-L1 (Opdivo and Keytruda) or block PD-L1 from binding to PD-1 (Tecentriq) to increase the ability of T-cells to kill cancer

Interleukin-2 (IL2)

Interleukin-2 (IL2) is a type of protein called a cytokine. Cytokines include many kinds of protein messengers. T lymphocytes (small white blood cells) make IL2.

IL2s boost the immune system—specifically lymphocytes—so that they can attack and destroy cancer cells.

Interferon (IFN)

Interferon-alpha2b (IFN) is another cytokine created by white blood cells (leukocytes) responding to a pathogen. Scientists make IFN treatments in a lab. IFN works by stimulating the immune system and attacking cancer cells.

Sometimes doctors combine IFN with chemotherapy or IL2, or all three together. Using IFN or IL2 can help some people with stage IV melanoma live longer. Higher doses of these drugs seem to be more effective, but they also have more severe side effects.

White blood cells make a cytokine called tumor necrosis factor (TNF) in response to exposure to a pathogen. TNF in melanoma treatment is lab-made. It boosts your immune system and can also cause necrosis (cell death) in some tumors.

Targeted Therapy

Targeted therapies attack cancer cells without harming regular cells (like some other standard cancer therapies, like chemotherapy and radiation, do). There are various targeted therapies used to treat melanoma.

Signal Transduction Inhibitor Therapy

Signal transduction inhibitor therapy blocks molecular signals inside a cell, which can help your body kill cancer cells. These are sometimes used in advanced-stage melanoma or if a doctor can’t surgically remove your tumor. These therapies include:

  • BRAF inhibitors, including Tafinlar (dabrafenib), Zelboraf (vemurafenib), and Braftovi (encorafenib): Drugs that block the protein made by mutant BRAF genes
  • MEK inhibitors, including Mekinst (trametinib), Cotellic (cobimetinib), and Mektovi (binimetinib): Drugs that block MEK1 and MEK2 proteins to stop the growth and survivability of cancer cells

Oncolytic Virus Therapy

Oncolytic virus therapy uses a virus to target and attack cancer cells but not normal cells. Talimogene laherparepvec is a therapeutic vaccine made with a herpes virus that scientists alter in the lab. Doctors inject these therapies directly into the tumor or lymph nodes.

Angiogenesis Inhibitors

Angiogenesis inhibitors block new blood vessel growth, stopping cancer cell growth by limiting the blood vessels cancer cells need to survive.

Sometimes doctors use a combination of targeted therapies and immunotherapies.

melanoma treatment with injection

Noctiluxx / Getty Images


Chemotherapy (chemo) is a specific medication used to kill cancer cells. Chemo is not typically the first-line treatment for melanoma because other therapies like immunotherapy and targeted drugs work better. Chemotherapy sometimes shrinks tumors; however, they often recur in advanced melanoma within a few months.

Chemo medications that treat melanoma include:

  • Carboplatin
  • Cisplatin
  • Dacarbazine (also called DTIC)
  • Nab-paclitaxel
  • Paclitaxel (Taxol)
  • Temozolomide

One type of chemo used with melanoma is isolated limb perfusion (ILP) and isolated limb infusion (ILI). This treatment involves injecting chemotherapy medication directly into the limb rather than throughout the entire body. A tourniquet stops blood flow and keeps the drug isolated.

Sometimes healthcare providers recommend biochemotherapy, a combination of chemotherapy and other drugs, like immunotherapies.

Radiation Therapy

Radiation therapy directs high-energy x-rays or other radiation toward the part of the body with cancer. Radiation kills cancer cells or stops them from growing.

Radiation may be used after surgery to lower the chance of cancer returning. In addition, doctors sometimes use radiation as palliative therapy—that means the purpose is more to relieve symptoms and improve quality of life than to cure the disease.

Clinical Trials

Since late-stage melanoma is difficult to treat with current therapies, you might want to discuss the prospect of clinical trials with your healthcare provider. Clinical trials of new chemotherapy drugs, new immunotherapy or vaccine therapy methods, and combinations of different types of treatments may be an option for some people.


Stage III and IV melanoma are more challenging to treat because cancer has spread to lymph nodes or other organs at these stages. That means treatment is more body-wide than localized. Treatments vary depending on your specific situation but may include surgery, immunotherapy, targeted therapy, chemotherapy, and radiation.

A Word From Verywell

Late-stage melanoma is an unnerving diagnosis, so if you’ve recently been diagnosed with stage III or IV melanoma, feeling scared is understandable. The good news is over the years, treatment has improved and become more effective. That means people diagnosed with melanoma today have a better outlook than ever before.

5 Sources
Verywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.
  1. National Cancer Institute. Melanoma treatment (PDQ)—health professional version.

  2. American Cancer Society. Treatment of melanoma skin cancer, by stage.

  3. American Cancer Society. Immunotherapy for melanoma skin cancer.

  4. Seth R, Messersmith H, Kaur V, et al. Systemic therapy for melanoma: ASCO guideline. J Clin Oncol. 2020;38(33):3947-3970. doi:10.1200/JCO.20.00198

  5. American Cancer Society. Chemotherapy for melanoma skin cancer.

By Timothy DiChiara, PhD
Timothy J. DiChiara, PhD, is a former research scientist and published writer specializing in oncology.