Melanomas are the most aggressive type of skin cancer. Most melanomas are found at an early stage when they are highly treatable and curable. About 84 percent of cutaneous melanomas are found at a localized stage, where the five-year relative survival rate is 98 percent. Patients whose melanoma has spread to regional lymph nodes, or stage III melanoma, have a five-year relative survival rate of about 62 percent. Patients whose melanoma is unstaged at diagnosis, the five-year relative survival rate is about 76 percent. And patients who havemetastatic disease, or stage IV melanoma, have a five-year relative survival rate of about 16 percent. 

While most melanomas occur on the outer part of the skin, about 7 percent of primary melanomas are noncutaneous. Noncutaneous melanomas develop most often in the eye and mucous membranous areas of the body such as the anus, rectum, vulva, vagina, nasal sinuses, and mouth. Such melanomas havepoorer prognoses compared to cutaneous melanomas.

Noncutaneous melanomas often go undetected until they develop into an advanced stage. This is because they are usuallyhidden deep within the eye or in mucosa, where they cause no early symptoms. Noncutanous melanomas spread more quickly than cutaneous melanomas because these areas of the body give the cancer access to rich lymphatic and/or vascularenvironments. Additionally, the genetic differences between cutaneous and noncutaneous melanomas cause them to have different biological behaviors and to respond differently to treatment.

Cutaneous melanomas can also differ depending on where on the skin they occur and the severity of sun damage to the skin. The invasiveness of cutaneous melanomas may vary according to histological subtype. Nodular melanomas are more invasive and more aggressive compared to superficial melanomas that spread such as lentigo and acral lentiginous melanomas.

The current treatment for metastatic melanoma is chemotherapywith dacarbazine. This has been shown to shrink melanoma tumors in only 10 to 15 percent of patients. However, chemotherapy resistance usually eventually develops and the effectiveness of chemotherapy does not often last longer than a few months. 

High-dose bolus IL-2, or interleukin-2, is an immunomodulatoryagent that works by stimulating the immune system to attackcancer cells. IL-2 has been proven to reduce melanoma tumors similar to those with dacarbazine. However, about half of the patients who respond to IL-2 go into remission for more than tenyears. Most patients who go into remission for more than ten years remain cancer free for the rest of their lives. 

IL-2 also happens to be one of the most toxic treatments for cancer. Side effects are brutal and can even be life-threatening. Therefore, high-dose IL-2 treatment requires patients to be hospitalized with cardiac monitoring or specialized intensive care. IL-2 treatment is only recommended for patients who are in very good health otherwise. Regardless of the potential side effects and precautions using IL-2, the treatment has a 1 to 2 percent mortality rate.

Unfortunately, the treatments that have been approved by the FDA have limited survival benefits. Therefore, most experts believe that clinical trials are the best option for patients with metastatic melanoma. However, the progress in clinical trials has been gradual. There have been some promising approachesthat have failed and there have also been only a few large, randomized trials due to the fact that metastatic melanoma is pretty uncommon. Regardless, researchers are working to develop a successful treatment for metastatic melanoma. 

Clinical trials are being done to test experimental agents that target the mutant BRAF protein in patients with melanoma. PLX4032, which is an oral medication that inhibits the most common BRAF mutation, received responses in more than 80 percent of patients with stage IV or unresectable stage III melanoma. The results supported the specificity of PLX4032 for the mutant BRAF protein because no patients who had a normal BRAF gene responded to it. 

Another clinical trial which is an immune-based approach, adaptive T cell therapy. This type of treatment involves harvesting T cells from the patient’s tumor. The T cells are multiplied and then are transfused back into the patient. While the T cells specifically target the tumor, there are not enough of them nor are they strong enough to completely get rid of it.Patients are given chemotherapy to exhaust the T cells before the tumor-specific T cells’ are transfused back into them. They are also given high-dose IL-2 to stimulate T cell growth after the T cells’ are transfused back into the cells. This is done in order to help the tumor-specific T cells multiply in the blood. So far, about 50 percent of patients with metastatic melanoma have had a clinical response to this type of treatment.