Metastatic Melanoma

Metastatic melanoma is a cancer that starts in the cells capable of producing a colored pigment called melanin and then has spread beyond its original skin location. It may already be present at the time of the primary or initial diagnosis of the melanoma, or may show up later after surgery has been performed. Metastatic melanoma may spread through the bloodstream or the lymph system.

When melanoma spreads through the bloodstream, the signs and symptoms will depend upon which organ system is involved and how much the tumor has grown there. Metastatic melanoma may be initially painless and symptom-free or may demonstrate ongoing problems according to the site. With lymphatic spread, swollen lymph glands or a string of nodules in the skin may be the presentation. These also are usually painless.

Tumor metastasis into the liver may cause weight loss, nausea, a swollen liver, and abnormal blood tests. Tumor in lymph nodes may cause swelling of the extremities and enlarged glands. Tumor in the lungs may cause shortness of breath, cough, and bloody sputum. Tumor in the brain may cause headaches, dizziness, and seizures. Tumor in bone may cause bone pain or unusual fractures.

Melanoma may spread to other areas of the skin and may be bluish-gray or flesh-colored nodules depending upon the amount of melanin in the tumor and depth in the skin. In staging melanoma, stage 3 is defined as local spread through lymphatic drainage (sentinel node biopsy helps with staging here), and stage 4 is defined as distant spread (metastasis) to other organs, presumably by spread through the bloodstream.

Ideally, melanoma is diagnosed and treated surgically while it is still small and thin and before it has had the chance to metastasize. The prognosis and survivability of metastatic melanoma remain poor compared to other types of cancer. Metastatic melanoma is less responsive to radiation therapy and traditional forms of chemotherapy than other forms of cancer.

Immunotherapy in which the body's own immune system is used to fight the tumor has been a focus of research for decades and immune system "stimulants" such as interferon-alpha and interleukin-2 have also been tried for many years.

A variety of newer medications target different points in the biologic pathways of melanoma growth and spread. The following are drugs currently in use, or being actively investigated. More should be available shortly.

• Inhibition of kinase enzymes needed in cell reproduction like MEK: cobimetinib (Cotellic), trametinib (Mekinist)
• Target cell growth signals from abnormal BRAF genes: dabrafenib (Tafinlar), vemurafenib (Zelboraf), nivolumab (Opdivo)
• Improve immune response to the tumor: pembrolizumab (Keytruda), ipilimumab (Yervoy)

As monotherapy (used by themselves), these drugs have not been shown to dramatically improve survival even if they did improve disease-free time. The hope is that combinations of medications targeting more than one part of the melanoma growth and metastasis pathway will provide more encouraging results.

All these medications have significant side effects, including life-threatening ones, and are indicated only for stage 3 tumors to try to prevent recurrence and spread, and stage 4 metastatic tumors which are no longer amenable to surgery.

The prognosis for thin melanomas completely removed by surgery remains quite good although patients require long-term monitoring to watch for both new melanomas as well as evidence of late recurrence and previously undiagnosed metastasis of the original one. Survival rates for melanoma, especially for metastatic melanoma, vary widely according to many factors, including the patient's age, overall health, location of the tumor, particular findings on the examination of the biopsy, and the depth and stage. Survival statistics are generally based on five-year survival. Much of the success reported for the targeted therapies focus on "disease free" time because, in many cases, the actual five-year survival is not affected. It is hoped that combination therapy with two or more agents targeting different stages of the melanoma cell cycle will change that.

• For stage 1 (thin melanoma, local only), five-year survival is near 100%.
• For stage 2 (thicker melanoma, local only), five-year survival is 80%-90%. (The reason for reduced survival rate is that even if the primary skin tumor has been completely removed, it had already metastasized by the time surgery was performed.)
• For stage 3 (local and nodal metastasis), five-year survival is around 50%.
• For stage 4 (distant metastasis), five-year survival is 10%-25% depending upon sex and other demographic factors.