For many years, the primary treatment for melanoma was surgery and a type of immunotherapy called interferon. According to the Melanoma Research Alliance, interferon works by stimulating the body’s immune system to kill any cancer cells that may have spread beyond the original tumor. John M. Kirkwood, M.D., professor of medicine, and director of the Melanoma Program at the University of Pittsburgh Medical Center’s Hillman Cancer Center, says a year of interferon treatment could reduce a patient’s relapse rate by 25-33 percent.
New research, however, has uncovered two types of novel agents that have revolutionized melanoma treatment. These new medications are considered adjuvant treatments, meaning they are used in addition to surgical tumor removal. They fall into two categories — immunotherapy and targeted therapy.
“We never used to talk about cures,” said Jeffrey S. Weber, M.D., deputy director of the Laura and Isaac Perlmutter Cancer Center at NYU Langone Health, and professor of medicine at the NYU School of Medicine in a phone call with HealthCentral. “Now we actually mention the ‘C word.’ We talk about long-term follow-up plans for metastatic patients. And now these same drugs are applied to adjuvant therapy. There’s a common pattern of research that says, if something works in metastatic disease … wouldn’t it work after surgery in the face of a high-risk of recurrence? The answer is, yeah.”
The immune system’s T cells are supposed to find abnormal cells, like cancer cells, throughout the body and kill them. But how do they know if a cell is a normal cell for blood, hair, or skin, or an abnormal cell that needs to be destroyed? One way is with ‘checkpoints.’ The American Cancer Society defines checkpoints as proteins on T cells that need to be turned on to create the immune response. Melanoma cells can trick these checkpoints and avoid being attacked.
A new class of immunotherapy drugs, called PD-1 inhibitors or CTLA-4 inhibitors, help turn these T-cell checkpoints on so they are ready to recognize and attack melanoma cells. According to the University of Pittsburgh's Dr. Kirkwood, these medications can lead to a 50 percent reduction in relapse rate.
The short-term side effects include fatigue, diarrhea, itching, and skin rashes. In some cases, because the cautionary measures have been taken off the patient’s immune system, these cells can have a hard time distinguishing between abnormal and the normal cells and may attack healthy tissue in the lungs, liver, intestines, or other organs.
“The side effects of the checkpoint blockade are very well known because these have become the agents du jour for many solid tumors and hematologic malignancies,” Kirkwood told HealthCentral in a phone interview. “The side effects are predominantly autoimmune toxicities that don’t happen quickly, but when they happen, they happen with durability that can compromise quality of life for a longer period of time.”
Targeted treatments, on the other hand, work in a different way. About half of all melanomas have a mutation in the BRAF gene. Cells with this mutation make an altered protein that helps them reproduce rapidly. These new drugs target the BRAF or the related MEK protein to slow or stop tumor growth and, according to Dr. Kirkwood, have been shown to reduce recurrence rate by over 50 percent.
Side effects can include skin thickening, rash, itching, headache, fever and joint pain, hair loss, and nausea.
“The BRAF and MEK toxicities are much more acute,” Dr. Kirkwood said. “They happen within days to weeks and when [a patient] stops those treatments they usually abate pretty predictably and pretty completely.”
What's in the future?
What does this mean for melanoma patients today and in the future?
The first step in evaluating and treating a patient today, according to Dr. Kirkwood, is to test the tumor’s BRAF mutation status to find out if the patient is a candidate for targeted therapy.
As for the future, NYU's Dr. Weber points to the hundreds of trials currently testing various drug combinations.
“I think the future of treatment is going to be all new combinations where you’ll have customized or personalized immunotherapy,” Weber said. “So we’ll figure out which bio markers to use and a patient will come in and you’ll get a blood test and a tumor biopsy and the doctor will say, ‘Oh, you should get this — it’s your best regimen.’ I think that era will be here by the time I retire in 10 years. That means we will be curing a significant majority, about 80 percent, of metastatic melanoma patients by 2030.”