A review in melanoma brain metastasis treatment

This study reviewed the currently available treatments for melanoma brain metastasis (MBM; spread to the brain). Researchers reported that treatment should be personalized for the different types of patients. 

Melanoma has the highest risk of spreading to the brain among all common cancer types. Until the last five years, treatment options for MBM were limited. Despite surgery, radiation therapy or chemotherapy, patients experienced rapid cancer progression.

New recent therapy options have changed the MBM treatment and outcomes. However, over time resistance to these treatments rises, providing new challenges to overcome. 

The study reviewed the current treatment options for MBM.

Surgery and radiation therapy are often used as first-line treatment for MBM, however with limited effectiveness. Moreover, these treatments cannot be given to patients with several MBM or with MBM resistant to radiation.

In 2011, two new agents were approved to treat MBM, vemurafenib (Zelboraf) and ipilimumab (Yervoy).  Some melanoma patients have a mutation (permanant change) in the BRAF gene. BRAF inhibitors (such as vemurafenib) are used to treat these tumors. Prior studies showed that vemurafenib led to tumor shrinkage of over 30%. However, patients can become resistant to this treatment. This resistance happens due to the reactivation of MAPK, a specific protein that allows tumor growth. Therefore, the addition of a MAKP inhibitor, such as dabrafenib (Tafinlar) helps to overcome BRAF resistance. The combination of dabrafenib with trametinib (Mekinist; MEK inhibitor) increased the overall survival rate to 23.8 months. Other studies investigating the combination of different therapies to overcome resistance are being carried out.

The most common negative side effects are skin changes, fever, headache, joint pain, thromboembolism (blockage of a blood vessel by a blood clot), heart disease and hyperglycemia (increased sugar in the blood).

Additionally, another option to overcome MAPK resistance is to treat MBM with a combination of MAPK inhibitor with immunotherapy. Immunotherapy, such as ipilimumab, helps the immune system to attack and kill cancer cells. Prior studies showed that this therapy increased the average survival of advanced melanoma patients from 6.4 months to 10.1 months. The most common side effects are diarrhea, rash, adrenal insufficiency (keeps adrenal glands from making hormones) and hypophysitis (inflammation of the pituitary gland).

Other immunotherapies, called PD-1 agents, have been shown to be active against advanced melanoma. Nivolumab (Opdivo) showed an average overall response rate of 28%. Pembrolizumab (Keytruda) showed response rates in 37-38% of the patients, tumor shrinkage in 77% and average response time of more than 11 months. Other studies investigating these treatments in MB patients are being carried out.

Recently, a combination of two immunotherapies, nivolumab and ipilimumab, to treat advanced melanoma was studied. 53% of the patients had a tumor response, with a rapid shrinkage of tumor. However, a number of side effects were reported, such as in the liver, in the gastrointestinal and renal system.

Another immunotherapy treatment option is interleukin-2 (IL-2). This has an overall response rate of 16%. However in high doses this can lead to capillary leak syndrome (rapid fall in blood pressure) and swelling of the bain. Adoptive cell transfer (ACT) is another immunotherapy option. ACT involves taking immune cells from the patient blood, activate them and putting them back into the blood system. This can help the cells to attack and kill cancer cells.

The resistance to these treatments have been reported, although less frequently than with BRAF inhibitors.   

This review concluded that treatment for MBM should be personalized and adequate for each type of patient. More investigation into new agents, overcoming resistance and side effects, and increasing survival are needed.