Anti-CTLA-4 and BRAF Inhibition in Patients With Metastatic Melanoma and Brain Metastases

Igor Puzanov; Jedd D Wolchok; Paolo A Ascierto; Omid Hamid; Kim Margolin


Expert Rev Dermatol. 2013;8(5):479-487. 

In This Article

Abstract and Introduction


Until recently, there were few treatment options for patients with advanced or metastatic melanoma associated with significant increases in overall survival. Of these, patients with disease that has metastasized to the brain have a particularly poor prognosis and generally ineffective treatment options. Recent advances in immuno-oncology have led to the approval of ipilimumab, an antibody that blocks cytotoxic T-lymphocyte antigen-4 to augment antitumour T-cell responses, and vemurafenib, a BRAF kinase inhibitor. These agents, along with others on the horizon, are promising treatment options for patients with melanoma and CNS involvement. Here we review the data generated to date in patients with melanoma and brain metastases and suggest the direction that future studies may take to optimize outcomes in this subpopulation of patients.


The incidence of melanoma is on the rise and although melanoma currently accounts for only 4% of all skin cancers, it is responsible for 80% of all skin cancer deaths.[1] Worldwide, the incidence of melanoma is roughly 200,000, leading to approximately 46,000 deaths.[101] Compared with primary lung, breast, renal or colorectal cancer, melanoma has the highest propensity to metastasize to the brain: over one-third of patients with metastatic melanoma will eventually develop a clinically apparent brain metastasis[2] Autopsy reports indicate that the incidence of brain metastases may be as high as 75% post-mortem,[3] but only 7% of patients have brain metastases discovered at initial diagnosis, which indicates that most patients develop brain metastases during the course of the disease.[4] There may be a substantial interval between treatment of the primary tumor site and appearance of cerebral lesions, with a median of 3.4 years reported with a very wide range of latency.[5]

The high incidence of brain metastasis in melanoma leads to a high frequency of inclusion of brain lesions in staging, and it is not unusual to identify small asymptomatic lesions during staging. When symptoms occur, they are nonspecific and vary depending on the location of the lesion. Headache is the most common presenting symptom, but patients may also present with more serious symptoms like seizures, hemiplegia or visual compromise due to raised intracranial pressure. These phenomena may suggest large (>4 cm) lesions, numerous lesions or frequently, tumoral hemorrhage which must be considered in patient management decisions.[6]

Patients with brain metastases have significantly worse progression-free survival (PFS), overall survival (OS) and overall prognosis than patients with no brain metastases.[7] The median OS in a large retrospective review of 702 patients with brain metastases was about 4 months and brain metastases contributed to the death of over 90% of the patients. This study also identified certain characteristics associated with longer survival such as the presence of a surgically treated, single brain metastasis in the absence of other visceral metastatic disease.[8] Among patients with brain metastases, the actual prognosis varies widely and depends on the number of lesions and patient status. In a single-institution experience, 70 Stage III, high-risk patients were monitored intensely and treated aggressively with biochemotherapy and stereotactic radiotherapy at the first sign of brain metastases. Of these patients, 20 were subsequently diagnosed with metastases in the brain and nevertheless had a median survival of 11 months, only 5 months shorter than those who did not develop brain metastases at the time of systemic relapse. However, this regimen and the routine use of this approach is not currently recommended.[9]