Melanoma is the third most common cause of brain metastases, after lung and breast cancer. The management of melanoma brain metastases can be broadly divided into symptom control and therapeutic strategies. Supportive treatments include corticosteroids to reduce peritumoral edema, antiepileptics for seizure control, and medications to preserve cognitive function. Until recently, therapeutic strategies consisted primarily of local treatments, including surgery, whole-brain radiation therapy (WBRT), and stereotactic radiosurgery (SRS). Surgery, WBRT, and SRS—alone and in various combinations—still play an important role in treatment, especially in patients with few and/or smaller brain lesions. Much work has been done recently to try to determine the optimal settings for these therapies, the most effective ways to combine them, and ideal radiation dose and fractions.
Recent progress in the management of advanced melanoma has resulted in improved 5-year survival rates; however, melanoma brain metastases remain a significant cause of morbidity and mortality. Approximately 20% of patients with metastatic melanoma have brain metastases at diagnosis. Overall, about 50% of patients with stage IV melanoma will develop symptomatic brain metastases.[1,2] Cerebral hemispheres are the site of 80% of brain lesions from melanoma, followed by the cerebellum (15%) and brainstem (5%). Common clinical manifestations include headache, neurologic deficits, cognitive impairment, and seizures. Until recently, patients with melanoma brain metastases had a dismal prognosis, with a median overall survival (OS) of 6 months.
The management of melanoma brain metastases can be broadly divided into supportive management and therapeutic strategies. Supportive treatments include corticosteroids to reduce peritumoral edema, antiepileptics for seizure control, and medications to preserve cognitive function. Traditionally, therapeutic strategies focused on local treatments, including surgery, whole-brain radiation therapy (WBRT), and stereotactic radiosurgery (SRS). Historically, systemic therapy has had limited utility in the management of melanoma brain metastases. However, the treatment paradigm has changed considerably with the advent of targeted therapy and immunotherapy. Approximately 50% of patients with advanced melanoma harbor a BRAF mutation, and a number of targeted agents for this mutation and the downstream pathway have shown promise in the management of metastatic melanoma. Immunotherapeutic agents such as those that target cytotoxic T-lymphocyte–associated antigen 4 and programmed death 1 (PD-1) have shown clinical efficacy in melanoma brain metastases and are now considered first-line treatment options for metastatic melanoma.
Biology of Brain Metastases
Until recently, melanoma brain metastases were believed to have the highest mutational discordance of any tumor type relative to the primary site. However, Chen et al reported molecular profiling that included hot spot mutations, global microRNA expression patterns, quantitative analysis of protein expression, and reverse phase protein array analysis of samples from 16 patients. The authors reported complete concordance in mutational profiles between intracranial and extracranial sites. Despite these similarities, expression of activation-specific protein markers of the phosphoinositide-3 kinase (PI3K)/AKT pathway was shown to be increased in brain metastases compared with extracranial metastases. Another study compared the expression of mutated BRAF at different metastatic sites in advanced melanoma and showed greater mutational concordance (16/20 patients) between brain metastases and the primary tumor than between other visceral/subcutaneous metastases and the primary site. These studies provide an initial understanding of the molecular characteristics of melanoma brain metastases.
With the advent of immunotherapy, the tumor microenvironment and immune infiltration have been a focus of intense research. The brain has traditionally been thought of as an immune-privileged organ, but recent studies have established the existence of a neuro-immune axis, throwing this belief into question. Our understanding of the unique interplay between the immune system and the central nervous system has evolved dramatically in recent years. Berghoff et al investigated the expression of PD-1, programmed death ligand 1 (PD-L1), CD3, CD8, CD45RO, forkhead box protein 3 (FoxP3), CD20, and BRAF V600E by immunohistochemistry in melanoma brain metastasis samples. The tumor-infiltrating lymphocytes (TILs) present varied among the samples: out of 43 specimens, 33 stained positive for CD3 TILs, 39 for CD8, 32 for CD45RO, 27 for PD-1, 21 for FoxP3, and 19 for CD20 TILs. Tumoral PD-L1 expression was observed in 22 specimens, with significant PD-L1 expression (> 5% of cells) seen in 9 of these, suggesting a role for immunotherapeutic agents in melanoma brain metastases.
Although the median OS of patients with melanoma brain metastases is dismal, approximately 5% of these patients are long-term survivors. Hence, prognostic factors that predict outcomes and that can guide treatment decisions and enrollment in clinical trials are of value. Several large single-center series have examined various primary tumor, brain metastasis, and patient characteristics predictive of survival.[1,10,11] Age, performance status, number of brain metastases, presence of extracranial metastases, time from primary tumor diagnosis, presence of neurologic symptoms, and elevated lactate dehydrogenase level are factors that determine survival.
Sperduto et al proposed a new disease-based scoring index based on data from 483 patients with newly diagnosed melanoma brain metastases from 8 different centers. On multivariate analysis, performance status and number of brain metastases were prognostic for survival in these patients. The outcomes of this Diagnostic-Specific Graded Prognostic Assessment (DS-GPA) for patients with melanoma brain metastases varied from a median survival of 3.4 months for those in GPA class I to a median survival of 13.2 months for patients in GPA class IV.
Prognostic indices have inherent limitations. All of them have been evaluated retrospectively, have had only OS as the endpoint, have not included a molecular and genetic profile of the primary malignancy, and have not taken systemic therapy into consideration. A large single-institution experience of 366 patients that included treatment of 1,336 brain metastases has also shed some light on the interplay of important prognostic variables in patients with melanoma brain metastases. In this series, characteristics associated with survival included younger age, lack of extracranial metastases, performance status, and treatment with BRAF inhibitors or immunotherapies. This work specifically highlights the improved outcomes in patients who are eligible for and receive newer targeted therapies. For example, the 12-month survival estimate for patients treated with BRAF inhibitors was 37%, compared with 23% for those who did not receive these therapies (P = .01). Moreover, the 12-month survival estimate for patients treated with immunotherapies was 47%, compared with 22% for those who did not receive these therapies (P = .04). Clearly, further work is needed to define the impact of mutation status, targeted drugs, and immunotherapy in the current era.
The neurologic symptoms associated with brain metastases include headaches; seizures; and cranial nerve, motor, and sensory deficits. All melanoma patients with neurologic symptoms worrisome for melanoma brain metastases should undergo a gadolinium-enhanced MRI scan of the brain, provided no contraindications exist. Guidelines recommend routine MRI of the brain with and without gadolinium contrast for patients with stage IV melanoma because of the high prevalence of asymptomatic brain metastases. CT of the brain with and without contrast can be used as an alternate imaging modality.
Management of Symptoms
Supportive care for patients with brain metastases typically consists of controlling the cerebral edema with steroids. Because of its minimal mineralocorticoid effect and long half-life, dexamethasone is the steroid of choice; however, other steroids at an equivalent dose can be used and tapered gradually over a 2-week period. A randomized trial conducted in 1994 compared different doses of dexamethasone, ranging from 4 mg/day to 16 mg/day, and concluded that 4 to 8 mg/day would provide the same degree of clinical improvement in 1 week. Routine use of prophylactic antiepileptics in patients with brain metastases is not recommended. When patients have seizures, several antiepileptics are available, including phenytoin, carbamazepine, valproic acid, and levetiracetam. Non–enzyme-inducing agents such as levetiracetam are preferred so as to avoid interactions with systemic anticancer agents.
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