Management of Brain Metastases in the Era of Targeted and Immunomodulatory Therapies

In this issue of ONCOLOGY, Lin and colleagues provide a succinct and insightful summary of emerging treatment approaches for brain metastases.[1] Metastases in the central nervous system represent an unmet need in current oncologic care. Although more effective systemic therapies for cancers are entering routine practice, patients with active brain metastases continue to be excluded from many clinical trials. However, with the success of these newer agents, patients are living longer and developing brain metastases while their extracranial disease remains under control. Historically, traditional chemotherapeutic agents have had limited activity in the brain. More recently, some targeted systemic therapies have demonstrated evidence of activity in the brain-specifically in melanoma, lung cancers, and breast cancers-and these agents warrant further study in clinical trials.

A signature example of this transition in modern cancer practice is seen in melanoma oncology, a field that has experienced remarkable recent success with novel systemic therapies. Melanoma had traditionally been resistant to radiation and chemotherapy, and many patients died either before, or shortly after, a diagnosis of CNS metastases. The development of agents targeting the immune system,[2] as well as the RAS-RAF-MAPK pathway,[3] has dramatically improved survival in metastatic melanoma. Despite good systemic disease control, a large proportion of patients with metastatic melanoma will develop metastasis in the CNS, and some patients can achieve prolonged survival after diagnosis of their intracranial disease.[4,5] The impact of these agents on disease in the brain is an area under active investigation, with several case series and phase II studies[5,6] noting promising activity in CNS disease.

Similarly, agents targeting specific oncogenic alterations have changed the management of metastatic lung cancer. Approximately 10% of patients with non–small-cell lung cancer (NSCLC) harbor activating mutations in the epidermal growth factor receptor (EGFR) gene[7] that predict sensitivity to EGFR inhibitors, including erlotinib[8] and gefitinib.[9] Small studies have reported activity of these inhibitors in newly diagnosed and recurrent brain metastases,[10] with higher responses in genetically selected tumors[11] and with appropriate dosing schedules that can overcome the blood-brain barrier. The administration of higher doses of weekly (pulsatile) erlotinib achieves higher concentrations in the cerebrospinal fluid compared with standard dosing and may be a useful strategy in EGFR-mutant leptomeningeal disease and brain metastases.[12,13] Alterations in the ALK gene occur in 2% to 7% of NSCLC patients,[14] and confer sensitivity to selective tyrosine kinase inhibitors, again limited by the degree of blood-brain barrier penetration. Although progression in the brain has been reported in patients receiving the first-generation anaplastic lymphoma kinase (ALK) inhibitor crizotinib,[15] promising responses in the CNS have been seen with newer-generation ALK inhibitors.[16,17] Furthermore, a study evaluating immunotherapy in CNS metastases from NSCLC is underway (Clinicaltrials.gov identifier: NCT02085070).

Targeted agents in breast cancer have also shown activity for CNS disease. Approximately 30% of patients with advanced human epidermal growth factor receptor 2 (HER2)-positive breast cancer develop brain metastases. Lapatinib, a small-molecule tyrosine kinase inhibitor of HER1 and HER2, shows modest activity as a single agent.[18] Higher response rates have been reported in combination with capecitabine.[19] The antiangiogenic agent bevacizumab, in combination with traditional cytotoxics, has been investigated in case series and phase II studies in HER2-positive and -negative disease.[20,21]

Bevacizumab also has efficacy in the treatment of symptomatic radiation necrosis and reactive cerebral edema following radiosurgery. In a pilot randomized study of 14 patients with symptomatic radiation necrosis, all bevacizumab-treated patients and none of the placebo-treated patients showed improvement in neurologic symptoms or signs and radiographic parameters.[22] A similar study of 8 patients who developed extensive cerebral edema following radiosurgery showed significant neurologic improvement with bevacizumab.[23]

With the advent of novel therapeutics, the use of a multidisciplinary approach to provide individualized care for patients with brain metastases continues to be critical. Treatment decisions are made by weighing potential short- and long-term toxicities, anticipated benefits to symptom control, and the impact on the patient’s predicted lifespan. A key determinant of survival that has emerged from the use of prognostic scoring systems to evaluate thousands of patients with brain metastases is functional performance status. Status of extracranial disease and age are also important determinants.[24,25]

For solitary brain metastases in patients with a favorable prognosis and controlled systemic disease, surgery or stereotactic radiosurgery (SRS) may be associated with improved overall survival.[26,27] In oligometastatic intracranial disease (2 to 4 metastases), whole-brain radiation therapy (WBRT), local control (with surgery and/or SRS), or the combination of locally directed therapies and WBRT are all options. As patients are living longer, the risk of neurotoxicity following WBRT needs to be factored into clinical decision making.[28] For multiple brain metastases, WBRT continues to be standard of care, but systemic treatment with agents that have activity in the CNS may be an alternative, preferably in the context of a clinical trial.

Indeed, effective systemic therapies as a means of deferring WBRT, especially immunotherapies or molecularly targeted therapies with blood-brain barrier penetration, can be considered upfront in patients with asymptomatic disease or with progression after CNS-directed local therapy. The role of emerging minimally invasive ablative technologies, such as laser interstitial thermal therapy and magnetic resonance–guided focused ultrasound surgery, will need to be incorporated into treatment protocols alongside surgical resection and SRS as locally directed modalities.

As therapies continue to improve and our understanding of the molecular drivers of brain metastases expands, we expect to see sustained improvement in the management of brain metastases over the next decade.