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Brain Metastases in Melanoma: Moving Toward Curing the Incurable.

Advanced melanoma has the highest percase rate of brain metastases but accounts for the third most frequent cause of death from brain metastases, because lung and breast cancers, with lower per-case rates, are far more common. Historically, solid tumor brainmetastases were treated based on retrospective reports of pooled tumors, predominantly lung, breast, and melanoma, but recent therapeutic advances in all three diseases now require separate approaches to therapy and scientific investigation. The review by Chukwueke et al discusses current therapies and the clinical basis for their use. Amore in-depth description of the science, the mechanisms of action, and approaches to overcome therapy resistance is beyond the scope of their review. It is critical, however, to learn more about when and how melanoma cells become capable of trafficking to and invading the brain, how they grow and resist apoptosis, and how they can evade therapies that may be active in the patient’s extracranial disease. The existing literature about risks and prognosis forbrainmetastases is composed of reports that range from basic molecular studies through genetically engineered animal models to purely clinical associations of brain metastases with other patient and tumor characteristics. In the present review, some of the authors’ conclusions require further explanation or alternative interpretations. For example, whole-brain radiotherapy in melanoma is waning because of its poor control of metastases rather than the risk of long-term neurocognitive decay, except perhaps in patients considered for prophylactic whole-brain radiotherapy after stereotactic radiosurgery for single or oligometastatic disease. Patients withmultiple metastases who are not candidates for stereotactic radiosurgery and are referred for whole-brain radiotherapy rarely survive long enough for late radiation toxicities—usually succumbing to extracranial and/or CNS progression, the latter potentially indistinguishable from neurotoxicity resulting from radiotherapy. Although agents used historically for metastatic melanoma probably failed to cross an intact blood-brain barrier, the principal reason for their poor results is low antitumor activity. Although temozolomide, a dacarbazine-like agent approved for primary brain malignancies, had high CNS penetrance, its low activity against melanoma with brain metastases confirmed thatmerelyenteringthebrain isnotsufficient for a drug to be effective there. Recent advances reflect changes in the treatment paradigm: ipilimumab, a human antibody against cytotoxic T-lymphocyte antigen-4, and pembrolizumab, a humanized antibody targeting programmed death-1, have both shown single-agent activity against melanoma metastatic to the brain, and combinations targeting both immune checkpoints are under investigation. Because immunoglobulin molecules do not cross the blood-brain barrier but lymphocytes do, further testing of immune checkpoint blockade and potentially other immunomodulatory agents,