Controversies in the Therapy of Brain Metastases: Shifting Paradigms in an Era of Effective Systemic Therapy and Longer-Term Survivorship

With the development of therapies that improve extracranial disease control and increase long-term survival of patients with metastatic cancer, effective treatment of brain metastases while minimizing toxicities is becoming increasingly important. An expanding arsenal that includes surgical resection, whole brain radiation therapy, radiosurgery, and targeted systemic therapy provides multiple treatment options. However, significant controversies still exist surrounding appropriate use of each modality in various clinical scenarios and patient populations in the context of cancer care strategies that control systemic disease for increasingly longer periods of time. While whole brain radiotherapy alone is still a reasonable and standard option for patients with multiple metastases, several randomized trials have now revealed that survival is maintained in patients treated with radiosurgery or surgery alone, without upfront whole brain radiotherapy, for up to four brain metastases. Indeed, recent data even suggest that patients with up to 10 metastases can be treated with radiosurgery alone without a survival detriment. In an era of dramatic advances in targeted and immune therapies that control systemic disease and improve survival but may not penetrate the brain, more consideration should be given to brain metastasis-directed treatments that minimize long-term neurocognitive deficits, while keeping in mind that salvage brain therapies will likely be more frequently required. Less toxic therapies now also allow for concurrent delivery of systemic therapy with radiosurgery to brain metastases, such that treatment of both extracranial and intracranial disease can be expedited, and potential synergies between radiotherapy and agents with central nervous system penetration can be harnessed.