Dr Warner often considers both anti-PD-1 monotherapy and a combination of ipilimumab plus nivolumab with stereotactic radiosurgery (SRS).

“Stereotactic radiosurgery can help control symptoms and buy time for systemic immunotherapy to work,” she said. “I generally hold targeted therapy while a patient with a BRAF mutation receives radiotherapy for less than 1 week. Patients tend to respond quickly to targeted therapy, and stereotactic radiosurgery is often not needed in those patients.”

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Whole-brain radiation therapy (WBRT) and glucocorticoids have historically been “the mainstay of treatment” for multiple brain metastases, Drs Makawita and Tawbi noted in their review. However, WBRT is associated with long-term neurocognitive side effects, such as memory and learning deficits.

“Stereotactic radiosurgery allows for improved local control and a better side effect profile, and has been shown to be effective in patients with multiple CNS metastases,” Dr Makawita said.

“At this point, stereotactic radiosurgery is standard of care for melanoma brain metastases,” Dr Warner said. “Few patients should get WBRT; toxicity is quite high, and the disease control rate is low. Melanoma is a relatively radiation-resistant tumor, and that’s why WBRT is not as effective.”

When multiple metastases are not addressed by SRS, WBRT can be used, Dr Warner said.

“I try to use systemic therapy first to control disease and [use] stereotactic radiosurgery for large symptomatic lesions,” she added.

Minimizing Neurocognitive Decline

“[L]ong-term neurocognitive effects are an important consideration in the treatment of CNS metastasis,” Drs Makawita and Tawbi noted in their review.

They pointed out, however, that hippocampal-sparing WBRT has been shown to minimize neurocognitive decline. Using systemic agents such as a memantine (an N-methyl-D-aspartate antagonist) along with WBRT has proven beneficial as well.

“Other systemic agents to reduce potential neuroinflammatory responses that could be damaging to normal brain tissue, such as blockade of the renin-angiotensin system pathway, coupled with further improvements in 3-dimensional imaging will be essential strides toward minimizing neurocognitive decline associated with local therapies,” Dr Makawita said.

Take-Home Message

The bottom line, Dr Warner said, is that “patients who have melanoma and brain metastases should get combination immunotherapy unless there is a compelling reason not to give it. Think carefully [about] when to use immunotherapy and targeted therapy.”

“Targeted therapy has a limited duration of response in the brain but can be effective in those with symptoms who need a fast response,” she said. “Immunotherapy leads to more durable responses, and you need to consider combination vs single-agent immunotherapy and whether the patient is on steroids or not.”

A centralized approach to the treatment of this complex patient population has been shown to be effective and feasible, Dr Makawita said.

“Our institutional experience shows a dedicated brain metastasis clinic, which allows for the coordinated care of patients with CNS metastases where surgical, radiation oncology, and medical oncology teams can evaluate the patient together in the outpatient setting, can result in improved patient and physician satisfaction, as well as improved patient care and opportunity for clinical trial development,” Dr Makawita said.


  1. Makawita S, Tawbi HA. Nonsurgical management of melanoma brain metastasis: current therapeutics, challenges, and strategies for progress. Am Soc Clin Oncol Educ Book. 2021;41:79-90. doi:10.1200/EDBK_321137
  2. Gutzmer R, Stroyakovskiy D, Gogas H, et al. Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAFV600 mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial.  Lancet.2020;395(10240):1835-1844. doi:10.1016/S0140-6736(20)30934-X

This article originally appeared on Cancer Therapy Advisor