Role of Radiosurgery

According to the National Comprehensive Cancer Network (NCCN) guidelines, it is the standard of care for patients with limited melanoma brain metastases to be treated with surgery, radiosurgery, or both.5

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“Many patients undergo radiosurgery to treat brain metastases while they are receiving immunotherapy,” explained Tyler Robin, MD, PhD, of the department of radiation oncology at the University of Colorado Anschutz Medical Campus and the University of Colorado Cancer Center, who is a researcher on the second study. “Yet, there are limited data to help us understand the potential benefits and potential toxicities of this combination.”

According to Dr Robin, their small study adds to the growing body of literature suggesting that radiosurgery is safe in patients receiving immune CPIs and further describes excellent CNS control and survival in patients who receive this type of therapeutic combination. 

In the study, 38 patients with newly diagnosed melanoma brain metastases were treated with Gamma Knife radiosurgery at Dr Robin’s institution between 2012 and 2017. All patients had initiated immune CPIs within 8 weeks before or after radiosurgery. The majority of patients (66%) were treated with anti-CTLA4 therapy and 34% of patients were treated with anti-PD-1 treatment with or without anti-CTLA4.

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The median overall survival was not yet reached at a median follow-up of 31.6 months in patients treated with CPIs and radiosurgery between 2012 and 2017. Although excellent outcomes were achieved in both treatment groups, compared with patients treated with anti-CTLA4 alone, patients treated with anti-PD-1 alone or in combination with anti-CTLA4 had statistically significant improvements in time to out-of-field CNS progression (= .049), extra-CNS progression (= .015), and progression-free survival (= .043). The median time to out-of-field CNS progression was not reached in the anti-PD1/anti-CTLA4 group compared with 3.1 months for patients in the anti-CTLA4 alone cohort. Median time to extra-CNS progression was not reached in the combination group compared with 4.4 months for anti-CTLA4; and median progression-free survival was 20.3 months for the combination regimen compared with 2.4 months for patients given CTLA4 inhibitors.

According to Dr Robin, these results led his team to hypothesize that while CPIs alone are active against brain metastases, “radiosurgery might enhance their efficacy, particularly in preventing the development of new brain metastases.”

However, he added that the mechanisms of the potential synergy between CPI therapy and radiosurgery should be investigated further.

Aval Aizer, MD, MHS, of the department of radiation oncology at Brigham and Women’s Hospital and the Dana-Farber Cancer Institute, and a researcher on the first study, said that “the risks and benefits of combining radiotherapy and immunotherapy should be considered on an individual patient level.”

“The benefit of adding radiotherapy is that immunotherapy does not always achieve local control in patients with brain metastases, particularly in primaries other than melanoma,” Dr Aizer said. “The risks are multiple, however, most notable is an increased risk of radiation necrosis in patients receiving stereotactic radiation.”

Another important contribution of the study by Dr Robin and colleagues was the addition of data on the safety of combining radiotherapy with immune CPIs. Although the dataset was small, Dr Robin said the combination treatment was well-tolerated overall.

Specifically, treatment with CPIs and radiosurgery resulted in 8% of patients experiencing grade 2 CNS toxicities (hemorrhagic conversion of treated metastases) and 8% of patients experiencing grade 3 CNS toxicities (radiation necrosis).

“This study alone is not enough to change practice,” Dr Robin said. “But the findings are thought-provoking, and will be valuable in the design of future studies exploring the potential interplay between radiosurgery and immunotherapy for brain metastases.” 


  1. Iorgulescu JB, Harary M, Zogg CK, et al. Improved risk-adjusted survival for melanoma brain metastases in the era of checkpoint blockade immunotherapies: results from a national cohort[published online July 12, 2018]. Cancer Immunol Res.doi:10.1158/2326-6066.
  2. Robin TP, Breeze RE, Smith DE, et al. Immune checkpoint inhibitors and radiosurgery for newly diagnosed melanoma brain metastases[published online June 16, 2018]. J Neurooncol. doi: 10.1007/s11060-018-2930-5.
  3. Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial.Lancet Oncol. 2012;13(5):459-465.
  4. Goldberg SB, Gettinger SN, Mahajan A, et al. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trialLancet Oncol.2016;17(7):976-983. 
  5. National Comprehensive Cancer Network. Melanoma. NCCN guidelines Version 2.2018. Updated February 21, 2018. Accessed July 31, 2018.