Stereotactic radiosurgery combined with immune checkpoint inhibitors or kinase inhibitors for patients with multiple brain metastases of malignant melanoma

Abstract

The aim was to evaluate toxicity and oncological outcome of combined stereotactic radiosurgery (SRS) and immunotherapy or targeted therapy in patients with multiple brain metastases originating from malignant melanoma. Despite the fact that both SRS and kinase inhibitors or immune checkpoint inhibitors are considered standard treatment options for this indication, the optimal combination and sequence of these modalities remains largely unknown, especially for patients with a high number of brain metastases. For this retrospective analysis, conducted in two large SRS dedicated centers, we identified patients with brain metastases from malignant melanoma and simultaneous application of immunotherapy or targeted therapy within 30 days of SRS. Forty-eight patients with a total of 250 lesions (median: 3) were treated in 65 single fraction SRS sessions from 2012 to 2018. After a median follow-up of 8.3 months (range: 1.2-43.6 months), the 6-month and 1-year overall survival rates were 75.3 and 50.8%, respectively. The local control rate at one year was 89.5%. Immunotherapy and the application of systemic treatment directly before or concomitant to SRS were both associated with improved overall survival (P = 0.037 and 0.045, respectively). We observed four grade III toxicities, of which only two can be clearly attributed to the combined treatment. Various combinations of SRS and kinase inhibitors or immune checkpoint inhibitors appear feasible and provide promising oncological results and safety profiles for treating few (n = 1-4) and also multiple (n ≥ 5) melanoma brain metastases.

Efficacy of BRAF Inhibitors in Combination With Stereotactic Radiosurgery for the Treatment of Melanoma Brain Metastases: A Systematic Review and Meta-Analysis

“…SRS has been increasingly used as the treatment of choice for local therapy ( 32 ). In fact, the combination of radiation therapy and immune checkpoint blockers, such as ipilimumab and nivolumab has shown synergistic responses in various retrospective studies ( 53 , 58 , 59 , 71 – 74 ). BRAF inhibitors have also shown intracranial responses, suggesting that the two treatments could work synergistically ( 33 – 36 ).…”

Predicting survival in melanoma patients treated with concurrent targeted- or immunotherapy and stereotactic radiotherapy

“…This might be explained by the effects of IT: patients might have received IT at an earlier time point which then achieved improved OS [3]. Additionally, it has been acknowledged, that the timing of IT/TT and SRT is crucial [12,33]. Recently, the immunomodulatory effects of SRT has been discussed in the literature leading to synergistic effects of the combined treatment as discussed above that might also be reflected in our finding [28,34].…”

Survival After Stereotactic Radiosurgery (SRS) or Fractionated Stereotactic Radiotherapy (FSRT) for Cerebral Metastases in the Elderly

“…Moreover, in a previous study, FSRT resulted in significantly better 1-year control of irradiated lesions than did SRS (91% versus 77%, p=0.01) (10). In order to improve the survival of patients with cerebral metastases, SRS and FSRT are increasingly more commonly combined with novel targeted therapies (11). Sequential treatment with radiotherapy using high doses per fraction and a targeted therapy may result in significant necrosis of brain tissue that can affect a volume considerable larger than the volume of the cerebral lesions (12,13).…”