Distant intracranial failure in melanoma brain metastases treated with stereotactic radiosurgery in the era of immunotherapy and targeted agents

Abstract

PurposeStereotactic radiosurgery (SRS) in combination with immunotherapy (IMT) or targeted therapy is increasingly being used in the setting of melanoma brain metastases (MBMs). The synergistic properties of combination therapy are not well understood. We compared the distant intracranial failure rates of intact MBMs treated with SRS, SRS + IMT, and SRS + targeted therapy.Methods and materialsCombination therapy was defined as delivery of SRS within 3 months of IMT (anti-CTLA-4 /anti-PD-1 therapy) or targeted therapy (BRAF/MEK inhibitors). The primary endpoint was distant intracranial failure after SRS, which was defined as any new MBM identified on brain magnetic resonance imaging. Outcomes were evaluated using the Kaplan Meier method and Cox proportional hazards.ResultsA total of 72 patients with melanoma with 233 MBMs were treated between April 2006 and April 2016. The number of MBMs within each treatment group was as follows: SRS: 121; SRS + IMT: 48; and SRS + targeted therapy: 64. The median follow-up was 8.9 months. One-year distant intracranial control rates for SRS, SRS + IMT, and SRS + targeted therapy were 11.5%, 60%, and 10%, respectively (P < .001). On multivariate analysis, after adjusting for steroid use and number of MBMs, SRS + IMT remained associated with a significant reduction in distant intracranial failure compared with SRS (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.29-0.80; P = .003) and compared with SRS + targeted therapy (HR, 0.41; 95% CI, 0.25-0.68; P = .001).One-year local control for SRS, SRS + IMT, and SRS + targeted therapy was 66%, 85%, and 72%, respectively (P = .044). On multivariate analysis, after adjusting for dose, SRS + IMT remained associated with a significant reduction in local failure compared with SRS alone (HR, 0.37; 95% CI, 0.14-0.95; P = .04).ConclusionsSRS with immunotherapy is associated with decreased distant and local intracranial failure compared with SRS alone. Prospective studies are warranted to validate this result.

Gamma Knife Radiosurgery for Metastatic Brain Tumors from Malignant Melanomas: A Japanese Multi-Institutional Cooperative and Retrospective Cohort Study (JLGK1501)

“…Our findings indicate that these immune checkpoint inhibitors are effective for controlling not only the primary melanoma but also distant metastases to the brain. Several previous reports have shown a regional immunomodulatory effect and penetration of novel systemic agents into the brain [8,11,12,15,18,20,21,23]. The present results might indicate passage of these agents thorough the bloodbrain barrier in melanoma patients, thereby leading to suppression of new metastases to the brain.…”

“…Brain metastasis from malignant melanoma occurs at a high incidence of almost 10%, and the rate exceeds 40% in patients with stage 4 disease [1,3,6,7,9,13,14,17,18,20,23,[26][27][28][29]. Single or multimodality therapies including surgical resection, whole-brain radiation therapy, and stereotactic radiosurgery (SRS) are generally performed for brain metastases depending on the systemic condition of the patient.…”

Association of Steroids Use with Survival in Patients Treated with Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis

“…In total, 346 potentially relevant citations were reviewed (Figure 1). Ultimately, 16 studies published from 2009 to 2019 that reported OS and/or PFS data were included in the final analysis [17,[19][20][21][22][27][28][29][30][31][32][33][34][35][36][37]. The total number of patients included was 4045 ranging from 45 to 1025 patients per study (median, 151).…”

Therapeutic Effectiveness of Immunoradiotherapy on Brain-metastatic BRAF/MEK Inhibitor-resistant Melanoma with Balloon Cell Change

“…As compared with wild-type BRAF, BRAF mutation is an independent predictor of better prognosis in patients with melanoma brain metastases receiving SRS (11). On the other hand, the combination of SRS and immune checkpoint inhibitor (ani-PD-1 antibody or anti-CTLA-4 antibody) is also associated with reduction of distant intracranial failures compared with SRS alone or SRS with BRAF inhibitor (12). X-ray irradiation induces PD-L1 expression in mouse cancer cells, but enhances a tumour-suppressing effect in combination with anti-PD-1 antibody (13).…”