Impact of concomitant systemic treatments on toxicity and intracerebral response after stereotactic radiotherapy for brain metastases

Abstract

Background The aim of this study was to determine the safety and efficacy of fractionated stereotactic radiotherapy (SRT) in combination with systemic therapies (ST) for brain metastases (BM). Methods Ninety-nine patients (171 BM) received SRT and concurrent ST (group 1) and 95 patients (131 BM) received SRT alone without concurrent ST (group 2). SRT was planned on a linear accelerator, using volumetric modulated arc therapy. All ST were allowed including chemotherapy (CT), immunotherapy (IT), targeted therapy (TT) and hormonotherapy (HT). Treatment was considered to be concurrent if the timing between the drug administration and SRT did not exceed 1 month. Local control (LC), freedom for distant brain metastases (FFDBM), overall survival (OS) and radionecrosis (RN) were evaluated. Results After a median follow-up of 11.9 months (range 0.7–29.7), there was no significant difference between the two groups. However, patients who received concurrent IT (n = 30) had better 1-year LC, OS, FFDBM but a higher RN rate compared to patients who did not: 96% versus 78% (p = 0.02), 89% versus 77% (p = 0.02), 76% versus 53% (p = 0.004) and 80% versus 90% (p = 0.03), respectively. In multivariate analysis, concurrent IT (p = 0.022) and tumor volume < 2.07 cc (p = 0.039) were significantly correlated with improvement of LC. The addition of IT to SRT compared to SRT alone was associated with an increased risk of RN (p = 0.03). Conclusion SRT delivered concurrently with IT seems to be associated with improved LC, FFDBM and OS as well as with a higher rate of RN.

Intracranial Treatment in Melanoma Patients with Brain Metastasis Is Associated with Improved Survival in the Era of Immunotherapy and Anti-BRAF Therapy

“…Safety of combination therapy in the literature is heterogeneous; however almost all authors agree that the putative slightly increased risk is manageable, particularly in light of the likely benefit on efficacy and survival [42,43]. In our study, 10% of the patients developed radionecrosis, which was, in most cases, reversible and manageable with transient steroid therapy and consistent with previously reported results [35]. However given this nonnegligible risk, and the difficulty of distinguishing it from local failure, multimodal MRI is strongly recommended during follow-up [44].…”

“…Many retrospective studies reported enhanced local control when radiotherapy was delivered in combination with immunotherapy, providing further evidence for a synergistic effect of ICIs and radiation therapy [34][35][36].…”

“…Several preclinical studies reported that the combination of low-dose fractionated radiation therapy and PD-1/PD-L1 axis inhibitors activates cytotoxic T cells infiltrating and immediately surrounding the tumour [37]. Recent studies reported clinical results of this synergy, leading to an immunotherapy-mediated abscopal effect [9,17,[34][35][36]. In a retrospective analysis of patients with BM from various tumours, patients who received immunotherapy in combination with fractionated SRT had significantly better 1-year local control (96% vs. 78%, p = 0.02) and improved distant intracranial disease-free survival (62% vs. 51%, p = 0.007) than those who did not [35].…”

“…Recent studies reported clinical results of this synergy, leading to an immunotherapy-mediated abscopal effect [9,17,[34][35][36]. In a retrospective analysis of patients with BM from various tumours, patients who received immunotherapy in combination with fractionated SRT had significantly better 1-year local control (96% vs. 78%, p = 0.02) and improved distant intracranial disease-free survival (62% vs. 51%, p = 0.007) than those who did not [35]. In a retrospective studies of 46 patients, better results in OS and local recurrence were reported if immunotherapy was delivered during (or before) SRT than after [37].…”

Evaluation of practical experiences of German speaking radiation oncologists in combining radiation therapy with checkpoint blockade

“…Thus, it became evident that combining local RT (e.g., SRT) with systemic IT (e.g., ICIs) might be beneficial to further improve disease control in general. For instance, albeit it remains unclear if the risk of radiation necrosis might be elevated, a clear benefit in terms of outcome has been shown for IT and stereotactic treatment for brain metastases 16 – 18 . Therefore, in current clinical practice, many patients with advanced stage diseases (e.g., Melanoma, Non-small cell lung cancer) receive IT either simultaneously or sequentially to RT.…”