Brain injury after cranial radiotherapy combined with immunotherapy for brain metastases in lung cancer: a retrospective study

Abstract Background: For patients with brain metastasis (BM) from lung cancer, whether cranial radiotherapy (CRT) combined with immune checkpoint inhibitors (ICIs) will increase the risk of radiation-induced brain injury (RBI) remains inconclusive. This retrospective study was performed with the aim of analyzing the incidence of RBI of CRT combined with ICIs and revealing the risk factors forRBI. Methods: We retrospectively reviewed the medical records of patients with BM from lung cancer who underwent CRT between January 2019 and December 2020 at Shandong Cancer Hospital and Institute. According to whether systemic treatment was used within 6 months before and after CRT, all patients were divided into theCRT+ICIs group and the CRT+non-ICIs group respectively. The diagnosis of brain radiation-induced necrosis (RN) and white matter lesions (WML) was evaluated by brain enhanced MRI. The Fazekas scale and CTCAE v5.0 were used to grade the injury. The risk factors for RBI were identified using univariate and multivariate analyses. Results: Overall, 210 BM patients undergoing CRT were included in our study. Within 6 months before and after CRT, 56 patients received ICIs, and 154 patients received other systemic therapeutic drugs, including tyrosine kinase inhibitors (TKIs) and chemotherapy. Seventeen (8.1%) patients developed RN, and 142 (67.6%) patients developed WML. The incidence of RN in theCRT+ICIs group vs. the CRT+non-ICIs group was 14.3% vs. 5.8% ( p =0.090). However, if ICIs were used within three months of CRT, the incidence of RN in the CRT+ICIs group was significantly higher than that in the CRT+non-ICIs group (18.5% vs. 5.4%, p =0.045). Multivariate analysis revealed that the maximum diameter of BM > 3.3 cm ( p = 0.023) and the total cumulative radiation dose of metastatic lesions > 75.7 Gy ( p = 0.018) were risk factors for RN. Additionally, re-radiotherapy was also a trend factor in the development of RN (OR 3.40; 95% CI 0.99-11.67, p =0.051). Conclusions: ICIs could increase the risk of RN, especially when used within three months of CRT. The total cumulative radiation dose of metastatic lesions is closely related to the development of RN, and re-radiotherapy is also a trend factor in the development of RN.