Introduction
High-grade gliomas (HGG), including glioblastoma (GBM) and anaplastic astrocytomas, are associated with a poor prognosis and quality of life (1-5). The majority of HGGs recur, at which point treatment options include re-resection, re-irradiation, bevacizumab, ‘off-label’ chemotherapy, tumor-treating fields, or clinical trial enrollment (6-8). Unfortunately, recurrent high-grade glioma (rHGG) trials historically produce high failure rates (9-11), necessitating the development of new therapeutic approaches.
Immune checkpoint inhibitors (ICIs) provided impressive results in melanoma, non-small cell lung cancer (12), and in untreated brain metastases secondary to these malignancies (13). While several clinical trials evaluating ICI in HGGs are ongoing, results are disappointing to date. Prior studies evaluating salvage re-irradiation report 6-month progression-free survival (PFS) rates of 28% to 39%, and a median 1-year overall survival (OS) of 26% (11, 14-18). Radiotherapy (RT) may improve ICI efficacy through several mechanisms, including altering tumor cell surface proteins, and enhancing the quantity and diversity of intracellular peptide pools. These effects, in conjunction with inducing MHC class I expression, provides a larger repertoire of antigenic targets to elicit an immune response. RT induces major histocompatibility complex (MHC) class I expression via upregulation of interferon-γ, which may play a role in T cell recruitment (19), conferring increased survival compared with either modality alone in mouse models (20, 21). Additionally, stereotactic body radiotherapy / fractionated stereotactic radiosurgery (SBRT), entailing conformally delivering higher RT doses in fewer treatments, may be preferable over conventional RT delivered over several weeks with regard to augmenting immune responses (22), while minimizing the impact on circulating lymphocytes.
There is a clear rationale for combining ICI with RT to increase the therapeutic ratio in rHGG, however, there is a paucity of data evaluating safety and efficacy of concurrent re-irradiation with ICI+SBRT. We report treatment-related adverse events (AE) in patients with rHGG treated with concurrent ICI + SBRT at our institution. PFS, OS and changes in tumor volume and perfusion characteristics after treatment were also evaluated.