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.