Image-guided radiotherapy (IGRT) enables optimal tumor targeting and sparing of organs-at-risk, which ultimately results in improved outcomes for patients. Magnetic resonance imaging (MRI) revolutionized diagnostic imaging with its superior soft tissue contrast, high spatiotemporal resolution, and freedom from ionizing radiation exposure. Over the past few years there has been burgeoning interest in MR-guided radiotherapy (MRgRT) to overcome current challenges in X-ray-based IGRT, including but not limited to, suboptimal soft tissue contrast, lack of efficient daily adaptation, and incremental exposure to ionizing radiation. In this review, we present an overview of the technologic advancements in IGRT that led to MRI-linear accelerator (MRL) integration. Our report is organized in three parts: (1) a historical timeline tracing the origins of radiotherapy and evolution of IGRT, (2) currently available MRL technology, and (3) future directions and aspirations for MRL applications.

Background: Brain metastases are the most common intracranial tumors in adults and are associated with significant morbidity and mortality. Whole-brain radiotherapy (WBRT) is used frequently in patients for palliation, but can result in neurocognitive deficits. While dose-dependent injury to individual areas such as the hippocampus has been demonstrated, global structural shape changes after WBRT remain to be studied. Methods: We studied healthy controls and patients with brain metastases and examined MRI brain anatomic surface data before and after WBRT. We implemented a validated graph convolutional neural network model to estimate patient’s “brain age”. We further developed a mixed-effects linear model to compare the estimated age of the whole brain and substructures before and after WBRT. Results: 4220 subjects were analyzed (4148 healthy controls and 72 patients). The median radiation dose was 30 Gy (range 25–37.5 Gy). The whole brain and substructures underwent structural change resembling rapid aging in radiated patients compared to healthy controls; the whole brain “aged” 9.32 times faster, the cortex 8.05 times faster, the subcortical structures 12.57 times faster, and the hippocampus 10.14 times faster. In a subset analysis, the hippocampus “aged” 8.88 times faster in patients after conventional WBRT versus after hippocampal avoidance (HA)-WBRT. Conclusions: Our findings suggest that WBRT causes the brain and its substructures to undergo structural changes at a pace up to 13x of the normal aging pace, where hippocampal avoidance offers focal structural protection. Correlating these structural imaging changes with neurocognitive outcomes following WBRT or HA-WBRT would benefit from future analysis.