Spatially Fractionated Radiotherapy in the Era of Immunotherapy.

Spatially fractionated radiotherapy (SFRT) includes historical grid therapy approaches but more recently encompasses the controlled introduction of one or more cold dose regions using intensity modulation delivery techniques. The driving hypothesis behind SFRT is that it may allow for an increased immune response that is otherwise suppressed by radiation effects. With both two- and three-dimensional SFRT approaches, SFRT dose distributions typically include multiple dose cold spots or valleys. Despite its unconventional methods, reported clinical experience shows that SFRT can sometimes induce marked tumor regressions, even in patients with large hypoxic tumors. Preclinical models using extreme dose distributions (i.e., half-sparing) have been shown to nevertheless result in full tumor eradications, a more robust immune response, and systemic anti-tumor immunity. SFRT takes advantage of the complementary immunomodulatory features of low- and high-dose radiotherapy to integrate the delivery of both into a single target. Clinical trials using three-dimensional SFRT (i.e., lattice-like dose distributions) have reported both promising tumor and toxicity results, and ongoing clinical trials are investigating synergy between SFRT and immunotherapies.