A Current Review of Spatial Fractionation: Back to the Future?

Spatially fractionated radiation therapy represents a significant departure from canonical thinking in radiation oncology despite having origins in the early 1900s. The original and most common implementation of spatially fractionated radiation therapy uses commercially available blocks or multileaf collimators to deliver a nonconfluent, sieve-like pattern of radiation to the target volume in a nonuniform dose distribution. Dosimetrically, this is parameterized by the ratio of the valley dose in cold spots to the peak dose in hot spots, or the valley-to-peak dose ratio. The radiobiologic mechanisms are postulated to involve radiation-induced bystander effects, microvascular alterations, and/or immunomodulation. Current indications include bulky or locally advanced disease that would not be amenable to conventional radiation or that has proved refractory to chemoradiation. Early-phase clinical trials have shown remarkable success, with some response rates >90% and minimal toxicity. This has promoted technological developments in 3-dimensional formats (LATTICE), micron-size beams (microbeam), and proton arrays. Nevertheless, more clinical and biological data are needed to specify ideal dosimetry parameters and to formulate robust clinical indications and guidelines for optimal standardized care.