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

Abstract

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.

Fig. 1.

Representative GRID patterns created by a (A) Cerrobend block or (B) multileaf collimators, reproduced with permission from Neuner et al.

Fig. 2.

(A) Taken with permission from Mohiuddin et al, a patient with an uncontrolled 18-cm nodal melanoma mass, progressing after IL-2, ipilumimab, and pembrolizumab. The authors treated with 20-Gy SFRT followed by 50-Gy conventional EBRT and pembrolizumab with a complete and sustained response. (B) Taken with permission from Kaiser et al, a rapidly progressing upper extremity spindle cell sarcoma despite conventional EBRT was treated with 18-Gy GRID boosted by 32-Gy EBRT. Tumor regression was 90%, including gross tumor involving the medial humerus that was shielded. Abbreviations: EBRT = external beam radiation therapy; SFRT = spatially fractionated radiation therapy.

Fig. 3.

Treatment planning of a patient with lung cancer, reproduced with permission from Almendral et al. (A) Anteroposterior view. (B) Transverse view. The nonuniform dose distribution peaks at entry near the skin and attenuates as it approaches the anterior aspects of the tumor.

Fig. 4.

Taken with permission from Kanagavelu et al (© 2019 Radiation Research Society), cartoon depiction of 3 radiotherapy conditions. Group II, with two 10% irradiated volumes, had better ipsilateral and contralateral tumor control.

Fig. 5.

Lattice radiation therapy treatment plan of bulky ovarian tumor involves creating high-dose spheres distributed within the 3-dimensional tumor volume, reproduced with permission from Blanco-Suarez et al.

Fig. 6.

Treatment planning for a brain tumor, reproduced with permission from Martinez-Rovira et al. Proton GRID allows for more precise dosing to spare normal tissue in sensitive organs at risk.