Divide and conquer: spatially fractionated radiation therapy

Abstract

Spatially fractionated radiation therapy (SFRT) challenges some of the classical dogmas in conventional radiotherapy. The highly modulated spatial dose distributions in SFRT have been shown to lead, both in early clinical trials and in small animal experiments, to a significant increase in normal tissue dose tolerances. Tumour control effectiveness is maintained or even enhanced in some configurations as compared with conventional radiotherapy. SFRT seems to activate distinct radiobiological mechanisms, which have been postulated to involve bystander effects, microvascular alterations and/or immunomodulation. Currently, it is unclear which is the dosimetric parameter which correlates the most with both tumour control and normal tissue sparing in SFRT. Additional biological experiments aiming at parametrizing the relationship between the irradiation parameters (beam width, spacing, peak-to-valley dose ratio, peak and valley doses) and the radiobiology are needed. A sound knowledge of the interrelation between the physical parameters in SFRT and the biological response would expand its clinical use, with a higher level of homogenisation in the realisation of clinical trials. This manuscript reviews the state of the art of this promising therapeutic modality, the current radiobiological knowledge and elaborates on future perspectives.

Radiobiological and Treatment-Related Aspects of Spatially Fractionated Radiotherapy

“…The two main variants of SFRT with photons that have been studied and implemented include GRID radiotherapy (GRID RT) and lattice radiotherapy (LRT)—a 3D configuration of GRID, delivering spherical subvolumes of a high dose within the tumour. Ultra-high-dose-rate methods, including FLASH and microbeam radiotherapy, and LRT are beyond the scope of this review and can be found elsewhere in the literature [ 2 , 10 , 31 , 38 , 39 , 40 ].…”

Should Peak Dose Be Used to Prescribe Spatially Fractionated Radiation Therapy?—A Review of Preclinical Studies

“…Spatially fractionated radiation therapy (SFRT) is an unconventional radiotherapy (RT) that has been used clinically since the 1970s. In parallel, SFRT has also been the subject of preclinical research for decades [ 1 , 2 , 3 , 4 , 5 , 6 , 7 ]. In recent years, SFRT has attracted renewed and enthusiastic interest in radiation oncology [ 5 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ].…”

“…In recent years, SFRT has attracted renewed and enthusiastic interest in radiation oncology [ 5 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ]. Compelling data from preclinical research and some, but still limited, clinical studies have indicated that SFRT may lead to a very high therapeutic ratio compared with conventional RT [ 5 , 6 , 7 ]. Instead of the seamless dose distribution of conventional RT, SFRT has its signature dose distribution, which is characterized by a juxtaposition of many small dose hot spots and cold spots in space in an oscillating pattern [ 5 ].…”

“…Numerous preclinical SFRT studies have shown that normal tissue tolerates irradiation exceptionally well, even when the peak dose is 100 Gy or more in a single treatment [ 17 , 18 , 19 , 20 ]. The sparing of normal tissue in conjunction with the tumor ablation of preclinical SFRT has been shown to significantly prolong animal survival [ 6 , 15 , 21 , 22 , 23 , 24 ]. For clinical application, SFRT is delivered in larger geometric dimensions (peak width in the order of 1 cm), originally in the form of GRID therapy [ 8 ], as shown in Figure 1 , and later in the form of lattice therapy for 3D fractionation (not shown) [ 9 ].…”

A matter of space: how the spatial heterogeneity in energy deposition determines the biological outcome of radiation exposure

“…It has also been known for quite a long time now that the use of heterogeneous spatially fractionated beams that deliver a non-uniform dose distribution to the target mass can lead to an advantage, particularly in terms of normal tissue sparing, while maintaining an anti-tumour effect (Prezado 2022 ). Examples of such spatially fractionated radiation treatments are grid therapy and the still pre-clinical mini- and microbeam therapy approaches.…”