Spatially fractionated radiation therapy: a critical review on current status of clinical and preclinical studies and knowledge gaps.

Spatially fractionated radiation therapy (SFRT) is a therapeutic approach with the potential to disrupt the classical paradigms of conventional radiation therapy. The high spatial dose modulation in SFRT activates distinct radiobiological mechanisms which lead to a remarkable increase in normal tissue tolerances. Several decades of clinical use and numerous preclinical experiments suggest that SFRT has the potential to increase the therapeutic index, especially in bulky and radioresistant tumors. To unleash the full potential of SFRT a deeper understanding of the underlying biology and its relationship with the complex dosimetry of SFRT is needed. This review provides a critical analysis of the field, discussing not only the main clinical and preclinical findings but also analyzing the main knowledge gaps in a holistic way.

Prezado Y ，Grams M ，Jouglar E ，Martínez-Rovira I ，Ortiz R ，Seco J ，Chang S ... -  《-》

A journey to understand SFRT.

This article tells the story of a medical physicist's journey to understand SFRT which started by accident more than 15 years ago. For decades, clinical application and preclinical research have shown that spatially fractionated radiation therapy (SFRT) can achieve a magically high therapeutic index. However, only recently, SFRT received well-deserved attention from mainstream radiation oncology. Today, our understanding of SFRT remains limited, which significantly hinders the advancement of SFRT for patient care. In this article, the author intends to shed some light on several important but unanswered SFRT research questions, including what is the essence of SFRT, which dosimetric parameters have clinical relevance and which do not, how does SFRT spare normal tissue but not tumor, and why radiobiological models developed for conventional radiation therapy may not be suitable for SFRT.

Chang S 《-》

Overview and Recommendations for Prospective Multi-institutional Spatially Fractionated Radiation Therapy Clinical Trials.

Li H ，Mayr NA ，Griffin RJ ，Zhang H ，Pokhrel D ，Grams M ，Penagaricano J ，Chang S ，Spraker MB ，Kavanaugh J ，Lin L ，Sheikh K ，Mossahebi S ，Simone CB ，Roberge D ，Snider JW ，Sabouri P ，Molineu A ，Xiao Y ，Benedict SH ... -  《-》

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.

McMillan MT ，Khan AJ ，Powell SN ，Humm J ，Deasy JO ，Haimovitz-Friedman A ... -  《-》

Clinical aspects of spatially fractionated radiation therapy treatments.

To provide clinical guidance for centers wishing to implement photon spatially fractionated radiation therapy (SFRT) treatments using either a brass grid or volumetric modulated arc therapy (VMAT) lattice approach. We describe in detail processes which have been developed over the course of a 3-year period during which our institution treated over 240 SFRT cases. The importance of patient selection, along with aspects of simulation, treatment planning, quality assurance, and treatment delivery are discussed. Illustrative examples involving clinical cases are shown, and we discuss safety implications relevant to the heterogeneous dose distributions. SFRT can be an effective modality for tumors which are otherwise challenging to manage with conventional radiation therapy techniques or for patients who have limited treatment options. However, SFRT has several aspects which differ drastically from conventional radiation therapy treatments. Therefore, the successful implementation of an SFRT treatment program requires the multidisciplinary expertise and collaboration of physicians, physicists, dosimetrists, and radiation therapists. We have described methods for patient selection, simulation, treatment planning, quality assurance and delivery of clinical SFRT treatments which were built upon our experience treating a large patient population with both a brass grid and VMAT lattice approach. Preclinical research and patient trials aimed at understanding the mechanism of action are needed to elucidate which patients may benefit most from SFRT, and ultimately expand its use.

Grams MP ，Deufel CL ，Kavanaugh JA ，Corbin KS ，Ahmed SK ，Haddock MG ，Lester SC ，Ma DJ ，Petersen IA ，Finley RR ，Lang KG ，Spreiter SS ，Park SS ，Owen D ... -  《-》