FLASH: Current status and the transition to clinical use

The rapid advancement of FLASH radiation research is changing our fundamental understanding of the in vivo interactions of high doses of radiation in both animals and humans. Based on the groundbreaking early report of differential normal tissue sparing at ultra-high dose rates (UHDR),1 taken here as >40 Gy/s, the use of FLASH potentially widens the therapeutic window and may change clinical practice by allowing higher tolerable total doses or reducing toxicities. However, the underlying science remains to be fully understood, and the required application techniques need to be developed. These gaps make the following research and development steps vital for a scientifically based transition to FLASH clinical practice. Therefore, we believe it is crucial now to address the current knowns and unknowns around FLASH and look to the horizon of how FLASH practice may evolve and the steps needed to get there. This special issue is organized into four FLASH topical divisions: the physics of FLASH technology and dosimetry, underlying mechanisms, preclinical investigations, and preparation for translation to clinical practice. The contributions are mainly from senior leaders in the field of FLASH, predominantly medical physicists (also biologists and clinicians), but also include some exciting results from early-career investigators. The first contribution in the FLASH physics section is “Ultra-High Dose Rate Radiation Production and Delivery Systems Intended for FLASH,” which considers the FLASH system requirements based on existing FLASH results and covers accelerator and UHDR delivery developments for preclinical and clinical use. As a review of a developing field, the paper also introduces a comprehensive set of FLASH terminology. The “Practical Guide to FLASH Investigations and Dosimetry” is intended to convey practice suggestions for new FLASH users. Next, the underlying FLASH mechanisms are explored. Crucial to our understanding of the potential physicochemical effects of FLASH is the manuscript “Model Studies of the Role of Oxygen in the FLASH Effect,” where three related hypotheses are proposed, compared, and contrasted with the current results. Adding further understanding is the “Radiobiology of the FLASH Effect” paper, where additional biological mechanisms, such as inflammatory processes, DNA damage and misrepair, altered metabolic and detoxification pathways, and/or repair pathways used by tumor cells, are considered. Subsequently, assessments of the current preclinical FLASH status for different radiation types are explored. Although most radiation therapy treatments are delivered using X-rays, few preclinical data generated using UHDR X-ray irradiation have been published. “FLASH Radiotherapy with Photon Beams” focuses on different methods that can be used to generate UHDR X-rays and their beam characteristics along with their effects. The contribution “Ultra-High Dose Rate Electron Beams and the FLASH Effect: From Preclinical Evidence to a New Radiotherapy Paradigm” provides a comprehensive review of the many results generated from electron FLASH experiments. “The Current Status of Preclinical Proton FLASH Radiation and Future Directions” presents the practical details of performing FLASH irradiations with existing proton therapy systems, including the growing preclinical evidence. The paper “FLASH Radiotherapy with Carbon Ion Beams” challenges the misconception that FLASH is not for heavier ions. The authors discuss the technical challenges in beam delivery and present a promising solution using 3D range-modulators to apply UHDR with carbon (C) ions. Furthermore, possible outcomes of C-ion therapy at UHDR on the level of the radiobiological and radiation chemical effects are discussed. The final topic leads us into the future of routine FLASH in clinical practice. In “Treatment Planning for FLASH Radiotherapy,” a few clinical sites are investigated for FLASH treatment planning. The potential, challenges, and dependencies for achieving UHDR in clinical cases are discussed. This paper also presents the necessary planning functions for optimizing and evaluating FLASH treatment plans. Next, the paper “Image Guidance for FLASH Radiotherapy” examines the needed developments, beyond state-of-the-art, in image-guidance techniques for better planning, delivery, and treatment response assessment of FLASH radiotherapy, including new opportunities enabled by the unique nature of UHDR pulsed beams. Following on from that, the paper “A Quantitative FLASH Effectiveness Model to Reveal Potentials and Pitfalls of High Dose Rate Proton Therapy” discusses the practical FLASH delivery potential of existing proton cyclotrons. As observed in “Treatment Planning for FLASH Radiotherapy,” new optimization tools are needed for FLASH planning. It is expected that such tools will become available in the future in treatment planning systems. A look at how the new treatment planning optimization tool might function is presented in the contribution “Simultaneous Dose and Dose Rate Optimization (SDDRO) of the FLASH Effect.” Notably, the final paper, “A Roadmap to Clinical Trials for FLASH,” serves as a caution regarding the critical need to perform FLASH prospective clinical trials safely and effectively. The paper reviews the state of FLASH's quality assurance and safety systems, and what is likely needed to move forward to clinical trials. Additional information is given in defining the critical data points necessary for curative FLASH investigations and a formal list of issues to be addressed before those trials. In summary, the advent of FLASH technology has the potential to improve treatment outcomes for cancer patients and reduce the toxicity burden associated with radiation therapy. As with any new science and technology, many of the details remain to be elucidated. Nevertheless, the need is urgent. This special issue provides a detailed perspective of the current state of knowledge regarding FLASH, and vitally, a view into current developments in the field and the soon-to-be-realized methods and systems leading us to the application of FLASH in clinical practice.