# Transformative Technology for FLASH Radiation Therapy
## 1 Introduction  
Radiation therapy is a dynamic research field driven by new technology developments. An exciting recent discovery is the sparing of normal (non-tumor) tissues when irradiated with ultra-high dose rates, but tumors are not spared when irradiated with the same radiation field, as first reported by [PERSON] and colleagues in 2014 [1]. This phenomenon, which is now called the FLASH effect, opens up a potential new modality in radiation therapy (RT). Tissue sparing means that much higher radiation doses than conventionalones are tolerated, increasing the potential for a cure with an accompanying reduction in side effects. Many preclinical and first clinical results indicate a dramatic reduction of the toxicity response at FLASH-RT dose rates compared to conventional dose rates. The first human patient was treated with FLASH RT in 2019 at CHUV, a 75-year-old man with progressive cutaneous T-cell lymphoma presenting with multiple skin lesions. Between 2008 and 2018, the patient was treated with conventionally fractionated RT 110 times for painful or ulcerated lesions. This led to local tumor control at those sites but was often associated with poor skin tolerance. FLASH RT was delivered to a previously untreated tumor site at a dose of 15 Gy with 5.4 MeV electrons in 90 ms [2]. Of note, the same dose of 15 Gy was delivered on the same day in 2.87 min as conventional electron therapy to another untreated lesion of similar size, allowing a comparison of the two modalities in the same patient. The skin reaction was minimal (grade 1) in both treated lesions, and the surrounding skin appeared normal 85 days after either FLASH or conventional radiotherapy. These first human data demonstrated that the dose range, if any, where noticeable improvement in human skin tolerance with FLASH RT occurs, is currently unknown [3]. At CHUV, a dose-finding study has been initiated with a clinical trial (IMPulse, NCT04986696) in refractory metastatic melanoma [4]. Most FLASH experiments and preclinical studies have been performed with electrons and, more recently, with cyclotron-generated protons. However, conventional radiotherapeutic electron beams (4-25 MeV) cannot penetrate enough to treat deep-seated tumors and are thus not likely to be widely used clinically for FLASH-RT. The distal dose fall-off of electrons in tissue is quite shallow as electrons are scattered and have considerable energy straggling, especially at low energies. Protons are currently the most commonly used heavy-charged particle in RT with a Bragg peak dose and finite range advantage. They are also beginning to be used for the first treatment-planning studies for clinical trials with FLASH-RT [5; 6] as well as clinical trials. For example, FAST-01 (NCT04592887) is a feasibility study of FLASH RT for the treatment of symptomatic bone metastases that completed recruitment and has been reported [7; 8], and FAST-02 (NCT05524064) is a follow-up clinical trial of FLASH RT for the treatment of symptomatic bone metastases in the thorax, currently recruiting. Heavy ions, such as carbon and helium, are not widely used despite a potentially much greater therapeutic effect due to the high linear energy transfer (LET). The high associated costs of ion accelerator and gantry technologies have prevented their widespread use. However, several carbon ion facilities are operational in Europe and Asia, particularly Japan. Considerable research and development (R&D) in this area is essential for optimizing and clinically realizing the curative potential of FLASH-RT with different radiation modalities. Currently, electron FLASH studies are performed using dedicated 4-6 MeV electron research accelerators that have been optimized for delivering FLASH radiation (Kinetron and Oriatron) or modified medical linacs, originally designed for treatment with electrons or X-rays (see [4] and references therein). These studies provide the strongest, most consistent preclinical evidence for the FLASH effect.