Minimum and optimal requirements for a safe clinical implementation of ultra-high dose rate radiotherapy: A focus on patient’s safety and radiation protection

tudies in multiple animal species have shown that ultra-high dose rate (UHDR) irradiations improve normal tissue sparing while providing equivalent tumor control compared to conventional dose rates. This effect is called the ‘FLASH’ effect.
After a number of favorable pre-clinical experiments and the first patients treated, clinical trials have been launched [1], [2], [3], [4], [5], [6], [7] and the clinical transfer of UHDR radiation therapy (UHDR-RT) will probably occur in the next few years. The clinical implementation of UHDR-RT needs to be performed with the highest level of safety to prevent adverse events.
Multiple UHDR-RT modalities have been proposed including high-energy electrons (HEE, 4–50 MeV) [8], [9], [10], very high-energy electrons (VHEE, 50–300 MeV) [11], [12], MV photons [13],proton [6], [14], [15], [16] and ion beams [17]. HEE and proton beams are closest to clinical transfer because existing (pre)clinical devices are already capable to reach UHDR conditions, and UHDR VHEE machines will most likely be clinically implemented in the next 5 years. Therefore, in the following discussion we will mainly focus on HEE, VHEE and proton beams. However, many of our recommendations could be extended to other beam types, and we will indicate such possibilities in the text. Taylor et al. [18] designed a roadmap to safe and effective clinical trials of FLASH RT highlighting the technological and process requirements with respect to conventional RT to enable the clinical translation. Several recommendations have been made, and among these one suggested that international organizations such as AAPM, ESTRO and EFOMP continue to collaborate on guidance. More recently, Zou et al. [19] proposed a framework on quality assurance (QA) on UHDR-RT clinical trials and reviewed current technology gaps to overcome, with a focus on electron and proton modalities.
The main objective of this document is to highlight specific requirements that the radiation oncology community should need to address to harmonize and standardize important aspects of UHDR-RT related to patient safety and radiation protection. In particular, because UHDR-RT is still in its infancy, two levels of requirements have been defined: (a) minimum requirements related to the state of the art for safe clinical implementation and (b) optimal requirements to be fulfilled when specific technology becomes available in the future. As much as possible, these requirements have been extended from and are in line with existing guidelines for conventional RT delivery techniques [20], [21], [22], [23], [24], [25], which represent the standard-of-care references for any novel UHDR delivery technique. For VHEE RT and other newly emerging UHDR treatment modalities for which no respective established conventional technique and recommendations exist, one or a mixture of multiple recommendations could be followed, as applicable. For instance, established recommendations for intensity-modulated radiotherapy, electron and proton RT may be relevant for VHEE RT using scanned beams. Therefore, inter-comparability based on conventionally established criteria should be ensured.
The FLASH effect has been observed in experiments starting from dose rates around 30 Gy/s and irradiation times below 1 s. Therefore, these recommendations can be considered to be valid starting from around this dose rate. However, the exact threshold in beam current for UHDR might be different depending on the delivery technique and/or the machine considered, and therefore particular care needs to be taken when implementing these recommendations, especially for dose rate levels close to this threshold.
Another objective is to steer a revision of RT regulations that takes into consideration the specific needs of UHDR-RT.
It is not the intent of this work to provide information about machine commissioning or technical and dosimetric challenges of UHDR-RT. These topics are or will be covered by publications coming from working groups, such as the UHDPulse project group [26], AAPM/ESTRO task group 359 [27], and the recently established ESTRO FLASH Focus Group.
This paper and another one in preparation on recording and reporting of UHDR-RT originated from the ESTRO physics workshop on “Physics aspects of FLASH”, held in October 2021.
This work is structured in three sections. The first section addresses patient and staff safety issues related to the use of UHDR beams, such as beam monitoring and the requirements for radiation protection. The second section deals with patient safety in the simulation, treatment delivery, and verification phases, and the last section is dedicated to QA.