FLASH radiotherapy: Challenges and its future

The goal of radiotherapy is to deliver a high dose to target and to spare the normal tissues and organs at risks. To achieve this goal, the innovative FLASH radiotherapy (FLASH-RT) showed more promising results, compared to conventional radiotherapy.[1,2] FLASH radiotherapy is an innovative technique which can deliver an extremely high dose of radiation (>40 Gy/s) to the tumor in a very short period of time, typically within a fraction of a second, whereas conventional radiotherapy (2–10 Gy/min) delivers radiation in multiple fractions over a period of many weeks.[1-4] In conventional radiotherapy, doses to the nearby organ at risks are a limiting factor, to escalate the dose to the tumor; on the other hand, FLASH-RT has the potential to increase the therapeutic ratio by selectively damaging cancer cells while minimizing damage to surrounding normal tissues.[2] Ultrahigh dose rate alone is not enough to describe the expected biological response, other variables, i.e. the dose per fraction, dose rate during the treatment, type of radiation, and overall irradiation time, must be considered for better treatment outcome.[1-5] However, mechanism behind the FLASH RT is not much known but as per widely accepted hypothesis, acute oxygen depletion takes place in the irradiated tissues which results in different biological response of normal tissue and cancer cells due to their different oxygen level status.[1-8] Oxygen works as radiation sensitizer, oxygen-rich tissue has stronger radiosensitivity compared to hypoxic tissue, when exposed to same radiation this effect is quantified by oxygen enhancement ratio (OER).[5-10] As FLASH-RT will be delivered in microseconds, oxygen in the tissue is rapidly exhausted, and this whole process is very fast so that it cannot be supplemented by circulating blood, which may be one of the reasons why FLASH-RT can protect normal tissue.[3-9] Studies conducted to evaluate toxicity in mouse models and bacteria and eukaryotic cellular models[5-10] show that ultrahigh dose rate reduces the oxygen level in normal tissue, resulting in radioresistance of healthy tissues, which helps in sparing normal tissues around the target.[7-10] Computer-based model analysis also showed that FLASH-RT can protect normal tissues and cells under complete hypoxia.[10] In early 1950, it was observed that less damage in normal tissues happens when exposed to ultrahigh dose rate of radiation compared to conventional dose rates.[1-3] Further, in preclinical studies observed depletion in bacterial cell sensitivity when exposed to large pulses of radiation in cells with oxygen hypoxia.[1-10] In 1971, Hornsey et al.[5] conducted a study on small animals and observed that the effectiveness of whole-body irradiation in mice was diminished when oxygen was administered during irradiation at dose rates exceeding 6 krads/min. In further studies (1978), Ling et al.[6] used two electron pulses separated by 3 ns to obtain the cell survival curves and found that the first pulse was sufficient for oxygen depletion.[6] In 2014, V. Favaudon et al.[7] coined the term FLASH. Further in preclinical research, 28–34 Gy has been delivered to pig skin (volume <10 cc) and showed no necrosis at nine months compared to conventional radiotherapy.[8] In 2019, Bourhis et al. safely treated the first patient of T-cell cutaneous lymphoma disseminated throughout the whole skin surface with FLASH radiotherapy at the Lausanne University Hospital, Switzerland; during that time most of FLASH-RT studies were carried out with high-energy electron beams.[3] FLASH-RT also showed encouraging results in first human trial, delivered with proton ultrahigh-dose-rate radiation to 10 patients, with one to three painful bone metastases at their extremities, as a result of FLASH-RT, seven out of the 10 patients experienced complete or partial pain relief in the trial conducted at Varian and the Cincinnati Children’s/UC Health Proton Therapy Center.[11] There are approximately only 12 heavy ion facilities around the world; therefore, not much published literature is available for heavy ion FLASH-RT. The use of photon for FLASH-RT was not explored much due to technological limitation and very low efficiency of photon FLASH generation. FLASH-RT has various limitations: firstly, due to significant difference in dose rates between conventional radiotherapy and FLASH-RT, it is difficult to correlate the biological response of FLASH-RT with previously established conventional biological dose rate fractionation models; therefore, they need to be explored further.[1-5] Proton energies (approximately 200 MeV) have sufficient range to penetrate in body (15–20 cm). Buonanno et al.[12] observed that proton radiation involves higher dose rates delivered in nanoseconds. Therefore, proton can be suitable energy for FLASH-RT, but influence of high LET and Bragg peak needs to be evaluated for FLASH-RT. The electron energies up to 25 MeV have limited penetration depth, while the use of very high-energy electrons (VHEE, 50–250 MeV) poses a technological limitation due to their generating devices and large lateral penumbra.[13,14] It is hard to consider the photon beam (15 MV) for FLASH-RT, because achieving ultrahigh dose rate with photon still needs to be worked out due to the requirement of thousand times more electron fluence generating linac compared to conventional linac.[12-14] The modification in currently available linear accelerator’s technology has to be worked out to generate ultrahigh dose rates for FLASH-RT. Petersson et al.[14] described the potential to convert conventional linacs into FLASH-RT devices. Lempart et al.[15] also demonstrated the possibility of generating ultrahigh dose rates with linear accelerators after modifications. Accurate dose measurement of FLASH-RT is challenging, as physical and chemical properties of a detector which is used for dose measurements are dependent on time. Studies have to be designed to explore for the suitable detector, which can measure the ultrahigh dose rate.[7-14] The passive thermoluminescent detectors (TLD), optically stimulated luminescence detectors (OSLD), and Gafchromic EBT3 film can be used for measurement of ultrahigh dose rates due to their dose rate independence.[10-15] If the limitations of FLASH-RT have been resolved, then it will bring great change in the field of radiation oncology as the treatment will be given in just the blink of an eye without much toxicity to normal tissues. Because FLASH RT can be delivered within a fraction of second, therefore need not to apply much corrections for intra fraction target motion. FLASH-RT will also solve the problem of large radiation treatment waiting list in developing countries. Even though this new technique of FLASH-RT looks very revolutionary, still many more aspects regarding this technique’s feasibility need to be explored before its clinical implementation.