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Year : 2020  |  Volume : 16  |  Issue : 6  |  Page : 1203-1209

Efficacy and toxicity of FLASH radiotherapy: A systematic review

1 Radiation Oncology Research Center, Cancer Institute, Tehran University of Medical Science, Tehran, Iran
2 Department of Medical Physics, Tehran University of Medical Sciences, Tehran, Iran
3 Misan Radiotherapy Center, Misan Health Directorate, Ministry of Health/ Environment; Department of Physiology, College of Medicine, University of Misan, Amarah, Iraq
4 Department of Medical Physics, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
5 Radiation Oncology Research Center, Cancer Institute; Department of Medical Physics, Tehran University of Medical Sciences, Tehran, Iran

Date of Submission16-Feb-2020
Date of Decision30-May-2020
Date of Acceptance12-Aug-2020
Date of Web Publication18-Dec-2020

Correspondence Address:
Somayeh Gholami
Radiation Oncology Research center, Cancer Institute, Tehran University of Medical Science, Tehran
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_180_20

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 > Abstract 

In recent times, research on the use of ultrahigh-dose rates delivered in super-fast times in cancer treatment has been garnering interest. This has brought about the term “FLASH” radiotherapy (RT). Thus, in the present study, we systematically review these recent studies on FLASH RT with regard to its efficacy and safety. The reporting of this systematic review was done in line with the statement of Preferred Reporting Items for Systematic reviews and Meta-Analyses. Electronic search of the databases such as PubMed, Scopus, and Embase was conducted to retrieve relevant studies investigating the FLASH effect. From an initial search of 216 potential articles, 16 articles (in vivo, in vitro , and clinical studies) were finally included in this systematic review. Results showed that FLASH RT dose rates had protective effects on normal tissues in addition to antitumor effect. Although still in its early research stages, FLASH RT has the potential to rival present RT regimens in terms of safety and antitumor effect. However, further studies are needed to address the aspects such as optimal dose rate, effect on deep tumors, tumor recurrence, longer follow-up time, and mechanism of action.

Keywords: FLASH, radiotherapy, toxicity, ultrahigh-dose rate

How to cite this article:
Omyan G, Musa AE, Shabeeb D, Akbardoost N, Gholami S. Efficacy and toxicity of FLASH radiotherapy: A systematic review. J Can Res Ther 2020;16:1203-9

How to cite this URL:
Omyan G, Musa AE, Shabeeb D, Akbardoost N, Gholami S. Efficacy and toxicity of FLASH radiotherapy: A systematic review. J Can Res Ther [serial online] 2020 [cited 2021 Nov 27];16:1203-9. Available from: https://www.cancerjournal.net/text.asp?2020/16/6/1203/303891

 > Introduction Top

Radiotherapy (RT) is a major treatment modality for cancer.[1] Moreover, most cancer patients will require RT at some point during their course of treatment.[1] One of the underlying principles behind RT is the fact that normal tissues have a higher recovery compared to tumor cells when exposed to ionizing radiation. This differential effect between normal and tumor cells is mediated by the fractionation of the total radiation dose, which is aimed at protecting normal tissues. This dose is conventionally set at 2 Gy per fraction or less.[1]

One of the major challenges limiting the therapeutic efficiency of RT is the fact that some tumors are radioresistant to conventional RT doses, which are set in line with the tolerance levels of normal tissues. This has led to the dose optimization techniques in RT, including the use of biomodulatory agents as well as targeted therapies.[2],[3]

Dose rate modulation has been proposed to improve the therapeutic efficiency of RT.[4] For instance, in brachytherapy, the use of different dose rates has been largely successful in the treatment of certain tumors.[5] However, utilizing various high-dose rates still remains to be fully implemented in external beam RT. This has led to further research which in recent times has brought about the term “FLASH RT.” FLASH RT makes use of ultrahigh-dose rates in the treatment of tumors. These dose rates (usually >40 Gy/s) are several thousand times higher compared to conventional dose rates (≥0.1 Gy/s) which are in use clinically.[6]

Even though the term “FLASH” RT was coined in 2014 in a study by Favaudon et al.,[6] several attempts have been made in the past to investigate the effect of ultrahigh-dose rates. Some of the earliest studies were observed for the skin and intestine in a mouse model,[7],[8] with their findings showing a decrease in normal tissue toxicities. This was further confirmed in a study by Hendry et al.[9] showing a reduction in necrosis in mice tail exposed to dose rates above 105 Gy/s from a 10 MeV electron beam. Increased cell survival after irradiation with ultrahigh-dose rates has also been reported for bacterial and mammalian cells.[10],[11] Although these early studies did not investigate the effect of ultrahigh-dose rates on tumors, they have given a good basis for further research into the use of ultrahigh-dose rates. Thus, in the present study, we systematically review recent findings on FLASH RT, discussing its efficacy, toxicity, and treatment outcomes.

 > Materials and Methods Top

Literature search

The reporting of this systematic review was done in line with the statement of Preferred Reporting Items for Systematic Reviews and Meta-Analyses.[12] An extensive literature search was performed on the databases of PubMed, Scopus, and Embase for recent articles (from 2014 up to the end of May 2020) investigating the use of FLASH RT. The search keywords were as follows: “FLASH,” “ultra-high dose rate,” and “radiotherapy.” Manual screening of references of retrieved studies was conducted to obtain relevant studies.

Inclusion criteria

Articles were included based on the following criteria:

  • Recent studies (from 2014 up to the end of May 2020) published in English language investigating the use of FLASH RT and its effects on normal and tumor cells
  • Experimental (in vivo and in vitro) and clinical studies with full texts.

Exclusion criteria

Studies were excluded based on the following criteria:

  • Studies in which FLASH RT was not investigated
  • Conference abstracts, modeling studies, simulation studies, review articles, letters, editorials, unpublished data, articles without full texts, and not published in English language
  • Studies describing just the physical, chemical, or dosimetry aspects of FLASH RT.

Study selection

All relevant articles from electronic and manual searches were exported into EndNote software (EndNote Version X6, Thomson Reuters, New York, NY, USA) for the removal of duplicates. Subsequently, the titles and abstracts of remaining studies were carefully screened by two authors for eligibility based on the inclusion and exclusion criteria. Factual evidence was used in cases of disagreements involving inclusion.

Data extraction

The following data were carefully extracted from each included article: first author name, study type, tissue type, RT beam type, energy, FLASH RT dose rate, toxicity, follow-up time, and main outcomes. These data were summarized and presented in a tabular form.

 > Results Top

A breakdown of our systematic search is presented in [Figure 1]. From our initial search, a total of 216 articles were identified. From these records, duplicate articles were removed, leaving behind 187 articles assessed for eligibility. From this figure, 153 articles were excluded after careful screening of their titles, abstracts, and study types. Afterward, the full-texts of 34 articles were obtained and carefully studied. Further, 18 studies did not meet the inclusion criteria, thereby leaving behind a total of 16 studies being included in our final review.
Figure 1: PRISMA flow diagram showing the process of study inclusion

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A summary of the included studies is presented in [Table 1]. These studies, published between 2014 and 2020, were mostly in vitro and in vivo while one human study has been achieved. Furthermore, these studies utilized proton, electron, or X-ray beams with energies of 4.5–224 MeV, 4.5–20 MeV, and 93–124 KeV, respectively. The average beam dose rates ranged from 0.1 to 5.6 × 106 Gy/s.
Table 1: Summary of included studies

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Effect of FLASH radiotherapy on normal tissues

Experimental studies investigating the use of FLASH RT have shown an increase in the normal tissue tolerance to ultrahigh-dose rates. In a study by Favaudon et al.,[6] they investigated the effect of irradiation with FLASH RT (>40 Gy/s) compared with conventional dose rates (≤0.03 Gy/s) in inducing toxicity to the lungs of mice. While all mice irradiated with conventional dose rates showed severe pneumonitis and fibrosis, these side effects were nonexistent in the FLASH-irradiated group at the same dose (17 Gy). Furthermore, the use of FLASH RT prevented the activation of transforming growth factor beta (TGFβ) as well as acute apoptosis in the bronchi and vessels of normal lung tissues.

Montay-Gruel et al.[13] observed the effect of varying dose rates on neurocognitive function of mice receiving whole-brain irradiation with FLASH RT. In this study, 10 Gy radiation dose delivered at a mean dose rate above 100 Gy/s preserved cognitive function in mice; however, some cognitive impairments were detected at lower dose rates (30 and 60 Gy/s). Similar outcomes were obtained in further studies.[14],[19] Simmons et al.[21] reported amelioration of cognitive deficits after whole-brain FLASH irradiation of mice at 200 and 300 Gy/s. Furthermore, reduced loss of hippocampal dendritic spines was observed, a finding of which was also reported by Montay-Gruel et al.[19]

To achieve future clinical translation, the progression from mouse models to larger animal models is a key toward this aim. This is an important step considering the fact that there have been reported cases in which cancer therapy using mouse models did not yield desired clinical translation.[28] Thus, Vozenin et al.[16] investigated the effect of FLASH RT on the skin of a mini-pig. The animal was administered different doses between 22 and 34 Gy at various sites on its back delivered at conventional dose rate (5 Gy/min) and FLASH dose rate (300 Gy/s). Findings from this study showed that irradiation with the conventional dose rate led to acute and late toxicity with severe fibronecrosis; however, FLASH RT gave only transient depilation. Further pathological assessments showed no significant difference between the skin tissues of FLASH-irradiated mini-pig and that of the unirradiated group.

In a study by Buonanno et al.,[17] the effect of proton FLASH RT on the normal lung fibroblasts was investigated. Their findings showed that compared to conventional dose rate (0.05 Gy/s), proton FLASH RT dose rate (1000 Gy/s) had a positive effect on the number of senescence cells and the expression of TGFβ1. In addition, they showed that proton FLASH dose rate could mitigate delayed adverse effects on the normal tissues. However, it had little influence on acute effects such as clonogenic cell survival and DNA damage. Fouillade et al.[25] also showed that compared to conventional RT dose rate, FLASH RT inhibited the induction of pro-inflammatory genes, thereby sparing normal lung fibroblasts against radiation-induced DNA double-strand breaks, as well as reduced the incidence of radiation-induced senescence in the lung stem cells both in vitro and in vivo.

RT treatment planning plays a key role in ensuring pinpoint accuracy and dose conformity, thereby giving a better dose distribution as well as lower doses to organs at risk.[29] As with every new RT method, studies are conducted to design an optimal treatment plan that maximally exploits the gains of the novel treatment approach. To this aim, van Marlen et al.[24] utilized 244 MeV scanning proton transmission beams to produce stereotactic lung RT FLASH treatment plans for seven patients. While a 100% FLASH dose rate could not be achieved due to the effects of distant spots with lower dose rates, the FLASH RT treatment plans from this study were more effective in sparing the lungs, thoracic wall, and heart compared to clinical volumetric modulated arc therapy treatment plans. Moreover, the properties of clinical proton beams including good penetration depth, electromagnetic steering, as well as production of conformal dose distributions with single to few beams were the key factors responsible for improved outcomes.

Studies have also reported no significant protection of healthy tissues following irradiation at ultrahigh-dose rates. Smyth et al.[15] did a comparison between FLASH dose rate and that of conventional RT in terms of toxicity. To this aim, mice were whole and partial body irradiated at ultrahigh-dose rates ranging from 37 to 41 Gy/s. Toxicities such as loss of body weight by at least 15%–20%, severe diarrhea, dehydration, loss of appetite, as well as inflammation and long-term pulmonary damage were reported in both RT types after 38–180 days. Thus, broad beam FLASH irradiation dose rates had no significant sparing of normal tissues when compared with conventional dose rates. Although, as earlier stated, Montay-Gruel et al.[14] reported significant sparing of neurocognitive function using synchrotron FLASH irradiation at a dose rate of 37 Gy/s, differences in the beam slice dose rates as well as endpoints have been suggested as possible reasons why the sparing effect of FLASH RT had contrasting outcomes in both studies.[30] Beyreuther et al.[20] investigated the feasibility of proton FLASH RT on zebrafish embryo. Although proton FLASH RT achieved a mean dose rate of 100 Gy/s, significant prevention of acute pericardial edema when compared to conventional dose rate of 5 Gy/min was only observed at one dose point. Moreover, there was mostly no FLASH effect as well as no significant toxicity difference for zebrafish embryos. This might be due to beam differences (lower dose rates within each micropulse from quasi-continuous proton FLASH beam compared to FLASH electron macropulses) as well as biological factors (long delay in postfertilization of zebrafish).[31]

A study by Venkatesulu et al.[22] at MD Anderson Cancer Center, Texas, USA, showed that FLASH RT could also induce detrimental effects. In their study, FLASH dose rate of 35 Gy/s was found to have a potent effect in inducing acute gastrointestinal toxicity as well as in increasing apoptosis and clonogenic cell death, compared to conventional dose rate (0.1 Gy/s). Moreover, following cardiac FLASH irradiation on mice, no lymphocyte-sparing effect was observed; in fact, lymphocytes were depleted. Possible reasons for the higher toxicity of FLASH RT in this study include the tissue-specific dose rate required for sparing effect, assay-specific variations, and dosimetric variations between the modes of delivery.[22]

Effect of FLASH radiotherapy on tumor

The antitumor effect of FLASH RT has been investigated in several studies. Favaudon et al.[6] demonstrated the isoefficacy of FLASH RT in comparison with conventional RT using subcutaneously xenografted tumors and orthotopic lung tumors. FLASH RT allowed for safe dose escalation for the lungs up to 28 Gy. Furthermore, it was shown that 8 weeks after RT, 70% of the 28 Gy FLASH-irradiated mice were free of pulmonary tumors and lung complications, while only 20% of the 15 Gy mice that exposed to conventional dose rate were tumor-free, albeit with severe pneumonitis and prefibrotic remodeling. This was the first study showing dose escalation by FLASH RT and consequently its promising antitumor efficacy.

Another dose escalation effect of FLASH RT was examined by Vozenin et al.[16] on six cats with locally advanced squamous cell carcinoma. From a starting dose of 25 Gy, it was steadily increased up to 41 Gy in the absence of dose-limiting toxicities. Findings from this study showed that macroscopic complete response was obtained in all six cats at 3 months as well as progression-free survival rate of 84% at 16 months. It is important to note that while this study showed impressive tumor control, significant sparing effect on the normal tissues was obtained. Moreover, no acute toxicity was observed in three cats, while the rest only showed transient erythema and moist desquamation which were well tolerated and healed after a few weeks. At last, the only late toxicity that was reported was depilation.

A study by Adrian et al.[23] used prostate cancer cell line DU145 to investigate how oxygen concentration influences the FLASH effect. Their results showed no differences between FLASH and conventional irradiation during normoxic conditions. However, FLASH irradiation showed increased survival compared to conventional at hypoxic conditions, hence showing that the oxygen concentration influences the FLASH effect. Studies by Diffenderfer et al.[26] (on pancreatic cancer flank tumors) and Levy et al.[27] (on ID8 ovarian cancer cells) also reported no differences between FLASH RT and conventional RT in terms of inhibition of tumor growth. However, FLASH RT significantly spared small intestinal tissues against loss of stem cells and radiation-induced fibrosis.

At present, studies investigating the antitumor effect of FLASH RT have been limited to just one human study by Bourhis et al.[18] on a 75-year-old patient with multiresistant CD30+ T-cell cutaneous lymphoma on the skin. The patient had previously undergone RT regimens of 20 Gy in 10 fractions or 21 Gy in 6 fractions. However, due to very poor tolerance of the patient's skin which led to acute skin reactions, a switch to FLASH RT was proposed. Thus, the patient underwent treatment with FLASH RT at 167 Gy/s to the planning target volume. Ten days after FLASH irradiation, the tumor began to shrink with a complete tumor response after 36 days. Side effects such as grade 1 epithelitis as well as grade 1 edema were observed after 3 weeks. These toxicities were only limited to these grades and were well tolerated. After a follow-up of 5 months, a rapid tumor response was observed. Thus, in addition to tumor control, FLASH RT showed no severe side effect on the normal tissues.

 > Discussion Top

From the results of included studies, FLASH RT dose rates appear to have a higher safety potential when compared to conventional RT dose rates. This has been validated by its reproducibility in various animal models (mice, rat, zebrafish, pig, and cats) and organs (lung, skin, gut, and brain). This consistency from experimental studies has given rise to favorable treatment outcomes as observed in the first clinical study.[18]

Although the biological mechanisms responsible for the protection or reduction of the normal tissue toxicities by FLASH RT dose rates are not fully understood, several possible reasons have been proposed. It has been shown that a lack of oxygen (hypoxia) in the immediate environment of a cell limits the extent of radiation-induced DNA damage.[32] Thus, irradiation of tissues at FLASH RT dose rates results in radiochemical oxygen depletion, leading to an extremely acute period of hypoxia within the irradiated tissue and consequently a transient radioresistance. In contrast to conventional irradiation delivered at much smaller pulses spanning longer period of time, oxygen depletion is limited; hence, there is sufficient time for oxygen to diffuse into the irradiated region to replace oxygen that has been lost. Therefore, oxygen concentration within the irradiated tissue is maintained.[30]

Free radicals also have a role in the mechanism of FLASH RT. Due to the ultra-short time of radiation delivery in FLASH RT, the irradiated tissue bed becomes saturated within microseconds. This leads to the production of instantaneous burst of free radicals, while irradiation at conventional dose rates produce free radicals in a more chronic manner spanning minutes.[11],[33] These free radicals could react either directly or indirectly with the DNA, leading to temporary or permanent DNA damages, respectively. If a hypoxic (radioresistant) tumor is surrounded by an oxic normal tissue (radiosensitive), ultrahigh-dose rates will enhance the radioresistance of the normal tissue with little effect on the already hypoxic tumor.[34] This gives rise to the improved therapeutic ratio as well as wider tumor control probability (TCP)–normal TCP window of FLASH RT. A radiochemical modeling study also showed that FLASH RT at a dose of ≥10 Gy has potentials to deplete molecular oxygen in the tissues at physiologic oxygen tensions, as oxygen rapidly reacts with radicals formed by radiolysis of water and other biomolecules (ROS).[35]

In view of the ultra-fast treatment time, its effect on chromatin remodeling as well as inflammatory and anti-inflammatory cell signaling has also been suggested as the possible factors behind the FLASH effect.[36] Thus, only the circulating immune cells within the treatment volume are irradiated and killed. Conversely, at conventional RT dose rate, circulating immune cells continuously flow into the irradiated volume with the blood so that more immune cells are irradiated and killed. Hence, FLASH RT may spare a substantial amount of circulating immune cells compared to conventional RT.

It has been proposed that to induce the FLASH effect, the irradiation beam should ideally be pulsed at a frequency in the order of 100 Hz.[30] In addition, within each pulse, irradiation should be delivered at sufficiently high dose per pulse (≥1 Gy) and dose rate within the pulse (≥106 Gy/s), leading to a maximum total treatment time of a few tenths of a second. Further, for studies making use of synchrotron irradiation beams, the dose rate within the beam slice is the most important parameter. Thus, variations in beam slice dose rate have a role in the normal tissue-sparing effect of FLASH RT. In contrast to synchrotron irradiation beams, proton minibeam radiation therapy maintains the spatial fractionation of the dose at the entrance of the beam as well as in the beam path. Furthermore, it generates a more uniform dose compared to synchrotron radiation in a target at depth, achieves a higher dose at any depth than in the path, and preserves tissues after the target by the inherent property of a determined range of proton beams.[31] Thus, for clinical treatment of tumors with proton beam, the beam needs to be scattered or scanned to cover the target volume which reduces the average dose rate.[24] The effect of increased linear energy transfer in the Bragg peak as well as scattering/scanning of the beam should be investigated in further experimental studies of the FLASH effect using proton beam.

Despite the promising results from the included studies, some concerns will need to be addressed. First, in terms of toxicity, in the study by Venkatesulu et al.,[22] FLASH irradiation when compared to conventional was observed to induce the potent detrimental effects including lymphocyte depletion as well as increased apoptosis and clonogenic cell death. Furthermore, acute gastrointestinal syndrome was also obtained, which is in contrast to a conference publication by Loo et al.[37] The study by Loo et al. gave whole abdominal irradiation on male C57BL/6 mice with doses between 10 and 22 Gy delivered at a conventional dose rate of 0.05 Gy/s as well as FLASH dose rates of 70 and 210 Gy/s. Their results showed significant increase in the survival for mice exposed to FLASH dose rates compared to conventional (90% vs. 29%). Thus, by comparing the outcomes from both studies, it appears that the normal tissue-sparing effect of FLASH RT is dose rate dependent. Thus, further studies would be required to investigate the optimal dose rate for FLASH RT.

With regard to treatment modality, FLASH RT was shown to be feasible using different RT beams including electron, proton, as well as synchrotron radiation and photons from medical linacs. However, it remains to be seen how these beams will be feasible when dealing with deeper tumors. If this is not achieved, future clinical translation of FLASH RT may just be limited to superficial tumors. Furthermore, the field sizes in the reviewed studies were very small. Thus, in view of potential dose inhomogeneities with field sizes below 4 cm, it is imperative for future studies to consider larger field sizes.

It was shown by one of the included studies that intracellular oxygen concentration plays a key role in the FLASH effect.[23] Thus, for future clinical translation, it is important that the radiobiological implications of FLASH RT be further elucidated for more insights about the effect of modulation of radiation dose rate on repair, reoxygenation, redistribution, repopulation, and radiosensitivity. It is also important to understand the effects of the FLASH dose rates on the entire tumor microenvironment and not just on the tumor cells.[38] These have not been addressed in the reviewed studies.

Although results have so far shown normal tissue protection and tumor suppression, it will be desirable for future studies to take into account the possibility of tumor recurrence. Thus, more studies investigating longer-term tumor control are needed to observe late recurrence rates derived from surviving and slowly progressing tumor stem cells.

If indeed FLASH RT achieves clinical translation in the future, its cost-effectiveness at present is yet to be ascertained. With the rising prevalence of cancer in developing countries,[39] it remains to be seen how they would benefit from this potentially revolutionary cancer treatment modality in view of its possible high costs. Nevertheless, if all or most gray areas surrounding FLASH RT can be resolved, its clinical translation could potentially reduce treatment times and enable more patients to be treated per machine. Moreover, its short time per fraction could eliminate intra-fraction motion (which is common in the conventional RT), thereby improving the quality of treatment delivery and patient comfort during RT. However, this would require further technological improvements to synchronize precisely the shot with any movement. At last, faster treatments could reduce the fraction of lymphocytes exposed to radiation, which could have a positive effect on patients' immune responses.

 > Conclusion Top

The present study has systematically reviewed recent studies on FLASH RT, with our findings indicating that FLASH RT dose rates could be potentially safer than that of the conventional RT. It also showed antitumor effect. However, further studies will be required to address the aspects such as optimal dose rate, effect on deep tumors, long-term tumor recurrence, radiobiological implications, longer follow-up time, and mechanism of action.

Financial support and sponsorship

This research was supported by Tehran University of Medical Sciences, Tehran, Iran.

Conflicts of interest

There are no conflicts of interest.

 > References Top

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