| 1. |
- Svendsen, Kristoffer, et al.
(författare)
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A focused very high energy electron beam for fractionated stereotactic radiotherapy
- 2021
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- An electron beam of very high energy (50–250 MeV) can potentially produce a more favourable radiotherapy dose distribution compared to a state-of-the-art photon based radiotherapy technique. To produce an electron beam of sufficiently high energy to allow for a long penetration depth (several cm), very large accelerating structures are needed when using conventional radio-frequency technology, which may not be possible due to economical or spatial constraints. In this paper, we show transport and focusing of laser wakefield accelerated electron beams with a maximum energy of 160 MeV using electromagnetic quadrupole magnets in a point-to-point imaging configuration, yielding a spatial uncertainty of less than 0.1 mm, a total charge variation below 1 % and a focal spot of 2.3×2.6mm2. The electron beam was focused to control the depth dose distribution and to improve the dose conformality inside a phantom of cast acrylic slabs and radiochromic film. The phantom was irradiated from 36 different angles to obtain a dose distribution mimicking a stereotactic radiotherapy treatment, with a peak fractional dose of 2.72 Gy and a total maximum dose of 65 Gy. This was achieved with realistic constraints, including 23 cm of propagation through air before any dose deposition in the phantom.
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| 2. |
- Adrian, Gabriel, et al.
(författare)
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Cancer Cells Can Exhibit a Sparing FLASH Effect at Low Doses Under Normoxic In Vitro-Conditions
- 2021
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Ingår i: Frontiers in Oncology. - : Frontiers Media SA. - 2234-943X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Background: Irradiation with ultra-high dose rate (FLASH) has been shown to spare normal tissue without hampering tumor control in several in vivo studies. Few cell lines have been investigated in vitro, and previous results are inconsistent. Assuming that oxygen depletion accounts for the FLASH sparing effect, no sparing should appear for cells irradiated with low doses in normoxia. Methods: Seven cancer cell lines (MDA-MB-231, MCF7, WiDr, LU-HNSCC4, HeLa [early passage and subclone]) and normal lung fibroblasts (MRC-5) were irradiated with doses ranging from 0 to 12 Gy using FLASH (≥800 Gy/s) or conventional dose rates (CONV, 14 Gy/min), with a 10 MeV electron beam from a clinical linear accelerator. Surviving fraction (SF) was determined with clonogenic assays. Three cell lines were further studied for radiation-induced DNA-damage foci using a 53BP1-marker and for cell cycle synchronization after irradiation. Results: A tendency of increased survival following FLASH compared with CONV was suggested for all cell lines, with significant differences for 4/7 cell lines. The magnitude of the FLASH-sparing expressed as a dose-modifying factor at SF=0.1 was around 1.1 for 6/7 cell lines and around 1.3 for the HeLasubclone. Similar cell cycle distributions and 53BP1-foci numbers were found comparing FLASH to CONV. Conclusion: We have found a FLASH effect appearing at low doses under normoxic conditions for several cell lines in vitro. The magnitude of the FLASH effect differed between the cell lines, suggesting inherited biological susceptibilities for FLASH irradiation.
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| 3. |
- Adrian, Gabriel, et al.
(författare)
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In vitro assays for investigating the FLASH effect
- 2022
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Ingår i: Expert Reviews in Molecular Medicine. - : Cambridge University Press (CUP). - 1462-3994. ; 24
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Forskningsöversikt (refereegranskat)abstract
- FLASH radiotherapy is a novel technique that has been shown in numerous preclinical in vivo studies to have the potential to be the next important improvement in cancer treatment. However, the biological mechanisms responsible for the selective FLASH sparing effect of normal tissues are not yet known. An optimal translation of FLASH radiotherapy into the clinic would require a good understanding of the specific beam parameters that induces a FLASH effect, environmental conditions affecting the response, and the radiobiological mechanisms involved. Even though the FLASH effect has generally been considered as an in vivo effect, studies finding these answers would be difficult and ethically challenging to carry out solely in animals. Hence, suitable in vitro studies aimed towards finding these answers are needed. In this review, we describe and summarise several in vitro assays that have been used or could be used to finally elucidate the mechanisms behind the FLASH effect.
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| 4. |
- Adrian, Gabriel, et al.
(författare)
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The FLASH effect depends on oxygen concentration
- 2019
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Ingår i: British Journal of Radiology. - : British Institute of Radiology. - 1748-880X .- 0007-1285. ; 93:1106
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Recent in vivo results have shown prominent tissue sparing effect of radiotherapy with ultra-high dose rates (FLASH) compared to conventional dose rates (CONV). Oxygen depletion has been proposed as the underlying mechanism, but in vitro data to support this have been lacking. The aim of the current study was to compare FLASH to CONV irradiation under different oxygen concentrations in vitro. METHODS: Prostate cancer cells were irradiated at different oxygen concentrations (relative partial pressure ranging between 1.6 and 20%) with a 10 MeV electron beam at a dose rate of either 600 Gy/s (FLASH) or 14 Gy/min (CONV), using a modified clinical linear accelerator. We evaluated the surviving fraction of cells using clonogenic assays after irradiation with doses ranging from 0 to 25 Gy. RESULTS: Under normoxic conditions, no differences between FLASH and CONV irradiation were found. For hypoxic cells (1.6%), the radiation response was similar up to a dose of about 5-10 Gy, above which increased survival was shown for FLASH compared to CONV irradiation. The increased survival was shown to be significant at 18 Gy, and the effect was shown to depend on oxygen concentration. CONCLUSION: The in vitro FLASH effect depends on oxygen concentration. Further studies to characterize and optimize the use of FLASH in order to widen the therapeutic window are indicated. ADVANCES IN KNOWLEDGE: This paper shows in vitro evidence for the role of oxygen concentration underlying the difference between FLASH and CONV irradiation.
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| 5. |
- Borg, David, et al.
(författare)
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Palliative short-course hypofractionated radiotherapy followed by chemotherapy in esophageal adenocarcinoma : the phase II PALAESTRA trial
- 2020
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Ingår i: Acta Oncologica. - 0284-186X. ; 59:2, s. 212-218
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Tidskriftsartikel (refereegranskat)abstract
- Background: The majority of patients with incurable esophageal adenocarcinoma suffer from dysphagia. We assessed a novel treatment strategy with initial short-course radiotherapy followed by chemotherapy with the primary aim to achieve long-term relief of dysphagia. Methods: This phase II trial included treatment-naîve patients with dysphagia due to esophageal adenocarcinoma not eligible for curative treatment. External beam radiotherapy with 20 Gy in five fractions to the primary tumor was followed by four cycles of chemotherapy (FOLFOX regimen). Dysphagia was assessed using a five-grade scale. Results: From October 2014 to May 2018 a total of 29 patients were enrolled. The rate of dysphagia improvement was 79%, median duration of improvement 6.7 months (12.2 months for responders) and median overall survival 9.9 months. In the pre-specified per protocol analysis (23 patients) the rate of dysphagia improvement was 91%, median duration of improvement 12.2 months (14.0 months for responders) and median overall survival 16.0 months. The most common grade 3–4 adverse events were neutropenia (29%), infection (25%), anorexia (11%), esophagitis (11%) and fatigue (11%). Conclusion: Initial palliative short-course radiotherapy followed by chemotherapy is a promising treatment strategy that can provide long-lasting relief of dysphagia in patients with esophageal adenocarcinoma.
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| 6. |
- Böhlen, Till Tobias, et al.
(författare)
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Effect of Conventional and Ultrahigh Dose Rate FLASH Irradiations on Preclinical Tumor Models : A Systematic Analysis
- 2023
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Ingår i: International Journal of Radiation Oncology Biology Physics. - 0360-3016. ; 117:4, s. 1007-1017
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Compared with conventional dose rate irradiation (CONV), ultrahigh dose rate irradiation (UHDR) has shown superior normal tissue sparing. However, a clinically relevant widening of the therapeutic window by UHDR, termed “FLASH effect”, also depends on the tumor toxicity obtained by UHDR. Based on a combined analysis of published literature, the current study examined the hypothesis of tumor isoefficacy for UHDR versus CONV and aimed to identify potential knowledge gaps to inspire future in vivo studies. Methods and Materials: A systematic literature search identified publications assessing in vivo tumor responses comparing UHDR and CONV. Qualitative and quantitative analyses were performed, including combined analyses of tumor growth and survival data. Results: We identified 66 data sets from 15 publications that compared UHDR and CONV for tumor efficacy. The median number of animals per group was 9 (range 3-15) and the median follow-up period was 30.5 days (range 11-230) after the first irradiation. Tumor growth assays were the predominant model used. Combined statistical analyses of tumor growth and survival data are consistent with UHDR isoefficacy compared with CONV. Only 1 study determined tumor-controlling dose (TCD50) and reported statistically nonsignificant differences. Conclusions: The combined quantitative analyses of tumor responses support the assumption of UHDR isoefficacy compared with CONV. However, the comparisons are primarily based on heterogeneous tumor growth assays with limited numbers of animals and short follow-up, and most studies do not assess long-term tumor control probability. Therefore, the assays may be insensitive in resolving smaller response differences, such as responses of radioresistant tumor subclones. Hence, tumor cure experiments, including additional TCD50 experiments, are needed to confirm the assumption of isoeffectiveness in curative settings.
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| 7. |
- Børresen, Betina, et al.
(författare)
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Evaluation of single-fraction high dose FLASH radiotherapy in a cohort of canine oral cancer patients
- 2023
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Ingår i: Frontiers in Oncology. - 2234-943X. ; 13, s. 1-10
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Tidskriftsartikel (refereegranskat)abstract
- Background: FLASH radiotherapy (RT) is a novel method for delivering ionizingradiation, which has been shown in preclinical studies to have a normal tissuesparing effect and to maintain anticancer efficacy as compared to conventionalRT. Treatment of head and neck tumors with conventional RT is commonlyassociated with severe toxicity, hence the normal tissue sparing effect of FLASHRT potentially makes it especially advantageous for treating oral tumors. In thiswork, the objective was to study the adverse effects of dogs with spontaneousoral tumors treated with FLASH RT.Methods: Privately-owned dogs with macroscopic malignant tumors of the oralcavity were treated with a single fraction of ≥30Gy electron FLASH RT andsubsequently followed for 12 months. A modified conventional linear acceleratorwas used to deliver the FLASH RT.Results: Eleven dogs were enrolled in this prospective study. High grade adverseeffects were common, especially if bone was included in the treatment field. Fourout of six dogs, who had bone in their treatment field and lived at least 5 monthsafter RT, developed osteoradionecrosis at 3-12 months post treatment. Thetreatment was overall effective with 8/11 complete clinical responses and 3/11partial responses.Conclusion: This study shows that single-fraction high dose FLASH RT wasgenerally effective in this mixed group of malignant oral tumors, but the risk ofosteoradionecrosis is a serious clinical concern. It is possible that the risk ofosteonecrosis can be mitigated through fractionation and improved doseconformity, which needs to be addressed before moving forward with clinicaltrials in human cancer patients.
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| 8. |
- Cooper, Christian R., et al.
(författare)
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Comet Assay Profiling of FLASH-Induced Damage : Mechanistic Insights into the Effects of FLASH Irradiation
- 2023
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Ingår i: International Journal of Molecular Sciences. - 1661-6596. ; 24:8
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Tidskriftsartikel (refereegranskat)abstract
- Numerous studies have demonstrated the normal tissue-sparing effects of ultra-high dose rate ‘FLASH’ irradiation in vivo, with an associated reduction in damage burden being reported in vitro. Towards this, two key radiochemical mechanisms have been proposed: radical–radical recombination (RRR) and transient oxygen depletion (TOD), with both being proposed to lead to reduced levels of induced damage. Previously, we reported that FLASH induces lower levels of DNA strand break damage in whole-blood peripheral blood lymphocytes (WB-PBL) ex vivo, but our study failed to distinguish the mechanism(s) involved. A potential outcome of RRR is the formation of crosslink damage (particularly, if any organic radicals recombine), whilst a possible outcome of TOD is a more anoxic profile of induced damage resulting from FLASH. Therefore, the aim of the current study was to profile FLASH-induced damage via the Comet assay, assessing any DNA crosslink formation as a putative marker of RRR and/or anoxic DNA damage formation as an indicative marker of TOD, to determine the extent to which either mechanism contributes to the “FLASH effect”. Following FLASH irradiation, we see no evidence of any crosslink formation; however, FLASH irradiation induces a more anoxic profile of induced damage, supporting the TOD mechanism. Furthermore, treatment of WB-PBLs pre-irradiation with BSO abrogates the reduced strand break damage burden mediated by FLASH exposures. In summary, we do not see any experimental evidence to support the RRR mechanism contributing to the reduced damage burden induced by FLASH. However, the observation of a greater anoxic profile of damage following FLASH irradiation, together with the BSO abrogation of the reduced strand break damage burden mediated by FLASH, lends further support to TOD being a driver of the reduced damage burden plus a change in the damage profile mediated by FLASH.
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| 9. |
- Cooper, Christian R, et al.
(författare)
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FLASH irradiation induces lower levels of DNA damage ex vivo, an effect modulated by oxygen tension, dose, and dose rate
- 2022
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Ingår i: British Journal of Radiology. - : British Institute of Radiology. - 1748-880X .- 0007-1285. ; 95:1133
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: FLASH irradiation reportedly produces less normal tissue toxicity, while maintaining tumour response. To investigate oxygen's role in the 'FLASH effect', we assessed DNA damage levels following irradiation at different oxygen tensions, doses and dose rates.METHODS: Samples of whole blood were irradiated (20 Gy) at various oxygen tensions (0.25-21%) with 6 MeV electrons at dose rates of either 2 kGy/s (FLASH) or 0.1 Gy/s (CONV), and subsequently with various doses (0-40 Gy) and intermediate dose rates (0.3-1000 Gy/s). DNA damage of peripheral blood lymphocytes (PBL) were assessed by the alkaline comet assay.RESULTS: Following 20 Gy irradiation, lower levels of DNA damage were induced for FLASH, the difference being significant at 0.25% (p < 0.05) and 0.5% O2 (p < 0.01). The differential in DNA damage at 0.5% O2 was found to increase with total dose and dose rate, becoming significant for doses ≥20 Gy and dose rates ≥30 Gy/s.CONCLUSION: This study shows, using the alkaline comet assay, that lower levels of DNA damage are induced following FLASH irradiation, an effect that is modulated by the oxygen tension, and increases with the total dose and dose rate of irradiation, indicating that an oxygen related mechanism, e.g. transient radiation-induced oxygen depletion, may contribute to the tissue sparing effect of FLASH irradiation.ADVANCES IN KNOWLEDGE: This paper is first to directly show that FLASH-induced DNA damage is modulated by oxygen tension, total dose and dose rate, with FLASH inducing significantly lower levels of DNA damage for doses ≥20 Gy and dose rates ≥30 Gy/s, at 0.5% O2.
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| 10. |
- Gjaldbæk, Bolette W., et al.
(författare)
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Long-term toxicity and efficacy of FLASH radiotherapy in dogs with superficial malignant tumors
- 2024
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Ingår i: Frontiers in Oncology. - 2234-943X. ; 14, s. 01-09
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: FLASH radiotherapy (RT) has emerged as a promising modality, demonstrating both a normal tissue sparing effect and anticancer efficacy. We have previously reported on the safety and efficacy of single fraction FLASH RT in the treatment of oral tumors in canine cancer patients, showing tumor response but also a risk of radiation-induced severe late adverse effects (osteoradionecrosis) for doses ≥35 Gy. Accordingly, the objective in this study was to investigate if single fraction high dose FLASH RT is safe for treating non-oral tumors. Methods: Privately-owned dogs with superficial tumors or microscopic residual disease were included. Treatment was generally delivered as a single fraction of 15-35 Gy 10 MeV electron FLASH RT, although two dogs were re-irradiated at a later timepoint. Follow-up visits were conducted up to 12 months post-treatment to evaluate treatment efficiency and adverse effects. Results: Fourteen dogs with 16 tumors were included, of which nine tumors were treated for gross disease whilst seven tumors were treated post-surgery for microscopic residual disease. Four treatment sites treated with 35 Gy had ulceration post irradiation, which was graded as severe adverse effect. Only mild adverse effects were observed for the remaining treatment sites. None of the patients with microscopic disease experienced recurrence (0/7), and all patients with macroscopic disease showed either a complete (5/9) or a partial response (4/9). Five dogs were euthanized due to clinical disease progression. Discussion: Our study demonstrates that single fraction high dose FLASH RT is generally safe, with few severe adverse effects, particularly in areas less susceptible to radiation-induced damage. In addition, our study indicates that FLASH has anti-tumor efficacy in a clinical setting. No osteoradionecrosis was observed in this study, although other types of high-grade adverse effects including ulcer-formations were observed for the highest delivered dose (35 Gy). Overall, we conclude that osteoradionecrosis following single fraction, high dose FLASH does not appear to be a general problem for non-oral tumor locations. Also, as has been shown previously for oral tumors, 30 Gy appeared to be the maximum safe dose to deliver with single fraction FLASH RT.
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