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Effect of Conventional and Ultrahigh Dose Rate FLASH Irradiations on Preclinical Tumor Models : A Systematic Analysis

Böhlen, Till Tobias ; Germond, Jean François ; Petersson, Kristoffer LU ; Ozsahin, Esat Mahmut ; Herrera, Fernanda G. ; Bailat, Claude ; Bochud, François ; Bourhis, Jean ; Moeckli, Raphaël and Adrian, Gabriel LU orcid (2023) In International Journal of Radiation Oncology Biology Physics 117(4). p.1007-1017
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... (More)

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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Contribution to journal
publication status
published
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in
International Journal of Radiation Oncology Biology Physics
volume
117
issue
4
pages
1007 - 1017
publisher
Elsevier
external identifiers
  • pmid:37276928
  • scopus:85164562080
ISSN
0360-3016
DOI
10.1016/j.ijrobp.2023.05.045
language
English
LU publication?
yes
id
7c292abc-d8da-4d04-99d2-ee10d6ed9389
date added to LUP
2023-09-22 14:27:51
date last changed
2024-04-19 01:33:29
@article{7c292abc-d8da-4d04-99d2-ee10d6ed9389,
  abstract     = {{<p>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 (TCD<sub>50</sub>) 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 TCD<sub>50</sub> experiments, are needed to confirm the assumption of isoeffectiveness in curative settings.</p>}},
  author       = {{Böhlen, Till Tobias and Germond, Jean François and Petersson, Kristoffer and Ozsahin, Esat Mahmut and Herrera, Fernanda G. and Bailat, Claude and Bochud, François and Bourhis, Jean and Moeckli, Raphaël and Adrian, Gabriel}},
  issn         = {{0360-3016}},
  language     = {{eng}},
  number       = {{4}},
  pages        = {{1007--1017}},
  publisher    = {{Elsevier}},
  series       = {{International Journal of Radiation Oncology Biology Physics}},
  title        = {{Effect of Conventional and Ultrahigh Dose Rate FLASH Irradiations on Preclinical Tumor Models : A Systematic Analysis}},
  url          = {{http://dx.doi.org/10.1016/j.ijrobp.2023.05.045}},
  doi          = {{10.1016/j.ijrobp.2023.05.045}},
  volume       = {{117}},
  year         = {{2023}},
}