Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

FLASH radiotherapy enables dose escalation resulting in improved survival in an orthotopic muscle-invasive bladder cancer mouse model

Ruan, Jia Ling ; Lee, Carl ; Sharma, Osheen ; Lövgren, Nathalie ; Paillas, Salomé ; Cooper, Christian ; Tullis, Iain D.C. ; Giaccia, Amato J. ; Kiltie, Anne E. and Petersson, Kristoffer LU (2026) In British Journal of Radiology 99(1182). p.1101-1113
Abstract

Objectives: FLASH radiotherapy is an innovative technique that delivers radiation at ultra-high dose rates (UHDR), offering tumor control comparable to conventional (CONV) radiotherapy while significantly reducing normal tissue toxicity. Here we aim to determine the effects of FLASH compared to CONV radiotherapy in muscle-invasive bladder cancer (MIBC) models. Methods: Using an in-house 6 MeV linear accelerator able to deliver electron beam at UHDR or CONV dose rate, we employed clonogenic survival assays, RNA sequencing (RNA-seq), and in vivo tumor growth analyses using MBT2 cells and C3H MIBC models. Both subcutaneous and orthotopic tumor models were used to assess tumor response, survival and treatment-related toxicity as... (More)

Objectives: FLASH radiotherapy is an innovative technique that delivers radiation at ultra-high dose rates (UHDR), offering tumor control comparable to conventional (CONV) radiotherapy while significantly reducing normal tissue toxicity. Here we aim to determine the effects of FLASH compared to CONV radiotherapy in muscle-invasive bladder cancer (MIBC) models. Methods: Using an in-house 6 MeV linear accelerator able to deliver electron beam at UHDR or CONV dose rate, we employed clonogenic survival assays, RNA sequencing (RNA-seq), and in vivo tumor growth analyses using MBT2 cells and C3H MIBC models. Both subcutaneous and orthotopic tumor models were used to assess tumor response, survival and treatment-related toxicity as demonstrated by weight loss. Results: Clonogenic analysis demonstrated comparable cancer cell survival between FLASH and CONV irradiation in vitro. RNA-seq analysis of in vitro irradiated cells revealed similar gene expression at 5 Gy but significant transcriptional divergence at 10 Gy. Intestinal organoids exhibited preserved growth after FLASH compared with CONV irradiation, consistent with a normal tissue sparing effect. In subcutaneous models, FLASH and CONV radiotherapy exhibited similar tumor responses. However, in the orthotopic model, FLASH radiotherapy enabled dose escalation, significantly extending survival at 15 Gy (P = .02) and 17.5 Gy (P = .004). Dose rate (100 vs. 106 Gy/s) did not significantly affect survival. The benefit of single-fraction FLASH was not retained with fractionated (3 × 7.3 Gy) delivery. Conclusions: FLASH radiotherapy demonstrates significant potential for treating MIBC, offering enhanced survival through effective dose escalation. These findings support continued investigation into optimal FLASH parameters and its clinical application. Advances in knowledge: This study demonstrates, for the first time, that UHDR radiotherapy enables safe dose escalation and improved survival in an orthotopic muscle-invasive bladder cancer model compared to conventional dose-rate treatment. Survival benefits of FLASH are dose- and fractionation-dependent, with significant improvements observed in single-fraction, high-dose treatments but not in fractionated delivery.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
dose rate, FLASH irradiation, muscle-invasive bladder cancer, normal tissue toxicity, orthotopic cancer models, radiotherapy
in
British Journal of Radiology
volume
99
issue
1182
pages
13 pages
publisher
British Institute of Radiology
external identifiers
  • pmid:41886336
  • scopus:105039748879
ISSN
0007-1285
DOI
10.1093/bjr/tqag071
language
English
LU publication?
yes
additional info
Publisher Copyright: © The Author(s) 2026. Published by Oxford University Press on behalf of the British Institute of Radiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
id
f5ca5942-6c3b-46ef-9ddd-f9c17c4e7767
date added to LUP
2026-07-21 12:52:36
date last changed
2026-09-15 16:41:06
@article{f5ca5942-6c3b-46ef-9ddd-f9c17c4e7767,
  abstract     = {{<p>Objectives: FLASH radiotherapy is an innovative technique that delivers radiation at ultra-high dose rates (UHDR), offering tumor control comparable to conventional (CONV) radiotherapy while significantly reducing normal tissue toxicity. Here we aim to determine the effects of FLASH compared to CONV radiotherapy in muscle-invasive bladder cancer (MIBC) models. Methods: Using an in-house 6 MeV linear accelerator able to deliver electron beam at UHDR or CONV dose rate, we employed clonogenic survival assays, RNA sequencing (RNA-seq), and in vivo tumor growth analyses using MBT2 cells and C3H MIBC models. Both subcutaneous and orthotopic tumor models were used to assess tumor response, survival and treatment-related toxicity as demonstrated by weight loss. Results: Clonogenic analysis demonstrated comparable cancer cell survival between FLASH and CONV irradiation in vitro. RNA-seq analysis of in vitro irradiated cells revealed similar gene expression at 5 Gy but significant transcriptional divergence at 10 Gy. Intestinal organoids exhibited preserved growth after FLASH compared with CONV irradiation, consistent with a normal tissue sparing effect. In subcutaneous models, FLASH and CONV radiotherapy exhibited similar tumor responses. However, in the orthotopic model, FLASH radiotherapy enabled dose escalation, significantly extending survival at 15 Gy (P = .02) and 17.5 Gy (P = .004). Dose rate (100 vs. 10<sup>6</sup> Gy/s) did not significantly affect survival. The benefit of single-fraction FLASH was not retained with fractionated (3 × 7.3 Gy) delivery. Conclusions: FLASH radiotherapy demonstrates significant potential for treating MIBC, offering enhanced survival through effective dose escalation. These findings support continued investigation into optimal FLASH parameters and its clinical application. Advances in knowledge: This study demonstrates, for the first time, that UHDR radiotherapy enables safe dose escalation and improved survival in an orthotopic muscle-invasive bladder cancer model compared to conventional dose-rate treatment. Survival benefits of FLASH are dose- and fractionation-dependent, with significant improvements observed in single-fraction, high-dose treatments but not in fractionated delivery.</p>}},
  author       = {{Ruan, Jia Ling and Lee, Carl and Sharma, Osheen and Lövgren, Nathalie and Paillas, Salomé and Cooper, Christian and Tullis, Iain D.C. and Giaccia, Amato J. and Kiltie, Anne E. and Petersson, Kristoffer}},
  issn         = {{0007-1285}},
  keywords     = {{dose rate; FLASH irradiation; muscle-invasive bladder cancer; normal tissue toxicity; orthotopic cancer models; radiotherapy}},
  language     = {{eng}},
  number       = {{1182}},
  pages        = {{1101--1113}},
  publisher    = {{British Institute of Radiology}},
  series       = {{British Journal of Radiology}},
  title        = {{FLASH radiotherapy enables dose escalation resulting in improved survival in an orthotopic muscle-invasive bladder cancer mouse model}},
  url          = {{http://dx.doi.org/10.1093/bjr/tqag071}},
  doi          = {{10.1093/bjr/tqag071}},
  volume       = {{99}},
  year         = {{2026}},
}