Evolution of the Supermodel: Progress in Modelling Radiotherapy Response in Mice

Butterworth, Karl T.

doi:10.1016/j.clon.2019.02.008

Cited by 26 publications

(20 citation statements)

References 80 publications

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“…Mice have been used in many biological studies ranging from pharmacology, drug development, and as disease models [118]. Radiation oncology has also benefitted from pre-clinical studies using the large variety of genetically modified mouse models [119,120]. Using conventionally accelerated protons or external beam radiotherapy for in vivo experiments is however much easier than doing similar experiments with laser-driven proton beams since, as mentioned earlier, the beam energy attained with laser-driven protons is generally not yet sufficient to fully irradiate deep-seated tumours with the required doses.…”

Section: Animal Based In-vivo Studiesmentioning

confidence: 99%

Radiobiology Experiments With Ultra-high Dose Rate Laser-Driven Protons: Methodology and State-of-the-Art

Chaudhary¹,

Milluzzo

Ahmed

et al. 2021

Front. Phys.

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The use of particle accelerators in radiotherapy has significantly changed the therapeutic outcomes for many types of solid tumours. In particular, protons are well known for sparing normal tissues and increasing the overall therapeutic index. Recent studies show that normal tissue sparing can be further enhanced through proton delivery at 100 Gy/s and above, in the so-called FLASH regime. This has generated very significant interest in assessing the biological effects of proton pulses delivered at very high dose rates. Laser-accelerated proton beams have unique temporal emission properties, which can be exploited to deliver Gy level doses in single or multiple pulses at dose rates exceeding by many orders of magnitude those currently used in FLASH approaches. An extensive investigation of the radiobiology of laser-driven protons is therefore not only necessary for future clinical application, but also offers the opportunity of accessing yet untested regimes of radiobiology. This paper provides an updated review of the recent progress achieved in ultra-high dose rate radiobiology experiments employing laser-driven protons, including a brief discussion of the relevant methodology and dosimetry approaches.

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Section: Animal Based In-vivo Studiesmentioning

confidence: 99%

Radiobiology Experiments With Ultra-high Dose Rate Laser-Driven Protons: Methodology and State-of-the-Art

Chaudhary¹,

Milluzzo

Ahmed

et al. 2021

Front. Phys.

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“…Whilst acknowledging the potential challenges of modelling radiation therapy response in mice [17] we have, for the first time, directly recapitulated clinical observations highlighting the base of the heart as a radiosensitive substructure. In our model, radiation dose to the base of the heart leads to systolic dysfunction manifested as decreased FS and EF compared to nonirradiated age-matched controls.…”

Section: Discussionmentioning

confidence: 82%

Cardiac sub-volume targeting demonstrates regional radiosensitivity in the mouse heart

Ghita

Gill

Walls

et al. 2020

Radiotherapy and Oncology

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Background and purpose: Radiation-induced cardiac toxicity (RICT) remains one of the most critical dose limiting constraints in radiotherapy. Recent studies have shown higher doses to the base of the heart are associated with worse overall survival in lung cancer patients receiving radiotherapy. This work aimed to investigate the impact of sub-volume heart irradiation in a mouse model using small animal image-guided radiotherapy.Materials and Methods: C57BL/6 mice were irradiated with a single fraction of 16 Gy to the base, middle or apex of the heart using a small animal radiotherapy research platform. Cone beam CT and echocardiography were performed at baseline and at 10 week intervals until 50 weeks post-treatment. Structural and functional parameters were correlated with mean heart dose (MHD) and volume of heart receiving 5 Gy (V5).Results: All irradiated mice showed a time dependent increase in left ventricle wall thickness in diastole of ~0.2 mm detected at 10 weeks post-treatment, with the most significant and persistent changes occurring in the heart base-irradiated animals. Similarly, statistically different functional effects (p<0.01) were observed in base-irradiated animals which showed the most significant decreases compared to controls. The observed functional changes did not correlate with MHD and V5 (R 2 <0.1), indicating that whole heart dosimetry parameters do not predict physiological changes resulting from cardiac sub-volume irradiation.Conclusions: This is the first report demonstrating the structural and functional consequences of sub-volume targeting in the mouse heart and reverse translates clinical observations indicating the heart base as a critical radiosensitive region.

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“…This paradigm was proven in mice; for example, a study demonstrating that three fractions of eight Gy had a better response than five fractions of six Gy in inducing anti-tumor immunity in combination with anti-CTLA-4 antibodies [ 33 ]. However, the physical and immunological impacts of XRT for mice and humans are not the same [ 34 ], making it difficult to relay on pre-clinical evidence for choosing the optimal manner to treat people. Some data from human studies besides our own also contradict the mice data.…”

Section: Discussionmentioning

confidence: 99%

Real-World Analysis of the Impact of Radiotherapy on Immunotherapy Efficacy in Non-Small Cell Lung Cancer

Onn

Gottfried

Stemmer

et al. 2021

Cancers

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Background: Immunotherapy (IO) provides a significant benefit for a subgroup of non-small cell lung cancer (NSCLC) patients. Radiotherapy (XRT) might enhance the efficacy of IO. We evaluated the impact of the specifics of XRT treatments on the OS of IO-treated NSCLC patients. Methods: Metastatic NSCLC patients treated with IO were retrospectively identified. Parameters included demographics, tumor characteristics, IO and XRT details. Correlation between the parameters and OS was tested with Cox regression. Results: 453 patients were included. No XRT was given to 167 (36.9%) patients, whereas XRT prior and after IO had 182 (40.2%) and 104 (22.9%) patients, respectively. XRT total doses between 30 and 40 Gy had better overall survival (OS) compared to non-irradiated patients (hazard ratio (HR) 0.5, 95% CI 0.25–1.0, p = 0.049). Worse outcome was seen with total doses ≤ 10 Gy (HR 1.67, 95% 1.13–2.5, p = 0.01), XRT fractions of 4.1–8 Gy (HR 1.48, 95% CI 1.05–2.1, p = 0.027) and XRT to the bone (HR 1.36, 95% CI 1.01–1.8, p = 0.04). Several clinical parameters correlated with OS in the univariate analysis of the IO-treated patients. While, in the multivariate analysis, only ECOG-PS, treatment line, type of IO, albumin and NLR remained statistically significant. Conclusion: Specific doses, fractions and sites of XRT correlated with the OS of IO-treated NSCLC patients in the univariate analysis, although not in the multivariate analysis.

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Evolution of the Supermodel: Progress in Modelling Radiotherapy Response in Mice

Cited by 26 publications

References 80 publications

Radiobiology Experiments With Ultra-high Dose Rate Laser-Driven Protons: Methodology and State-of-the-Art

Radiobiology Experiments With Ultra-high Dose Rate Laser-Driven Protons: Methodology and State-of-the-Art

Cardiac sub-volume targeting demonstrates regional radiosensitivity in the mouse heart

Real-World Analysis of the Impact of Radiotherapy on Immunotherapy Efficacy in Non-Small Cell Lung Cancer

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