Combined DNA Damage Repair Interference and Ion Beam Therapy: Development, Benchmark, and Clinical Implications of a Mechanistic Biological Model

Liew, Hans; Meister, Sarah; Mein, Stewart; Tessonnier, Thomas; Kopp, Benedikt; Held, T.; Haberer, Thomas; Abdollahi, Amir; Debus, Jürgen; Đokić, Ivana; Mairani, A.

doi:10.1016/j.ijrobp.2021.09.048

Cited by 7 publications

(27 citation statements)

References 73 publications

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“…It is supposed to help interpret pre-clinical studies, support the development of innovative radiotherapy concepts, and assess the necessity as well as implications of including additional parameters into clinical treatment planning. For example, the ion beam model of the framework was recently established [ 9 ], including a description of the effect of interference on the DNA damage repair process, which is consistent with its earlier published implementation for conventional radiation sources [ 6 ]. This allowed for the investigation of the effect of such a modifier of radiation action on the predicted RBE and its meaning for clinical scenarios.…”

Section: Introductionmentioning

confidence: 76%

“…While the determination of a mixed field dose-rate adapted RBE remains computationally expensive, the value was found to be well approximated by the no-repair RBE for the dose rates and LET at the investigated positions. Predictions for the no-repair RBE value can also be swiftly calculated for mixed LET fields within our existing modelling framework using pre-processed databases [ 9 ]. Taken together, the prediction of the measured dose-rate dependent RBE within the given setup is approximated using the no-repair RBE multiplied by the factor,

—and is shown in the middle and right panel of Figure 4 (solid lines):

…”

Section: Resultsmentioning

confidence: 99%

“…The UNIVERSE is a modelling framework developed to describe the effects of ionizing radiation in biological systems considering numerous factors, including the effect of interference with the DNA damage repair process [ 6 , 9 ], radical scavengers [ 7 ], and the applied dose rate [ 8 , 10 ]. For this study, the implementation of DNA repair kinetics and that of ion beams from two recent publications [ 8 , 9 ] are combined to study the dose-rate effects in ion beams. For detailed descriptions of the implementation and parameters of the individual sub-components, we kindly refer to the respective references.…”

Section: Methodsmentioning

confidence: 99%

“…The model was previously tuned [ 4 ] and benchmarked [ 5 ] using extensive in-vitro data on the biological effect of helium beams as a function of dose and LET. The “UNIfied and VERSatile bio-response Engine” (UNIVERSE) is a mechanistic modeling framework being developed with the goal of enabling the description of clinically relevant modifying factors of radiation action for both conventional and ion beam irradiations [ 6 , 7 , 8 , 9 , 10 ]. It is supposed to help interpret pre-clinical studies, support the development of innovative radiotherapy concepts, and assess the necessity as well as implications of including additional parameters into clinical treatment planning.…”

Section: Introductionmentioning

confidence: 99%

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Impact of DNA Repair Kinetics and Dose Rate on RBE Predictions in the UNIVERSE

Liew

Mein

Tessonnier

et al. 2022

IJMS

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Accurate knowledge of the relative biological effectiveness (RBE) and its dependencies is crucial to support modern ion beam therapy and its further development. However, the influence of different dose rates of the reference radiation and ion beam are rarely considered. The ion beam RBE-model within our “UNIfied and VERSatile bio response Engine” (UNIVERSE) is extended by including DNA damage repair kinetics to investigate the impact of dose-rate effects on the predicted RBE. It was found that dose-rate effects increase with dose and biological effects saturate at high dose-rates, which is consistent with data- and model-based studies in the literature. In a comparison with RBE measurements from a high dose in-vivo study, the predictions of the presented modification were found to be improved in comparison to the previous version of UNIVERSE and existing clinical approaches that disregard dose-rate effects. Consequently, DNA repair kinetics and the different dose rates applied by the reference and ion beams might need to be considered in biophysical models to accurately predict the RBE. Additionally, this study marks an important step in the further development of UNIVERSE, extending its capabilities in giving theoretical guidance to support progress in ion beam therapy.

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Section: Introductionmentioning

confidence: 76%

—and is shown in the middle and right panel of Figure 4 (solid lines):

…”

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Impact of DNA Repair Kinetics and Dose Rate on RBE Predictions in the UNIVERSE

Liew

Mein

Tessonnier

et al. 2022

IJMS

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“…UNIVERSE is a mechanistic model of radiation action in biological systems which has been used to describe low LET (linear energy transfer) and higher LET radiation both alone and in combination with genetic or pharmaceutical DNA damage repair interference [ 27 , 28 ]. Furthermore, a mechanism to model the effect of radical scavengers for low LET radiation was implemented [ 29 ].…”

Section: Methodsmentioning

confidence: 99%

The Impact of Sub-Millisecond Damage Fixation Kinetics on the In Vitro Sparing Effect at Ultra-High Dose Rate in UNIVERSE

Liew

Mein

Tessonnier

et al. 2022

IJMS

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The impact of the exact temporal pulse structure on the potential cell and tissue sparing of ultra-high dose-rate irradiation applied in FLASH studies has gained increasing attention. A previous version of our biophysical mechanistic model (UNIVERSE: UNIfied and VERSatile bio response Engine), based on the oxygen depletion hypothesis, has been extended in this work by considering oxygen-dependent damage fixation dynamics on the sub-milliseconds scale and introducing an explicit implementation of the temporal pulse structure. The model successfully reproduces in vitro experimental data on the fast kinetics of the oxygen effect in irradiated mammalian cells. The implemented changes result in a reduction in the assumed amount of oxygen depletion. Furthermore, its increase towards conventional dose-rates is parameterized based on experimental data from the literature. A recalculation of previous benchmarks shows that the model retains its predictive power, while the assumed amount of depleted oxygen approaches measured values. The updated UNIVERSE could be used to investigate the impact of different combinations of pulse structure parameters (e.g., dose per pulse, pulse frequency, number of pulses, etc.), thereby aiding the optimization of potential clinical application and the development of suitable accelerators.

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Robustness of carbon‐ion radiotherapy against DNA damage repair associated radiosensitivity variation based on a biophysical model

Liew,

Tessonnier,

Mein

et al. 2024

Medical Physics

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BackgroundInterpatient variation of tumor radiosensitivity is rarely considered during the treatment planning process despite its known significance for the therapeutic outcome.PurposeTo apply our mechanistic biophysical model to investigate the biological robustness of carbon ion radiotherapy (CIRT) against DNA damage repair interference (DDRi) associated patient‐to‐patient variability in radiosensitivity and its potential clinical advantages against conventional radiotherapy approaches.Methods and MaterialsThe “UNIfied and VERSatile bio response Engine” (UNIVERSE) was extended by carbon ions and its predictions were compared to a panel of in vitro and in vivo data including various endpoints and DDRi settings within clinically relevant dose and linear energy transfer (LET) ranges. The implications of UNIVERSE predictions were then assessed in a clinical patient scenario considering DDRi variance.ResultsUNIVERSE tests well against the applied benchmarks. While in vitro survival curves were predicted with an R2 > 0.92, deviations from in vivo RBE data were less than 5.6% The conducted paradigmatic patient plan study implies a markedly reduced significance of DDRi based radiosensitivity variability in CIRT (13% change of in target) compared to conventional radiotherapy (62%) and that boosting the LET within the target further amplifies this robustness of CIRT (8%). In the case of heightened tumor radiosensitivity, a dose de‐escalation strategy for photons allows a reduction of the maximum effective dose within the normal tissue (NT) from a of 2.65 to 1.64 Gy, which lies below the level found for CIRT ( = 2.41 Gy) for the analyzed plan and parameters. However, even after de‐escalation, the integral effective dose in the NT is found to be substantially higher for conventional radiotherapy in comparison to CIRT ( of 0.75, 0.46, and 0.24 Gy for the conventional plan, its de‐escalation and CIRT, respectively).ConclusionsThe framework offers adequate predictions of in vitro and in vivo radiation effects of CIRT while allowing the consideration of DRRi based solely on parameters derived from photon data. The results of the patient planning study underline the potential of CIRT to minimize important sources of interpatient divergence in therapy outcome, especially when combined with techniques that allow to maximize the LET within the tumor. Despite the potential of de‐escalation strategies for conventional radiotherapy to reduce the maximum effective dose in the NT, CIRT appears to remain a more favorable option due to its ability to reduce the integral effective dose within the NT.

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Combined DNA Damage Repair Interference and Ion Beam Therapy: Development, Benchmark, and Clinical Implications of a Mechanistic Biological Model

Cited by 7 publications

References 73 publications

Impact of DNA Repair Kinetics and Dose Rate on RBE Predictions in the UNIVERSE

Impact of DNA Repair Kinetics and Dose Rate on RBE Predictions in the UNIVERSE

The Impact of Sub-Millisecond Damage Fixation Kinetics on the In Vitro Sparing Effect at Ultra-High Dose Rate in UNIVERSE

Robustness of carbon‐ion radiotherapy against DNA damage repair associated radiosensitivity variation based on a biophysical model

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