Quantification of the Relative Biological Effectiveness for Ion Beam Radiotherapy: Direct Experimental Comparison of Proton and Carbon Ion Beams and a Novel Approach for Treatment Planning

Elsässer, Thilo; Weyrather, Wilma K.; Friedrich, Thomas; Durante, Marco; Iancu, Gheorghe; Krämer, M.; Kragl, G.; Brons, Stephan; Winter, Marcus; Weber, Klaus-Josef; Scholz, M.

doi:10.1016/j.ijrobp.2010.05.014

Cited by 292 publications

(347 citation statements)

References 34 publications

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“…In conclusion, our approach gives an independent validation of the generalization of the LEM principles recently introduced [24], where cell death is derived by simply predicting isolated and clustered DSBs. For many years, our community has been focusing on complex DSBs generated by HZE which are believed to be more difficult to repair accurately, leading to more cell death and mutations [41].…”

Section: Discussionmentioning

confidence: 84%

“…On the other hand, this length is three times larger than the theoretical voxel size of 0.54 µm reported in the LEM model. The LEM voxel size is derived by doing a parameter sweep leading to the best RBE predictions across a wide range of ions [24]. In contrast, the domain size we report reflects observable repair processes in the nucleus.…”

Section: Discussionmentioning

confidence: 98%

“…In contrast, the generalized LEM model first evaluates the local equivalent X-ray dose that leads to the same number of isolated and clustered DSB for a given ion. The linearquadratic dose dependence of X-ray for cell death is then computed for the equivalent dose to predict cell death [24]. X-ray survival curves in nonmalignant breast epithelial cells (MCF10A) were published by the Bedford group [19] and are used here to determine a and γ survival parameters.…”

Section: Predicting Cell Survival Rbe With Dsb Clusteringmentioning

confidence: 99%

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Combinatorial DNA Damage Pairing Model Based on X-Ray-Induced Foci Predicts the Dose and LET Dependence of Cell Death in Human Breast Cells

et al. 2014

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In contrast to the classic view of static DNA double strand breaks (DSBs) being repaired at the site of damage, we hypothesize that DSBs move and merge with each other over large distances (µm). As X-ray dose increases, the probability of having DSB clusters increases and so does the probability of misrepair and cell death. Experimental work characterizing the dose dependence of radiation-induced foci (RIF) from X-ray in nonmalignant human mammary epithelial cells (MCF10A) is used here to validate a DSB clustering model. We then use the principles of the local effect model (LEM) to predict the yield of DSB at the sub-micron level. Two mechanisms for DSB clustering are first compared: random coalescence of DSBs versus active movement of DSBs into repair domains. Simulations that best predict both RIF dose dependence and cell survival following X-ray favor the repair domain hypothesis, suggesting the nucleus is divided into an array of regularly spaced repair domains of ~1.55 µm sides. Applying the same approach to high-LET ion tracks, we can predict experimental RIF/µm along tracks with an overall relative error of 12%, for LET ranging between 30 and 350 keV/µm and for three different ions. Finally, cell death is predicted by assuming an exponential dependence on the total number of DSBs and of all possible combinations of paired DSBs within each simulated RIF. RBE predictions for cell survival of MCF10A exposed to high-LET show an LET dependence that matches previous experimental results for similar cell types. Overall, this work suggests that microdosimetric properties of ion tracks at the sub-micron level are sufficient to explain both RIF data and survival curves for any LET, similarly to the LEM assumption. On the other hand, high-LET death mechanism does not have to infer linear-quadratic dose formalism as done in the LEM. In addition, the size of repair domains derived in our model are based on experimental RIF and are three times larger than the hypothetical LEM voxel used to fit survival curves. Our model is therefore an alternative to previous approaches by providing a testable biological mechanism (i.e. RIF). More generally, DSB pairing will help develop more accurate alternatives to the simplistic linear cancer risk model (LNT) currently used for regulating exposure to very low levels of ionizing radiation.Vadhavkar et al.

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 98%

Section: Predicting Cell Survival Rbe With Dsb Clusteringmentioning

confidence: 99%

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Combinatorial DNA Damage Pairing Model Based on X-Ray-Induced Foci Predicts the Dose and LET Dependence of Cell Death in Human Breast Cells

et al. 2014

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“…The relative biological effectiveness (RBE) following the local effect model (LEM) IV [Elsaesser et al, 2010]. For a conservative estimation, an alpha-beta ratio of 6 Gy and 2 Gy were used for target and OARs, respectively.…”

Section: Carbon-ion Treatment Planningmentioning

confidence: 99%

In silico comparison of photons versus carbon ions in single fraction therapy of lung cancer

et al. 2016

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Stereotactic body image guided radiation therapy (SBRT) shows excellent results for the local control of early stage lung cancer. However, not all patients are eligible for SBRT, and advanced stage treatment is less successful and often associated with severe side effects. Scanned carbon ion therapy (PT) can deliver more conformal dose likely benefiting these patient groups.Therefore an in silico trial was conducted on early and advanced stage patients to identify potential advantages of PT. The patients were treated with SBRT at Champalimaud Center for the Unknown, Lisbon (Portugal). PT plans were simulated on 4DCTs, and rescanning was investigated for motion mitigation in 4D-dose calculations. A dedicated strategy for 4D intensity modulated particle therapy (IMPT) was developed and applied for advanced stage patients with multiple lesions. For clinically valid and reliable results the deformable image registrationnecessary for 4D-dose calculation -a quality assurance tool was developed and applied in the study.The results showed that target coverage was comparable in SBRT and PT, while PT delivered significantly lower doses to most critical structures, especially the heart, lungs, and esophagus.A highly complex case of advanced stage lung cancer could be treated in a single fraction of 24 Gy with PT, while SBRT could not deliver the full ablative dose treatment due to an excessive heart dose. The mean heart dose was reduced from 10 Gy to 0.8 Gy with PT for this specific patient.

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“…2 Earlier studies reported that G0 cells possessed better repair systems than cycling cells. 3 However, the underlying mechanism of radioresistance is still unknown.…”

Section: Introductionmentioning

confidence: 99%

RAC2-P38 MAPK-dependent NADPH oxidase activity is associated with the resistance of quiescent cells to ionizing radiation

et al. 2016

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Our recent study showed that quiescent G0 cells are more resistant to ionizing radiation than G1 cells; however, the underlying mechanism for this increased radioresistance is unknown. Based on the relatively lower DNA damage induced in G0 cells, we hypothesize that these cells are exposed to less oxidative stress during exposure. As a catalytic subunit of NADPH oxidase, Ras-related C3 botulinum toxin substrate 2 (RAC2) may be involved in the cellular response to ionizing radiation. Here, we show that RAC2 was expressed at low levels in G0 cells but increased substantially in G1 cells. Relative to G1 cells, the total antioxidant capacity in G0 phase cells increased upon exposure to X-ray radiation, whereas the intracellular concentration of ROS and malondialdehyde increased only slightly. The induction of DNA single-and double-stranded breaks in G1 cells by X-ray radiation was inhibited by knockdown of RAC2. P38 MAPK interaction with RAC2 resulted in a decrease of functional RAC2. Increased phosphorylation of P38 MAPK in G0 cells also increased cellular radioresistance; however, excessive production of ROS caused P38 MAPK dephosphorylation. P38 MAPK, phosphorylated P38 MAPK, and RAC2 regulated in mutual feedback and negative feedback regulatory pathways, resulting in the radioresistance of G0 cells.

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Quantification of the Relative Biological Effectiveness for Ion Beam Radiotherapy: Direct Experimental Comparison of Proton and Carbon Ion Beams and a Novel Approach for Treatment Planning

Cited by 292 publications

References 34 publications

Combinatorial DNA Damage Pairing Model Based on X-Ray-Induced Foci Predicts the Dose and LET Dependence of Cell Death in Human Breast Cells

Combinatorial DNA Damage Pairing Model Based on X-Ray-Induced Foci Predicts the Dose and LET Dependence of Cell Death in Human Breast Cells

In silico comparison of photons versus carbon ions in single fraction therapy of lung cancer

RAC2-P38 MAPK-dependent NADPH oxidase activity is associated with the resistance of quiescent cells to ionizing radiation

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