A phenomenological biological dose model for proton therapy based on linear energy transfer spectra

Rørvik, Eivind; Thörnqvist, S.; Stokkevåg, C.H.; Fjæra, Lars Fredrik; Ytre-Hauge, Kristian S.

doi:10.1002/mp.12216

Cited by 39 publications

(44 citation statements)

References 55 publications

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“…This is also of relevance for the validation of RBE models used in treatment planning, since many empirical models in particular used for application in proton therapy assume a linear RBE(LET D ) relationship . Apart from our analysis, Rørvik et al introduced a phenomenological RBE model based on the LET distribution rather than the LET D and found that nonlinear models could give a better representation of the RBE(LET) relationship in mixed radiation fields even though a linear dependency could not be rejected completely. The key question to be discussed is thus whether such a linear RBE(LET) relationship also exists for monoenergetic protons under track segment conditions which would justify the use of a linear RBE(LET D ) relationship for protons independent of the particle composition and the complexity in mixed radiation fields.…”

Section: Discussionmentioning

confidence: 92%

Is the dose‐averaged LET a reliable predictor for the relative biological effectiveness?

et al. 2019

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Purpose The dose‐averaged linear energy transfer (LETD) is frequently used as representative quantity for the biological effectiveness of a radiation field. Moreover, relative biological effectiveness (RBE) values measured or calculated in mixed radiation fields are typically plotted vs the LETD. In this study, we will investigate whether the LETD is an appropriate quantity to describe the RBE of any mixed radiation field of protons and heavier ions and discuss potential limitations. Methods To study the reliability of LETD, we investigate model predictions of RBE in monoenergetic beams under track segment conditions and pristine Bragg peaks as well as spread out Bragg peaks (SOBP) in water. Both, the pristine Bragg peaks and the SOBPs are regarded as mixed radiation fields in this analysis, that is, they are characterized by a certain width of the energy spectrum of the projectile, although the underlying energy distribution is much broader in the case of an SOBP as compared to a pristine peak. For both cases, the corresponding RBE values are compared to those of strictly monoenergetic particles under track segment conditions, characterized by a single LET value. For the planning we use the treatment planning software TRiP98 together with the Local Effect Model to predict the RBE of protons, helium, and carbon ions. We further compare our model predictions for protons with a simplistic linear RBE‐LET relationship representative for the phenomenological models in literature. Results Regarding pristine Bragg peaks in water, the deviations in RBE compared to monoenergetic particles under track segment conditions for the same LET value are low (mostly 0–5%), except for the distal fall‐off region. The situation changes in SOBPs for which we found deviations in the order of up to 25% for the lighter particles and even more pronounced deviations for heavier particles like carbon ions. Conclusions The analysis showed that LETD is a sufficiently accurate predictor for RBE only in regions with comparably narrow, but not in regions with broad, LET distribution as in a single SOBP or in multiple overlapping fields. The deviations are caused by the nonlinearity of the RBE(LET) relationship in the case of track segment conditions. Thus, independent of the underlying RBE model and the particle type regarded, as long as the RBE(LET) relationship deviates from being purely linear, LETD is not a good predictor for RBE, and especially for heavier particles like carbon ions knowledge of the underlying LET distribution is mandatory to describe the RBE in mixed radiation fields.

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Section: Discussionmentioning

confidence: 92%

Is the dose‐averaged LET a reliable predictor for the relative biological effectiveness?

et al. 2019

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“…Several phenomenological RBE models have been developed [5][6][7][8][9][10][11], based on in vitro experiments, in order to model the observed variable RBE. Dose-averaged linear energy transfer (LET D ) is often used as input for these models.…”

Section: Introductionmentioning

confidence: 99%

Using the Proton Energy Spectrum and Microdosimetry to Model Proton Relative Biological Effectiveness

Newpower

Patel

Bronk

et al. 2019

International Journal of Radiation Oncology*Biology*Physics

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We introduce a methodology to calculate the microdosimetric quantity dose-mean lineal energy for input into the microdosimetric kinetic model (MKM) to model the relative biological effectiveness (RBE) of proton irradiation experiments. Methods and Materials: The data from seven individual proton RBE experiments were included in this study. In each experiment, the RBE at several points along the Bragg curve was measured. Monte Carlo (MC) simulations to calculate the lineal energy probability density function of 172 different proton energies were carried out with use of Geant4 DNA. We calculated the fluence-weighted lineal energy probability density function (݂ ௪ ሺ‫ݕ‬ሻ), based on the proton energy spectra calculated through MC at each experimental depth, calculated ‫ݕ‬ for input into the MKM, and then computed the RBE. The radius of the domain ‫ݎ(‬ ௗ) was varied to reach the best agreement between the MKM-predicted RBE and experimental RBE. A generic RBE model as a function of dose averaged linear energy transfer (LET D) with one fitting parameter was presented and fit to the experimental RBE data as well, to facilitate a comparison to the MKM. Results: Both the MKM and LET D based models modeled the RBE from experiments well. Values for ‫ݎ‬ ௗ were similar to those of other cell lines under proton irradiation that were modeled with the MKM. Analysis of the performance of each model revealed neither model was clearly superior to the other. Conclusions: Our three key accomplishments include the following: (1) Developed a method that uses the proton energy spectra and lineal energy distributions of those protons to calculate

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“…The main reason for an increased biological effectiveness is the clustered damages to the DNA structure within one nucleus, which is more difficult for the cell to repair and which leads to increased cell killing [ 34 ]. As a result, the RBE varies spatially within the patient and increases toward the distal end of a SOBP, as LET values increases with the depth of the beam [ 35 ]. It is known that the RBE is highly dependent on both cell type and the studied endpoint but also on particle species, due to the different dose deposition profiles on microscopic scale [ 36 ].…”

Section: Introductionmentioning

confidence: 99%

“…It is known that the RBE is highly dependent on both cell type and the studied endpoint but also on particle species, due to the different dose deposition profiles on microscopic scale [ 36 ]. The study of Rorvik et al, developed linear as well as and non-linear RBE models for protons by applying the LET spectrum as a parameter for the radiation quality [ 35 ]. The study demonstrated that non-linear models give a better representation of the RBE-LET relationship for protons compared to linear models.…”

Section: Introductionmentioning

confidence: 99%

“…On the other hand, if the dose is too high, the chances for acute and last side effects will increase. Disregarding this RBE and LET variations could have negative clinical implications, especially when an organ at risk is located near the distal end of a tumor [ 35 ]. A fixed RBE during fractionated exposures disregards any effects due to the variation of dose per fraction and the total number of fractions delivered in relation to the LET.…”

Section: Introductionmentioning

confidence: 99%

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New insights in the relative radiobiological effectiveness of proton irradiation

2018

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BackgroundProton radiotherapy is a form of charged particle therapy that is preferentially applied for the treatment of tumors positioned near to critical structures due to their physical characteristics, showing an inverted depth-dose profile. The sparing of normal tissue has additional advantages in the treatment of pediatric patients, in whom the risk of secondary cancers and late morbidity is significantly higher. Up to date, a fixed relative biological effectiveness (RBE) of 1.1 is commonly implemented in treatment planning systems with protons in order to correct the physical dose. This value of 1.1 comes from averaging the results of numerous in vitro experiments, mostly conducted in the middle of the spread-out Bragg peak, where RBE is relatively constant. However, the use of a constant RBE value disregards the experimental evidence which clearly demonstrates complex RBE dependency on dose, cell- or tissue type, linear energy transfer and biological endpoints. In recent years, several in vitro studies indicate variations in RBE of protons which translate to an uncertainty in the biological effective dose delivery to the patient. Particularly for regions surrounding the Bragg peak, the more localized pattern of energy deposition leads to more complex DNA lesions. These RBE variations of protons bring the validity of using a constant RBE into question.Main bodyThis review analyzes how RBE depends on the dose, different biological endpoints and physical properties. Further, this review gives an overview of the new insights based on findings made during the last years investigating the variation of RBE with depth in the spread out Bragg peak and the underlying differences in radiation response on the molecular and cellular levels between proton and photon irradiation. Research groups such as the Klinische Forschergruppe Schwerionentherapie funded by the German Research Foundation (DFG, KFO 214) have included work on this topic and the present manuscript highlights parts of the preclinical work and summarizes the research activities in this context.Short conclusionIn summary, there is an urgent need for more coordinated in vitro and in vivo experiments that concentrate on a realistic dose range of in clinically relevant tissues like lung or spinal cord.

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A phenomenological biological dose model for proton therapy based on linear energy transfer spectra

Cited by 39 publications

References 55 publications

Is the dose‐averaged LET a reliable predictor for the relative biological effectiveness?

Is the dose‐averaged LET a reliable predictor for the relative biological effectiveness?

Using the Proton Energy Spectrum and Microdosimetry to Model Proton Relative Biological Effectiveness

New insights in the relative radiobiological effectiveness of proton irradiation

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