Variable Relative Biological Effectiveness Research Articles

Report of the AAPM TG-256 on the relative biological effectiveness of proton beams in radiation therapy.

The biological effectiveness of proton beams relative to photon beams in radiation therapy has been taken to be 1.1 throughout the history of proton therapy. While potentially appropriate as an average value, actual relative biological effectiveness (RBE) values may differ. This Task Group report outlines the basic concepts of RBE as well as the biophysical interpretation and mathematical concepts. The current knowledge on RBE variations is reviewed and discussed in the context of the current clinical use of RBE and the clinical relevance of RBE variations (with respect to physical as well as biological parameters). The following task group aims were designed to guide the current clinical practice: Assess whether the current clinical practice of using a constant RBE for protons should be revised or maintained. Identifying sites and treatment strategies where variable RBE might be utilized for a clinical benefit. Assess the potential clinical consequences of delivering biologically weighted proton doses based on variable RBE and/or LET models implemented in treatment planning systems. Recommend experiments needed to improve our current understanding of the relationships among invitro, invivo, and clinical RBE, and the research required to develop models. Develop recommendations to minimize the effects of uncertainties associated with proton RBE for well-defined tumor types and critical structures.

A mechanistic approach towards determining double strand breaks and Relative Biological Effectiveness variation along proton tracks

Relative Biological Effectiveness (RBE) is an important but complex quantity which is used in Proton Therapy to compare the efficacy of cell-killing of protons relative to x-ray. It is known to depend on many factors (such as proton’s energy, dose, and cell type) and varies along the track of a particle. The exact RBE value is also known to be subjected to a large amount of uncertainties. In light of these complexities and uncertainties, this paper presents the calculation of the biologically and clinically relevant parameters - RBE (for double strand breaks) and double strand breaks yield, using a mechanistic and radiobiology-inspired approach. This paper is divided into two main parts. The first features the debut of our in-house radiobiology simulation software known as Integrated Radiobiology Simulation with Geant4 and System Biology (IRSGS). The software and the methodology employed will be covered in details including chromosome geometry construction and processing of direct and indirect effect. The second part focuses on the derivation of the spatial distribution of strand breaks (especially double strand breaks) and RBE for protons.

Establishment of a New Three-Dimensional Dose Evaluation Method Considering Variable Relative Biological Effectiveness and Dose Fractionation in Proton Therapy Combined with High-Dose-Rate Brachytherapy.

Purpose:The purpose of this study is to evaluate the influence of variable relative biological effectiveness (RBE) of proton beam and dose fractionation has on dose distribution and to establish a new three-dimensional dose evaluation method for proton therapy combined with high-dose-rate (HDR) brachytherapy.Materials and Methods:To evaluate the influence of variable RBE and dose fractionation on dose distribution in proton beam therapy, the depth-dose distribution of proton therapy was compared with clinical dose, RBE-weighted dose, and equivalent dose in 2 Gy fractions using a linear-quadratic-linear model (EQD2LQL). The clinical dose was calculated by multiplying the physical dose by RBE of 1.1. The RBE-weighted dose is a biological dose that takes into account RBE variation calculated by microdosimetric kinetic model implemented in Monte Carlo code. The EQD2LQL is a biological dose that makes the RBE-weighted dose equivalent to 2 Gy using a linear-quadratic-linear (LQL) model. Finally, we evaluated the three-dimensional dose by taking into account RBE variation and LQL model for proton therapy combined with HDR brachytherapy.Results:The RBE-weighted dose increased at the distal of the spread-out Bragg peak (SOBP). With the difference in the dose fractionation taken into account, the EQD2LQL at the distal of the SOBP increased more than the RBE-weighted dose. In proton therapy combined with HDR brachytherapy, a divergence of 103% or more was observed between the conventional dose estimation method and the dose estimation method we propose.Conclusions:Our dose evaluation method can evaluate the EQD2LQL considering RBE changes in the dose distribution.

Fixed- versus Variable-RBE Computations for Intensity Modulated Proton Therapy

PurposeTo evaluate how using models of proton therapy that incorporate variable relative biological effectiveness (RBE) versus the current practice of using a fixed RBE of 1.1 affects dosimetric indices on treatment plans for large cohorts of patients treated with intensity modulated proton therapy (IMPT). Methods and MaterialsTreatment plans for 4 groups of patients who received IMPT for brain, head-and-neck, thoracic, or prostate cancer were selected. Dose distributions were recalculated in 4 ways: 1 with a fast-dose Monte Carlo calculator with fixed RBE and 3 with RBE calculated to 3 different models—McNamara, Wedenberg, and repair-misrepair-fixation. Differences among dosimetric indices (D02, D50, D98, and mean dose) for target volumes and organs at risk (OARs) on each plan were compared between the fixed-RBE and variable-RBE calculations. ResultsIn analyses of all target volumes, for which the main concern is underprediction or RBE less than 1.1, none of the models predicted an RBE less than 1.05 for any of the cohorts. For OARs, the 2 models based on linear energy transfer, McNamara and Wedenberg, systematically predicted RBE >1.1 for most structures. For the mean dose of 25% of the plans for 2 OARs, they predict RBE equal to or larger than 1.4, 1.3, 1.3, and 1.2 for brain, head-and-neck, thorax, and prostate, respectively. Systematically lower increases in RBE are predicted by repair-misrepair-fixation, with a few cases (eg, femur) in which the RBE is less than 1.1 for all plans. ConclusionsThe variable-RBE models predict increased doses to various OARs, suggesting that strategies to reduce high-dose linear energy transfer in critical structures should be developed to minimize possible toxicity associated with IMPT.

Feasibility Study of a Proton Irradiation Facility for Radiobiological Measurements at an 18 MeV Cyclotron

A feasibility study of an experimental setup for the irradiation of biological samples at the cyclotron facility installed at the National Centre of Accelerators (Seville, Spain) is presented. This cyclotron, which counts on an external beam line for interdisciplinary research purposes, produces an 18 MeV proton beam, which is suitable for the irradiation of mono-layer cultures for the measurement of proton cell damages and Relative Biological Effectiveness (RBE) at energies below the beam nominal value. Measurements of this kind are of interest for proton therapy, since the variation of proton RBE at the distal edge of the Bragg curve may have implications in clinical proton therapy treatments. In the following, the characteristics of the beam line and the solutions implemented for the irradiation of biological samples are described. When dealing with the irradiation of cell cultures, low beam intensities and broad homogeneous irradiation fields are required, in order to assure that all the cells receive the same dose with a suitable dose rate. At the cyclotron, these constraints have been achieved by completely defocusing the beam, intercepting the beam path with tungsten scattering foils and varying the exit-window-to-sample distance. The properties of the proton beam thus obtained have been analysed and compared with Monte Carlo simulations. The results of this comparison, as well as the experimental measurement of the lateral dose profiles expected at the position of samples are presented. Meaningful dose rates of about 2–3 Gy/min have been obtained. Homogeneous lateral dose profiles, with maximum deviations of 5%, have been measured at a distance of approximately 50 cm in air from the exit window, placing a tungsten scattering foil of 200 μm in the beam path.

Introducing Proton Track-End Objectives in Intensity Modulated Proton Therapy Optimization to Reduce Linear Energy Transfer and Relative Biological Effectiveness in Critical Structures

We propose the use of proton track-end objectives in intensity modulated proton therapy (IMPT) optimization to reduce the linear energy transfer (LET) and the relative biological effectiveness (RBE) in critical structures. IMPT plans were generated for 3 intracranial patient cases (1.8Gy (RBE) in 30 fractions) and 3 head-and-neck patient cases (2Gy (RBE) in 35 fractions), assuming a constant RBE of 1.1. Two plans were generated for each patient: (1) physical dose objectives only (DOSEopt) and (2) same dose objectives as the DOSEopt plan, with additional proton track-end objectives (TEopt). The track-end objectives penalized protons stopping in the risk volume of choice. Dose evaluations were made using a RBE of 1.1 and the LET-dependent Wedenberg RBE model, together with estimates of normal tissue complication probabilities (NTCPs). In addition, the distributions of proton track-ends and dose-average LET (LETd) were analyzed. The TEopt plans reduced the mean LETd in the critical structures studied by an average of 37% and increased the mean LETd in the primary clinical target volume (CTV) by an average of 23%. This was achieved through a redistribution of the proton track-ends, concurrently keeping the physical dose distribution virtually unchanged compared to the DOSEopt plans. This resulted in substantial RBE-weighted dose (DRBE) reductions, allowing the TEopt plans to meetall clinical goals for both RBE models and reduce the NTCPs by 0 to 19 percentage points compared to the DOSEopt plans, assuming the Wedenberg RBE model. The DOSEopt plans metall clinical goalsassuming a RBE of 1.1 but failed 10 of 19 normal tissue goals assuming the Wedenberg RBE model. Proton track-end objectives allow for LETd reductions in critical structures without compromising the physical target dose. This approach permits the lowering of DRBE and NTCP in critical structures, independent of the variable RBE model used, and it could be introduced in clinical practice without changing current protocols based on the constant RBE of 1.1.

Impact of potentially variable RBE in liver proton therapy

Currently, the relative biological effectiveness (RBE) is assumed to be constant with a value of 1.1 in proton therapy. Although trends of RBE variations are well known, absolute values in patients are associated with considerable uncertainties. This study aims to evaluate the impact of a variable proton RBE in proton therapy liver trials using different fractionation schemes.Sixteen liver cancer cases were evaluated assuming two clinical schedules of 40 Gy/5 fractions and 58.05 Gy/15 fractions. The linear energy transfer (LET) and physical dose distribution in patients were simulated using Monte Carlo. The variable RBE distribution was calculated using a phenomenological model, considering the influence of the LET, fraction size and α/β value. Further, models to predict normal tissue complication probability (NTCP) and tumor control probability (TCP) were used to investigate potential RBE effects on outcome predictions.Applying the variable RBE model to the 5 and 15 fractions schedules results in an increase in mean fraction-size equivalent dose (FED) to the normal liver of 5.0% and 9.6% respectively. For patients with a mean FED to the normal liver larger than 29.8 Gy, this results in a non-negligible increase in the predicted NTCP of the normal liver averaging 11.6%, ranging from 2.7% to 25.6%. On the other hand, decrease in TCP was less than 5% for both fractionation regimens for all patients when assuming a variable RBE instead of constant. Consequently, the difference in TCP between the two fractionation schedules did not change significantly assuming a variable RBE while the impact on the NTCP difference was highly case specific. In addition, both the NTCP and TCP decrease with increasing α/β value for both fractionation schemes, with the decreases being more pronounced when using a variable RBE compared to using RBE = 1.1.Assuming a constant RBE of 1.1 most likely overestimates the therapeutic ratio in proton therapy for liver cancer, predominantly due to underestimation of the RBE-weighted dose to the normal liver. The impact of applying a variable RBE (as compared to RBE = 1.1) on the NTCP difference of the two fractionation regimens is case dependent. A variable RBE results in a slight increase in TCP difference. Variations in patient radiosensitivity increase when using a variable RBE.

Exploration and application of phenomenological RBE models for proton therapy

The relative biological effectiveness (RBE) of protons varies with multiple physical and biological factors. Phenomenological RBE models have been developed to include such factors in the estimation of a variable RBE, in contrast to the clinically applied constant RBE of 1.1. In this study, eleven published phenomenological RBE models and two plan-based models were explored and applied to simulated patient cases. All models were analysed with respect to the distribution and range of linear energy transfer (LET) and reference radiation fractionation sensitivity ((α/β)x) of their respective experimental databases. Proton therapy plans for a spread-out Bragg peak in water and three patient cases (prostate adenocarcinoma, pituitary adenoma and thoracic sarcoma) were optimised using an RBE of 1.1 in the Eclipse™ treatment planning system prior to recalculation and modelling in the FLUKA Monte Carlo code. Model estimated dose-volume parameters for the planning target volumes (PTVs) and organs at risk (OAR) were compared. The experimental in vitro databases for the various models differed greatly in the range of (α/β)x values and dose-averaged LET (LETd). There were significant variations between the model estimations, which arose from fundamental differences in the database definitions and model assumptions. The greatest variations appeared in organs with low (α/β)x and high LETd, e.g. biological doses given to late responding OARs located distal to the target in the treatment field. In general, the variation in maximum dose (D2%) was larger than the variation in mean dose and other dose metrics, with D2% of the left optic nerve ((α/β)x = 2.1 Gy) in the pituitary adenoma case showing the greatest discrepancies between models: 28–52 Gy(RBE), while D2% for RBE1.1 was 30 Gy(RBE). For all patient cases, the estimated mean RBE to the PTV was in the range 1.09–1.29 ((α/β)x = 1.5/3.1/10.6 Gy). There were considerable variations between the estimations of RBE and RBE-weighted doses from the different models. These variations were a consequence of fundamental differences in experimental databases, model assumptions and regression techniques. The results from the implementation of RBE models in dose planning studies should be evaluated in light of these deviations.

I007] Treatment planning in proton therapy

Purpose To present the most important physics aspects of proton therapy (PT) treatment planning for scanning beams and compare them with photon-based radiotherapy. Methods The most important differences of protontherapy treatment planning with pencil beam scanning (PBS) with respect to what is considered now the norm in radiotherapy with photons (XRT) are the following: 1) The dosimetric inaccuracies in the map of proton stopping power (PSP) estimated via CT imaging are larger than similar error in estimating electron density for photons. This is the reason behind the development of more refined methods (e.g. dual energy CT or proton CT) and the current impossibility of MR-based protontherapy; 2) The pristine beam is in principle simpler to model than in photons, as no beam modifiers are used to shape the beam, with one significant exception: the preabsorber (aka “range shifter”); 3) Up until recently, dose calculation was performed with pencil beam-based algorithms. Now a transition is happening towards Monte Carlo-based algorithms, however for reasons that are different than in XRT; 4) In XRT geometrical uncertainties are handled during planning with ad hoc volume such as the planning target volume (PTV). In PT this approach is hardly satisfactory, albeit still common, and most advanced planning solutions are in fact based on PTV-less so called “robust optimization”, where the effect of range and setup uncertainties is essentially part of the cost function. This leaves open the issue of dose reporting, which is now approached in different ways at different PT centers; 5) PT treatment planning is performed assuming a constant 1.1 relative biological effectiveness (RBE) of protons with respect to XRT. This is an approximation, and the need of variable RBE in proton planning is one of the “hot topic” at the moment; 6) Adaptive therapy, and as a consequence adaptive treatment planning, is an area of development that has to be explored further. PT may be a field where the concept of “online adaptive” may have a clinical impact, but the times are still premature for a large scale implementation of these techniques.

Monte Carlo GEANT4-based application for in vivo RBE study using small animals at LNS-INFN preclinical hadrontherapy facility

Preclinical studies represent an important step towards a deep understanding of the biological response to ionizing radiations. The effectiveness of proton therapy is higher than photons and, for clinical purposes, a fixed value of 1.1 is used for the relative biological effectiveness (RBE) of protons considered 1.1. Recent in vitro studies have reported that the RBE along the spread-out Bragg peak (SOBP) is not constant and, in particular, the RBE value increases on the distal part of SOBP. The present work has been carried-out in the perspective of a preclinical hadrontherapy facility at LNS-INFN and was focused on the experimental preparation of an in vivo study concerning the RBE variation along the SOBP. The main purpose of this work was to determine, using GEANT4-based Monte Carlo simulations, the best configuration for small animal treatments. The developed GEANT4 application simulates the proton-therapy beam line of LNS-INFN (CATANA facility) and allows to import the DICOM-CT images as targets. The RBE will be evaluated using a deterministic radiation damage like myelopathy as end-point. In fact, the dose at which the 50% of animals will show the myelopathy is supposed to be LET-dependent. In this work, we studied different treatment configurations in order to choose the best two that maximize the LET difference reducing as much as possible the dose released to healthy tissue. The results will be useful to plan hadrontherapy treatments for preclinical in vivo studies and, in particular, for the future in vivo RBE studies.

Research Facility for Radiobiological Studies at the University Proton Therapy Dresden.

In order to take full advantage of proton radiotherapy, the biological effect of protons in normal and tumor tissue should be investigated and understood in detail. The ongoing discussion on variable relative biological effectiveness along the proton depth dose distribution (eg, Paganetti 2015), and also the administration of concomitant treatments, demands dedicated in vitro trials that prepare the translation into the clinics. Therefore, a setup for radiobiological studies and the corresponding dosimetry should be established that enables in vitro experiments at a horizontal proton beam and a clinical 6 MV photon linear accelerator (Linac) as reference. The experimental proton beam at the University Proton Therapy Dresden is characterized by high beam availability and reliability throughout the day in parallel to patient treatment. For cell irradiation, a homogeneous 10 × 10 cm2 proton field with an optional spread-out Bragg-peak can be formed. A water-filled phantom was installed that allows for precise positioning of different sample geometries along the proton path. Depth-dose profiles within the phantom and dose homogeneity over different cell samples were characterized for the proton beam and the photon reference source. A daily quality assurance protocol was implemented that provides absolute dose information required for significant and reproducible in vitro experiments. Cell survival test experiments were performed to demonstrate the feasibility of such experiments. In the experimental room of the University Proton Therapy Dresden, clinically relevant conditions for proton in vitro experiments have been realized. The established cell phantom and dosimetry facilitate irradiation in an aqueous environment and are transferable to other proton, photon and ion beam facilities. Precise positioning and easy exchange of cell samples, monitor unit-based dose delivery, and high beam availability allow for systematic in vitro experiments. The close vicinity to the radiotherapy and radiobiology departments provides access to clinical linacs and the interdisciplinary basis for further translational steps.

Proton Relative Biological Effectiveness - Uncertainties and Opportunities.

Proton therapy treatments are prescribed using a biological effectiveness relative to photon therapy of 1.1, that is, proton beams are considered to be 10% more biologically effective. Debate is ongoing as to whether this practice needs to be revised. This short review summarizes current knowledge on relative biological effectiveness variations and uncertainties in vitro and in vivo. Clinical relevance is discussed and strategies toward biologically guided treatment planning are presented.

Asymptomatic Late-phase Radiographic Changes Among Chest-Wall Patients Are Associated With a Proton RBE Exceeding 1.1

Clinical practice assumes a fixed proton relative biological effectiveness (RBE) of 1.1, but invitro experiments demonstrate higher RBEs at the distal edge of the proton spread-out Bragg peak, that is, in a region that falls within the lung for chest-wall patients. We performed retrospective qualitative and quantitative analyses of lung-density changes-indicative of asymptomatic fibrosis-for chest-wall patients treated with protons or photons. Our null hypothesis was that, assuming a fixed RBE of 1.1, these changes would be the same for the 2 cohorts, supporting current RBE practice. Our alternative hypothesis was that radiographic abnormalities would be greater for the proton cohort, suggesting an RBE > 1.1. We analyzed follow-up computed tomography (CT) scans for 20 proton and photon patients. All were prescribed 50.4Gy (RBE) in 28 fractions, assuming a fixed RBE of 1.1 for protons and 1 for photons. Deformable registrations enabled us to calculate density changes in the normal lung, specifically (1) median Hounsfield unit (HU) values among posttreatment CT scans and (2) changes in median HU values between pretreatment and posttreatment CT scans, both as a function of grays (RBE). In addition, qualitative abnormality grading was performed by a radiologist. Proton patients exhibited higher values of HU/Gy (RBE) (endpoint 1) and ΔHU/Gy (RBE) (endpoint 2): P=.049 and P=.00019, respectively, were obtained (likelihood ratio tests of full linear mixed-effects models against models without "modality"). Furthermore, qualitative radiologic scoring indicated a significant difference between the cohorts (Wilcoxon P=.018; median score, 3 of 9 for protons and 1.5 of 9 for photons). Our data support the hypothesis that the proton RBE for lung-density changes exceeds 1.1. This RBE elevation could be attributable to (1) the late, normal tissue endpoint that we consider or (2) end-of-range proton linear energy transfer elevation-or a combination of the two. Regardless, our results suggest that variations in proton RBE prove important invivo as well as invitro.

Selection of carbon beam therapy: biophysical models of carbon beam therapy.

Variation in the relative biological effectiveness (RBE) within the irradiation field of a carbon beam makes carbon-ion radiotherapy unique and advantageous in delivering the therapeutic dose to a deep-seated tumor, while sparing surrounding normal tissues. However, it is crucial to consider the RBE, not only in designing the dose distribution during treatment planning, but also in analyzing the clinical response retrospectively. At the National Institute of Radiological Sciences, the RBE model was established based on the response of human salivary gland cells. The response was originally handled with a linear–quadratic model, and later with a microdosimetric kinetic model. Retrospective analysis with a tumor-control probability model of non–small cell cancer treatment revealed a steep dose response in the tumor, and that the RBE of the tumor was adequately estimated using the model. A commonly used normal tissue complication probability model has not yet fully been accountable for the variable RBE of carbon ions; however, analysis of rectum injury after prostate cancer treatment suggested a highly serial-organ structure for the rectum, and a steep dose response similar to that observed for tumors.

The Radiobiology of Proton Therapy: Challenges and Opportunities Around Relative Biological Effectiveness

With the current UK expansion of proton therapy there is a great opportunity for clinical oncologists to develop a translational interest in the associated scientific base and clinical results. In particular, the underpinning controversy regarding the conversion of photon dose to proton dose by the relative biological effectiveness (RBE) must be understood, including its important implications. At the present time, the proton prescribed dose includes an RBE of 1.1 regardless of tissue, tumour and dose fractionation. A body of data has emerged against this pragmatic approach, including a critique of the existing evidence base, due to choice of dose, use of only acute-reacting in vivo assays, analysis methods and the reference radiations used to determine the RBE. Modelling systems, based on the best available scientific evidence, and which include the clinically useful biological effective dose (BED) concept, have also been developed to estimate proton RBEs for different dose and linear energy transfer (LET) values. The latter reflect ionisation density, which progressively increases along each proton track. Late-reacting tissues, such as the brain, where α/β = 2 Gy, show a higher RBE than 1.1 at a low dose per fraction (1.2–1.8 Gy) at LET values used to cover conventional target volumes and can be much higher. RBE changes with tissue depth seem to vary depending on the method of beam delivery used. To reduce unexpected toxicity, which does occasionally follow proton therapy, a more rational approach to RBE allocation, using a variable RBE that depends on dose per fraction and the tissue and tumour radiobiological characteristics such as α/β, is proposed.

Proton and helium ion radiotherapy for meningioma tumors: a Monte Carlo-based treatment planning comparison

BackgroundDue to their favorable physical and biological properties, helium ion beams are increasingly considered a promising alternative to proton beams for radiation therapy. Hence, this work aims at comparing in-silico the treatment of brain and ocular meningiomas with protons and helium ions, using for the first time a dedicated Monte Carlo (MC) based treatment planning engine (MCTP) thoroughly validated both in terms of physical and biological models.MethodsStarting from clinical treatment plans of four patients undergoing proton therapy with a fixed relative biological effectiveness (RBE) of 1.1 and a fraction dose of 1.8 Gy(RBE), new treatment plans were optimized with MCTP for both protons (with variable and fixed RBE) and helium ions (with variable RBE) under the same constraints derived from the initial clinical plans. The resulting dose distributions were dosimetrically compared in terms of dose volume histograms (DVH) parameters for the planning target volume (PTV) and the organs at risk (OARs), as well as dose difference maps.ResultsIn most of the cases helium ion plans provided a similar PTV coverage as protons with a consistent trend of superior OAR sparing. The latter finding was attributed to the ability of helium ions to offer sharper distal and lateral dose fall-offs, as well as a more favorable differential RBE variation in target and normal tissue.ConclusionsAlthough more studies are needed to investigate the clinical potential of helium ions for different tumour entities, the results of this work based on an experimentally validated MC engine support the promise of this modality with state-of-the-art pencil beam scanning delivery, especially in case of tumours growing in close proximity of multiple OARs such as meningiomas.

Biological and dosimetric characterisation of spatially fractionated proton minibeams

The biological effectiveness of proton beams varies with depth, spot size and lateral distance from the beam central axis. The aim of this work is to incorporate proton relative biological effectiveness (RBE) and equivalent uniform dose (EUD) considerations into comparisons of broad beam and highly modulated proton minibeams. A Monte Carlo model of a small animal proton beamline is presented. Dose and variable RBE is calculated on a per-voxel basis for a range of energies (30–109 MeV). For an open beam, the RBE values at the beam entrance ranged from 1.02–1.04, at the Bragg peak (BP) from 1.3 to 1.6, and at the distal end of the BP from 1.4 to 2.0. For a 50 MeV proton beam, a minibeam collimator designed to produce uniform dose at the depth of the BP peak, had minimal impact on the open beam RBE values at depth. RBE changes were observed near the surface when the collimator was placed flush with the irradiated object, due to a higher neutron contribution derived from proton interactions with the collimator. For proton minibeams, the relative mean RBE weighted entrance dose (RWD) was ~25% lower than the physical mean dose. A strong dependency of the EUD with fraction size was observed. For 20 Gy fractions, the EUD varied widely depending on the radiosensitivity of the cells. For radiosensitive cells, the difference was up to ~50% in mean dose and ~40% in mean RWD and the EUD trended towards the valley dose rather than the mean dose. For comparative studies of uniform dose with spatially fractionated proton minibeams, EUD derived from a per-voxel RWD distribution is recommended for biological assessments of reproductive cell survival and related endpoints.

Biological dose and complication probabilities for the rectum and bladder based on linear energy transfer distributions in spot scanning proton therapy of prostate cancer

Background: The increased linear energy transfer (LET) at the end of the Bragg peak causes concern for an elevated and spatially varying relative biological effectiveness (RBE) of proton therapy (PT), often in or close to dose-limiting normal tissues. In this study, we investigated dose-averaged LET (LETd) distributions for spot scanning PT of prostate cancer patients using different beam angle configurations. In addition, we derived RBE-weighted (RBEw) dose distributions and related normal tissue complication probabilities (NTCPs) for the rectum and bladder.Material and methods: A total of 21 spot scanning proton plans were created for each of six patients using a prescription dose of 78 Gy(RBE1.1), with each plan using two ‘mirrored’ beams with gantry angles from 110°/250° to 70°/290°, in steps of 2°. Physical dose and LETd distributions were calculated as well as RBEw dose distributions using either RBE = 1.1 or three different variable RBE models. The resulting biological dose distributions were used as input to NTCP models for the rectum and bladder.Results: For anterior oblique (AO) configurations, the rectum LETd volume and RBEw dose increased with increasing angles off the lateral opposing axis, with the RBEw rectum dose being higher than for all posterior oblique (PO) configurations. For PO configurations, the corresponding trend was seen for the bladder. Using variable RBE models, the rectum NTCPs were highest for the AO configurations with up to 3% for the 80°/280° configuration while the bladder NTCPs were highest for the PO configurations with up to 32% for the 100°/260°. The rectum D1cm3 constraint was fulfilled for most patients/configurations when using uniform RBE but not for any patient/configuration with variable RBE models.Conclusions: Compared to using constant RBE, the variable RBE models predicted increased biological doses to the rectum, bladder and prostate, which in turn lead to substantially higher estimated rectum and bladder NTCPs.

Introducing Proton Track-End Objectives as a Tool to Mitigate the Elevated Relative Biological Effectiveness in Critical Structures

The increased linear energy transfer (LET) near the end of the proton range often reach into normal tissues. This could potentially increase the risk of adverse effects due to the elevated relative biological effectiveness (RBE) with increased LET. By introducing proton track-end objectives in the optimization, the increased RBE in critical structures may be mitigated by lowering the LET. Intensity modulated proton therapy (IMPT) plans were generated for a head and heck (H&N) and an intracranial patient case. 2 Gy(RBE) per fraction (assuming the generic RBE of 1.1) were prescribed to the target using physical dose objectives. 35 fractions were planned for the H&N case and 30 for the intracranial case. Subsequently, both plans were re-optimized using proton track-end objectives in addition to the physical dose objectives. The track-end objectives penalized track-ends falling in the volume of choice and were used for the brainstem, chiasm, parotid glands and spinal cord. The resulting dose distributions were compared with the original plans using both RBE=1.1 and the variable RBE model by Wedenberg et al. (2013), where the RBE is a function of dose, dose-averaged LET (LETd) and α/β. An α/β of 10 Gy was assumed for the targets and 3 Gy for all normal tissues. Additionally, the distributions of proton track-ends and LETd were analyzed. The original plans satisfied the clinical goals for the target and the critical structures assuming RBE=1.1. The redistribution of the proton track-ends in the re-optimized plans allowed for LETd and RBE reductions in the critical structures, with only minimal degradation of the physical dose distribution. The median LETd in the H&N plan was reduced from 1.8 to 1.7 keV/μm for the brainstem, from 3.5 to 2.4 keV/μm for the parotid glands and from 2.2 to 2.1 keV/μm for the spinal cord when introducing the track-end objectives. The corresponding reduction for the intracranial plan was 4.7 to 4.1 keV/μm for the brainstem and 6.9 to 6.1 keV/μm for the chiasm. This allowed for a reduction from 29.3 to 27.6 Gy(RBE) in the mean dose to the parotid glands and 64.2 to 62.1 Gy(RBE) in D2% for the chiasm using the Wedenberg model. Although the track-end objectives allowed for this RBE-weighted dose reduction, it still predicted substantially higher values than the generic RBE of 1.1, which predicted a mean dose of 25.2 Gy(RBE) to the parotid glands and a D2% of 53.9 Gy(RBE) for the chiasm. Variable RBE models often predicts RBE values substantially higher than 1.1 in critical structures due to high LETd and low α/β values. By including proton track-end objectives in the optimization of IMPT plans, LETd reductions in critical structures may be accomplished without compromising the physical dose. This could mitigate potential adverse effects near the end of the proton range independently of tissue or patient-specific RBE.

Relating the proton relative biological effectiveness to tumor control and normal tissue complication probabilities assuming interpatient variability in α/β

Background: Proton therapy uses a constant relative biological effectiveness (RBE) of 1.1. The use of variable RBE values has been suggested but is currently not feasible due to uncertainties. The impact of variable RBE has solely been studied using dosimetric indices. This work elucidates the impact of RBE variations on tumor control and normal tissue complication probabilities (TCP/NTCP).Methods: Models to estimate TCP and NTCP were used in combination with an empirical proton RBE model. Variations in outcome as a function of linear-quadratic model parameters for cellular radiosensitivity were determined for TCP in prostate and ependymoma. In addition, NTCP analysis was done for brainstem necrosis.Results: Considering a variable proton RBE as a dose-modifying factor for prescription doses and dose constraints is misleading, as TCP/NTCP do not simply scale with RBE. The dependency of RBE on α/β cannot be interpreted independent of TCP/NTCP because variations in radiosensitivity affect both photon and proton treatments. Assuming interpatient variability in radiosensitivity results in lower TCP for patients with low α/β. In proton therapy, the magnitude of TCP variations is reduced due to an RBE increase as α/β decreases. The TCP in proton therapy is less affected by interpatient variability in α/β. On the other hand, patients with a lower α/β would have a lower complication probability, which is counteracted by an increase in RBE as α/β decreases. Toxicities in proton therapy would be more affected by α/β variations compared to photon therapy.Conclusions: Assessment of variable RBE in proton therapy should be based on TCP and NTCP. Potential interpatient variability in radiosensitivity causes a smaller variance in TCP but a larger variance in NTCP for proton patients. The relative TCP as a function of α/β was found to be higher than the RBE, whereas the relative NTCP was lower than a calculated RBE.