Optimizing proton minibeam radiotherapy by interlacing and heterogeneous tumor dose on the basis of calculated clonogenic cell survival.

Proton minibeam radiotherapy (pMBRT) is a spatial fractionation method using sub-millimeter beams at center-to-center (ctc) distances of a few millimeters to widen the therapeutic index by reduction of side effects in normal tissues. Interlaced minibeams from two opposing or four orthogonal directions are calculated to minimize side effects. In particular, heterogeneous dose distributions applied to the tumor are investigated to evaluate optimized sparing capabilities of normal tissues at the close tumor surrounding. A 5 cm thick tumor is considered at 10 cm depth within a 25 cm thick water phantom. Pencil and planar minibeams are interlaced from two (opposing) directions as well as planar beams from four directions. An initial beam size of σ0 = 0.2 mm (standard deviation) is assumed in all cases. Tissue sparing potential is evaluated by calculating mean clonogenic cell survival using a linear-quadratic model on the calculated dose distributions. Interlacing proton minibeams for homogeneous irradiation of the tumor has only minor benefits for the mean clonogenic cell survival compared to unidirectional minibeam irradiation modes. Enhanced mean cell survival, however, is obtained when a heterogeneous dose distribution within the tumor is permitted. The benefits hold true even for an elevated mean tumor dose, which is necessary to avoid cold spots within the tumor in concerns of a prescribed dose. The heterogeneous irradiation of the tumor allows for larger ctc distances. Thus, a high mean cell survival of up to 47% is maintained even close to the tumor edges for single fraction doses in the tumor of at least 10 Gy. Similar benefits would result for heavy ion minibeams with the advantage of smaller minibeams in deep tissue potentially offering even increased tissue sparing. The enhanced mean clonogenic cell survival through large ctc distances for interlaced pMBRT with heterogeneous tumor dose distribution results in optimum tissue sparing potential. The calculations show the largest enhancement of the mean cell survival in normal tissue for high-dose fractions. Thus, hypo-fractionation or even single dose fractions become possible for tumor irradiation. A widened therapeutic index at big cost reductions is offered by interlaced proton or heavy ion minibeam therapy.

Simulation of Proton-Induced DNA Damage Patterns Using an Improved Clustering Algorithm.

Simulations of deoxyribonucleic acid (DNA) molecular damage use the traversal algorithm that has the disadvantages of being time-consuming, slowly converging, and requiring high-performance computer clusters. This work presents an improved version of the algorithm, "density-based spatial clustering of applications with noise" (DBSCAN), using a KD-tree approach to find neighbors of each point for calculating clustered DNA damage. The resulting algorithm considers the spatial distributions for sites of energy deposition and hydroxyl radical attack, yielding the statistical probability of (single and double) DNA strand breaks. This work achieves high accuracy and high speed at calculating clustered DNA damage that has been induced by proton treatment at the molecular level while running on an i7 quad-core CPU. The simulations focus on the indirect effect generated by hydroxyl radical attack on DNA. The obtained results are consistent with those of other published experiments and simulations. Due to the array of chemical processes triggered by proton treatment, it is possible to predict the effects that different track structures of various energy protons produce on eliciting direct and indirect damage of DNA.

A Monte Carlo study of bone-tissue interface microdosimeters.

Radiation-induced bone diseases were frequently reported in radiotherapy patients. To study the diseases, microdosimeters were constructed with walls of A150-A150, A150-B100, B100-A150 and B100-B100 interfaces. Monte Carlo simulations of these microdosimeters were performed to determine the lineal energy spectra of an interface site at different depths in water for 230 MeV protons. Comparing these spectra with data of ICRU tissue and bone walls, better agreements were found at shallow depths for protons and delta-rays than deep depths for nuclear interactions.

Mechanistic DNA damage simulations in Geant4-DNA Part 2: Electron and proton damage in a bacterial cell.

We extended a generic Geant4 application for mechanistic DNA damage simulations to an Escherichia coli cell geometry, finding electron damage yields and proton damage yields largely in line with experimental results. Depending on the simulation of radical scavenging, electrons double strand breaks (DSBs) yields range from 0.004 to 0.010 DSB Gy-1 Mbp-1, while protons have yields ranging from 0.004 DSB Gy-1 Mbp-1 at low LETs and with strict assumptions concerning scavenging, up to 0.020 DSB Gy-1 Mbp-1 at high LETs and when scavenging is weakest. Mechanistic DNA damage simulations can provide important limits on the extent to which physical processes can impact biology in low background experiments. We demonstrate the utility of these studies for low dose radiation biology calculating that in E. coli, the median rate at which the radiation background induces double strand breaks is 2.8 × 10-8 DSB day-1, significantly less than the mutation rate per generation measured in E. coli, which is on the order of 10-3.

RADIATION PROTECTION MEASUREMENTS WITH THE VARIANCE-COVARIANCE METHOD IN THE STRAY RADIATION FIELDS FROM PHOTON AND PROTON THERAPY FACILITIES.

The microdosimetric variance-covariance method was used to study the stray radiation fields from the photon therapy facility at the Technical University of Denmark and the scanned proton therapy beam at the Skandion Clinic in Uppsala, Sweden. Two TEPCs were used to determine the absorbed dose, the dose-average lineal energy, the dose-average quality factor and the dose equivalent. The neutron component measured by the detectors at the proton beam was studied through Monte Carlo simulations using the code MCNP6. In the photon beam the stray absorbed dose ranged between 0.3 and 2.4 µGy per monitor unit, and the dose equivalent between 0.4 and 9 µSv per monitor unit, depending on beam energy and measurement position. In the proton beam the stray absorbed dose ranged between 3 and 135 µGy per prescribed Gy, depending on detector position and primary proton energy.

Prospective study of proton beam radiation therapy for adjuvant and definitive treatment of thymoma and thymic carcinoma: Early response and toxicity assessment.

BACKGROUND AND PURPOSE: Radiation is an important modality in treatment of thymic tumors. However, toxicity may reduce its overall benefit. We hypothesized that double-scattering proton beam therapy (DS-PT) can achieve excellent local control with limited toxicity in patients with thymic malignancies. METHODS AND MATERIALS: Patients with thymoma or thymic carcinoma treated with DS-PT between 2011 and 2015 were prospectively analyzed for toxicity and patterns of failure on an IRB-approved study. RESULTS: Twenty-seven consecutive patients were evaluated. Patients were a median of 56 years and had thymoma (85%). They were treated with definitive (22%), salvage (15%) or adjuvant (63%) DS-PT to a median of 61.2/1.8 Gy [CGE]. No patient experienced grade ⩾3 toxicity. Acute grade 2 toxicities included dermatitis (37%), fatigue (11%), esophagitis (7%), and pneumonitis (4%). Late grade 2 toxicity was limited to a single patient with chronic dyspnea. At a median follow-up of 2 years, 100% local control was achieved. Three-year regional control, distant control, and overall survival rates were 96% (95% CI 76-99%), 74% (95% CI 41-90%), and 94% (95% CI 63-99%), respectively. CONCLUSIONS: This is the first cohort and prospective series of proton therapy to treat thymic tumors, demonstrating low rates of early toxicity and excellent initial outcomes.

Dose assessment for the fetus considering scattered and secondary radiation from photon and proton therapy when treating a brain tumor of the mother.

The goal of this work was to determine the scattered photon dose and secondary neutron dose and resulting risk for the sensitive fetus from photon and proton radiotherapy when treating a brain tumor during pregnancy. Anthropomorphic pregnancy phantoms with three stages (3-, 6-, 9-month) based on ICRP reference parameters were implemented in Monte Carlo platform TOPAS, to evaluate the scattered dose and secondary neutron dose and dose equivalent. To evaluate the dose equivalent, dose averaged quality factors were considered for neutrons. This study compared three treatment modalities: passive scattering and pencil beam scanning proton therapy (PPT and PBS) and 6-MV 3D conformal photon therapy. The results show that, for 3D conformal photon therapy, the scattered photon dose equivalent to the fetal body increases from 0.011 to 0.030 mSv per treatment Gy with increasing stage of gestation. For PBS, the neutron dose equivalent to the fetal body was significantly lower, i.e. increasing from 1.5 × 10(-3) to 2.5 × 10(-3) mSv per treatment Gy with increasing stage of gestation. For PPT, the neutron dose equivalent of the fetus decreases from 0.17 to 0.13 mSv per treatment Gy with the growing fetus. The ratios of dose equivalents to the fetus for a 52.2 Gy(RBE) course of radiation therapy to a typical CT scan of the mother's head ranged from 3.4-4.4 for PBS, 30-41 for 3D conformal photon therapy and 180-500 for PPT, respectively. The attained dose to a fetus from the three modalities is far lower than the thresholds of malformation, severe mental retardation and lethal death. The childhood cancer excessive absolute risk was estimated using a linear no-threshold dose-response relationship. The risk would be 1.0 (95% CI: 0.6, 1.6) and 0.1 (95% CI: -0.01, 0.52) in 10(5) for the 9-month fetus for PBS with a prescribed dose of 52.2 Gy(RBE). The increased risks for PPT and photon therapy are about two and one orders of magnitude larger than that for PBS, respectively. We can conclude that a pregnant woman with a brain tumor could be treated with pencil beam scanning with acceptable risks to the fetus.

Extension of TOPAS for the simulation of proton radiation effects considering molecular and cellular endpoints.

The aim of this work is to extend a widely used proton Monte Carlo tool, TOPAS, towards the modeling of relative biological effect (RBE) distributions in experimental arrangements as well as patients. TOPAS provides a software core which users configure by writing parameter files to, for instance, define application specific geometries and scoring conditions. Expert users may further extend TOPAS scoring capabilities by plugging in their own additional C++ code. This structure was utilized for the implementation of eight biophysical models suited to calculate proton RBE. As far as physics parameters are concerned, four of these models are based on the proton linear energy transfer, while the others are based on DNA double strand break induction and the frequency-mean specific energy, lineal energy, or delta electron generated track structure. The biological input parameters for all models are typically inferred from fits of the models to radiobiological experiments. The model structures have been implemented in a coherent way within the TOPAS architecture. Their performance was validated against measured experimental data on proton RBE in a spread-out Bragg peak using V79 Chinese Hamster cells. This work is an important step in bringing biologically optimized treatment planning for proton therapy closer to the clinical practice as it will allow researchers to refine and compare pre-defined as well as user-defined models.

Evaluation of neutron dose equivalent from the Mevion S250 proton accelerator: measurements and calculations.

Neutron production is of concern for proton therapy, especially for passive scattering proton beam delivery methods. The levels of neutron dose equivalent vary significantly with system design and treatment parameters. The purpose of this study was to examine neutron dose equivalent per therapeutic dose (H/D) around the Mevion S250 proton therapy system, a novel design of proton therapy systems. The benchmark comparisons between measurement and simulation were found to be within a factor of 2 for most cases. The H/D values were evaluated as a function of various parameters. The results showed that, at a standard reference condition (10 × 10 cm(2) field size, distance 1 m detector-to-isocenter lateral to the primary proton beam direction), the H/D values range from 0.72 to 3.37 mSv Gy(-1) for all configurations studied. The H/D values generally (1) decreased as the neutron detectors moved away from the isocenter, (2) decreased with increasing aperture field sizes, (3) increased with increasing angle from the initial beam axis and (4) were independent of treatment nozzle position. The H/D trends were consistent with other existing passive scattering proton accelerators reported in the literature.

Photons or protons for non-central nervous system solid malignancies in children: a historical perspective and important highlights.

Over the years, major advances have occurred in radiotherapy techniques, delivery, and treatment planning. Although radiotherapy is an integral treatment component of pediatric solid tumors, it is associated with potential acute and long-term untoward effects and risk of secondary malignancy particularly in growing children. Two major advances in external beam radiotherapy are intensity-modulated radiotherapy (IMRT) and proton beam radiotherapy. Their use in the treatment of children with cancer has been steadily increasing. IMRT uses multiple modulated radiation fields that enhance the conformality of the dose distribution to the target volume and avoid high doses to normal tissues. However, IMRT may be associated with increased volume of normal tissue that receives low doses and potential risk of secondary malignancy. Contrary to IMRT, proton beam radiotherapy uses a few beams and a fast dose fall-off distal to the target volume. Although both modalities require substantial personnel time and effort, the very high cost and limited availability of proton radiotherapy have constrained its widespread use. It is anticipated that both modalities may markedly improve tumor control and quality of life for long-term cancer survivors. Clinical trials with long-term follow-up are needed to confirm the premise that proton beam therapy will decrease late effects and secondary malignancies without compromising local control in pediatric patients with cancer.

A novel shielding scheme studied by the Monte Carlo method for electron beam radiotherapy.

Lead that has been employed widely for shielding in electron beam radiotherapy can produce bremsstrahlung photons during the shielding process. A novel shielding scheme with a two-layer structure has been studied using a Monte Carlo method in order to reduce this bremsstrahlung effect. Compared with the conventional lead, the novel shielding scheme, comprised of a Styrene-Ethylene-Butylene-Styrene Block Co-polymer (SEBS) above and lead below, can efficiently reduce the generation of bremsstrahlung while providing better shielding for incident electrons. Therefore, this novel shielding scheme may play an important role in future applications.

Intensity-modulated radiation therapy, proton therapy, or conformal radiation therapy and morbidity and disease control in localized prostate cancer.

CONTEXT: There has been rapid adoption of newer radiation treatments such as intensity-modulated radiation therapy (IMRT) and proton therapy despite greater cost and limited demonstrated benefit compared with previous technologies. OBJECTIVE: To determine the comparative morbidity and disease control of IMRT, proton therapy, and conformal radiation therapy for primary prostate cancer treatment. DESIGN, SETTING, AND PATIENTS: Population-based study using Surveillance, Epidemiology, and End Results-Medicare-linked data from 2000 through 2009 for patients with nonmetastatic prostate cancer. MAIN OUTCOME MEASURES: Rates of gastrointestinal and urinary morbidity, erectile dysfunction, hip fractures, and additional cancer therapy. RESULTS: Use of IMRT vs conformal radiation therapy increased from 0.15% in 2000 to 95.9% in 2008. In propensity score-adjusted analyses (N = 12,976), men who received IMRT vs conformal radiation therapy were less likely to receive a diagnosis of gastrointestinal morbidities (absolute risk, 13.4 vs 14.7 per 100 person-years; relative risk [RR], 0.91; 95% CI, 0.86-0.96) and hip fractures (absolute risk, 0.8 vs 1.0 per 100 person-years; RR, 0.78; 95% CI, 0.65-0.93) but more likely to receive a diagnosis of erectile dysfunction (absolute risk, 5.9 vs 5.3 per 100 person-years; RR, 1.12; 95% CI, 1.03-1.20). Intensity-modulated radiation therapy patients were less likely to receive additional cancer therapy (absolute risk, 2.5 vs 3.1 per 100 person-years; RR, 0.81; 95% CI, 0.73-0.89). In a propensity score-matched comparison between IMRT and proton therapy (n = 1368), IMRT patients had a lower rate of gastrointestinal morbidity (absolute risk, 12.2 vs 17.8 per 100 person-years; RR, 0.66; 95% CI, 0.55-0.79). There were no significant differences in rates of other morbidities or additional therapies between IMRT and proton therapy. CONCLUSIONS: Among patients with nonmetastatic prostate cancer, the use of IMRT compared with conformal radiation therapy was associated with less gastrointestinal morbidity and fewer hip fractures but more erectile dysfunction; IMRT compared with proton therapy was associated with less gastrointestinal morbidity.

Comparison of whole-body phantom designs to estimate organ equivalent neutron doses for secondary cancer risk assessment in proton therapy.

Secondary neutron fluence created during proton therapy can be a significant source of radiation exposure in organs distant from the treatment site, especially in pediatric patients. Various published studies have used computational phantoms to estimate neutron equivalent doses in proton therapy. In these simulations, whole-body patient representations were applied considering either generic whole-body phantoms or generic age- and gender-dependent phantoms. No studies to date have reported using patient-specific geometry information. The purpose of this study was to estimate the effects of patient­phantom matching when using computational pediatric phantoms. To achieve this goal, three sets of phantoms, including different ages and genders, were compared to the patients' whole-body CT. These sets consisted of pediatric age specific reference, age-adjusted reference and anatomically sculpted phantoms. The neutron equivalent dose for a subset of out-of-field organs was calculated using the GEANT4 Monte Carlo toolkit, where proton fields were used to irradiate the cranium and the spine of all phantoms and the CT-segmented patient models. The maximum neutron equivalent dose per treatment absorbed dose was calculated and found to be on the order of 0 to 5 mSv Gy(-1). The relative dose difference between each phantom and their respective CT-segmented patient model for most organs showed a dependence on how close the phantom and patient heights were matched. The weight matching was found to have much smaller impact on the dose accuracy except for very heavy patients. Analysis of relative dose difference with respect to height difference suggested that phantom sculpting has a positive effect in terms of dose accuracy as long as the patient is close to the 50th percentile height and weight. Otherwise, the benefit of sculpting was masked by inherent uncertainties, i.e. variations in organ shapes, sizes and locations.Other sources of uncertainty included errors associated with beam positioning, neutron weighting factor definition and organ segmentation. This work demonstrated the importance of hybrid phantom height matching for more accurate organ dose calculation in proton therapy and the potential limitations of reference phantoms released by regulatory bodies for radiation therapy applications.

Influence of secondary neutrons induced by proton radiotherapy for cancer patients with implantable cardioverter defibrillators.

BACKGROUND: Although proton radiotherapy is a promising new approach for cancer patients, functional interference is a concern for patients with implantable cardioverter defibrillators (ICDs). The purpose of this study was to clarify the influence of secondary neutrons induced by proton radiotherapy on ICDs. METHODS: The experimental set-up simulated proton radiotherapy for a patient with an ICD. Four new ICDs were placed 0.3 cm laterally and 3 cm distally outside the radiation field in order to evaluate the influence of secondary neutrons. The cumulative in-field radiation dose was 107 Gy over 10 sessions of irradiation with a dose rate of 2 Gy/min and a field size of 10 × 10 cm². After each radiation fraction, interference with the ICD by the therapy was analyzed by an ICD programmer. The dose distributions of secondary neutrons were estimated by Monte-Carlo simulation. RESULTS: The frequency of the power-on reset, the most serious soft error where the programmed pacing mode changes temporarily to a safety back-up mode, was 1 per approximately 50 Gy. The total number of soft errors logged in all devices was 29, which was a rate of 1 soft error per approximately 15 Gy. No permanent device malfunctions were detected. The calculated dose of secondary neutrons per 1 Gy proton dose in the phantom was approximately 1.3-8.9 mSv/Gy. CONCLUSIONS: With the present experimental settings, the probability was approximately 1 power-on reset per 50 Gy, which was below the dose level (60-80 Gy) generally used in proton radiotherapy. Further quantitative analysis in various settings is needed to establish guidelines regarding proton radiotherapy for cancer patients with ICDs.

Monte Carlo simulations of therapeutic proton beams for relative biological effectiveness of double-strand break.

PURPOSE: The relative biological effectiveness (RBE) values relative to (60)Co for the induction of double-strand breaks (DSB) were calculated for therapeutic proton beams. RBE-weighted absorbed doses were determined at different depths in a water phantom for proton beams. MATERIALS AND METHODS: The depth-dose distributions and the fluence spectra for primary protons and secondary particles were calculated using the FLUKA (FLUktuierende KAskade) MC (Monte Carlo) transport code. These spectra were combined with the MCDS (Monte Carlo damage simulation) code to simulate the spectrum-averaged yields of clustered DNA lesions. RBE for the induction of DSB were then determined at different depths in a water phantom for the unmodulated and modulated proton beams. RESULTS: The maximum RBE for the induction of DSB at 1 Gy absorbed dose was found about 1.5 at 0.5 cm distal to the Bragg peak maximum for an UNMODULATED 160 MeV proton beam. The RBE-weighted absorbed dose extended the biologically effective range of the proton beam by 1.9 mm. The corresponding maximum RBE value was inversely proportional to the proton beam energy, reaching a value of about 1.9 for 70 MeV proton beam. For a modulated 160 MeV proton beam, the RBE weightings were more pronounced near the spread-out Bragg peak (SOBP) distal edge. CONCLUSIONS: It was demonstrated that a fast MCDS code could be used to simulate the DNA damage yield for therapeutic proton beams. Simulated RBE for the induction of DSB were comparable to RBE measured in vitro and in vivo. Depth dependent RBE values in the SOBP region might have to be considered in certain treatment situations.

A comparison of X-ray and proton beam low energy secondary electron track structures using the low energy models of Geant4.

PURPOSE: Lethal cell damage by ionising radiation is generally initiated by the formation of complex strand breaks, resulting from ionisation clusters in the DNA molecule. A better understanding of the effect of the distribution of ionisation clusters within the cell and particularly in regard to DNA segments could be beneficial to radiation therapy treatment planning. Low energy X-rays generate an abundance of low energy electrons similar to that associated with MeV protons. The study and comparison of the track structure of photon and proton beams could permit the substitution of photon microbeams for single cell ion irradiations at proton facilities used to predict the relative biological effectiveness (RBE) of charged particle fields. MATERIALS AND METHODS: The track structure of X-ray photons is compared with proton pencil beams in voxels of approximate DNA strand size (2 × 2 × 5 nm). The Very Low Energy extension models of the Monte Carlo simulation toolkit GEometry ANd Tracking 4 (Geant4) is used. Simulations were performed in a water phantom for an X-ray and proton beam of energies 100 keV and 20 MeV, respectively. RESULTS: The track structure of the photon and proton beams are evaluated using the ionisation cluster size distribution as well as the radial dose deposition of the beam. CONCLUSIONS: A comparative analysis of the ionisation cluster distribution and radial dose deposition obtained is presented, which suggest that low energy X-rays could produce similar ionisation cluster distributions to MeV protons on the DNA scale of size at depths greater than ∼10 µm and at distances greater than ∼1 µm from the beam centre. Here the ionisation cluster size for each beam is less than ∼100. The radial dose deposition is also approximately equal at large depths and at distances greater than 10 µm from the beam centre.

Theoretical ionization and capture cross sections for DNA nucleobases impacted by light ions.

PURPOSE: Although DNA lesions are considered of prime importance for describing the post-irradiation cellular survival, they still remain rarely studied on both experimental and theoretical sides. Under these conditions, we here propose different theoretical models for predicting the single ionization and single capture total cross sections for DNA bases impacted by protons. MATERIAL AND METHODS: Three theoretical approaches are developed: a first classical one based on a classical trajectory Monte Carlo (CTMC) model and two quantum mechanical ones, namely, a Coulomb Born (CB1) and a continuum-distorted wave eikonal-initial-state (CDW-EIS) model. RESULTS: Ionization and capture processes induced by protons on DNA bases (adenine, cytosine, thymine and guanine) are here studied in terms of total cross sections. CONCLUSIONS: A very good agreement is obtained between the different models at high enough impact velocities but discrepancies are observed between them at low impact energies (E(i) ≤ 100 keV). Furthermore, it is shown that the theoretical cross sections underestimate the rare existing experimental data in particular for adenine and thymine whereas a reasonable agreement is found for cytosine.

Effects of radiation quality and oxygen on clustered DNA lesions and cell death.

Radiation quality and cellular oxygen concentration have a substantial impact on DNA damage, reproductive cell death and, ultimately, the potential efficacy of radiation therapy for the treatment of cancer. To better understand and quantify the effects of radiation quality and oxygen on the induction of clustered DNA lesions, we have now extended the Monte Carlo Damage Simulation (MCDS) to account for reductions in the initial lesion yield arising from enhanced chemical repair of DNA radicals under hypoxic conditions. The kinetic energy range and types of particles considered in the MCDS have also been expanded to include charged particles up to and including (56)Fe ions. The induction of individual and clustered DNA lesions for arbitrary mixtures of different types of radiation can now be directly simulated. For low-linear energy transfer (LET) radiations, cells irradiated under normoxic conditions sustain about 2.9 times as many double-strand breaks (DSBs) as cells irradiated under anoxic conditions. New experiments performed by us demonstrate similar trends in the yields of non-DSB (Fpg and Endo III) clusters in HeLa cells irradiated by γ rays under aerobic and hypoxic conditions. The good agreement among measured and predicted DSBs, Fpg and Endo III cluster yields suggests that, for the first time, it may be possible to determine nucleotide-level maps of the multitude of different types of clustered DNA lesions formed in cells under reduced oxygen conditions. As particle LET increases, the MCDS predicts that the ratio of DSBs formed under normoxic to hypoxic conditions by the same type of radiation decreases monotonically toward unity. However, the relative biological effectiveness (RBE) of higher-LET radiations compared to (60)Co γ rays (0.24 keV/µm) tends to increase with decreasing oxygen concentration. The predicted RBE of a 1 MeV proton (26.9 keV/µm) relative to (60)Co γ rays for DSB induction increases from 1.9 to 2.3 as oxygen concentration decreases from 100% to 0%. For a 12 MeV (12)C ion (681 keV/µm), the 'predicted RBE for DSB induction increases from 3.4 (100% O(2)) to 9.8 (0% O(2)). Estimates of linear-quadratic (LQ) cell survival model parameters (α and ß) are closely correlated to the Monte Carlo-predicted trends in DSB induction for a wide range of particle types, energies and oxygen concentrations. The analysis suggests α is, as a first approximation, proportional to the initial number of DSBs per cell, and ß is proportional to the square of the initial number of DSBs per cell. Although the reported studies provide some evidence supporting the hypothesis that DSBs are a biologically critical form of clustered DNA lesion, the induction of Fpg and Endo III clusters in HeLa cells irradiated by γ rays exhibits similar trends with oxygen concentration. Other types of non-DSB cluster may still play an important role in reproductive cell death. The MCDS captures many of the essential trends in the formation of clustered DNA lesions by ionizing radiation and provides useful information to probe the multiscale effects and interactions of ionizing radiation in cells and tissues. Information from Monte Carlo simulations of cluster induction may also prove useful for efforts to better exploit radiation quality and reduce the impact of tumor hypoxia in proton and carbon-ion radiation therapy.

Estimated radiation pneumonitis risk after photon versus proton therapy alone or combined with chemotherapy for lung cancer.

BACKGROUND: Traditionally, radiation therapy plans are optimized without consideration of chemotherapy. Here, we model the risk of radiation pneumonitis (RP) in the presence of a possible interaction between chemotherapy and radiation dose distribution. MATERIAL AND METHODS: Three alternative treatment plans are compared in 18 non-small cell lung cancer patients previously treated with helical tomotherapy; the tomotherapy plan, an intensity modulated proton therapy plan (IMPT) and a three dimensional conformal radiotherapy (3D-CRT) plan. All plans are optimized without consideration of the chemotherapy effect. The effect of chemotherapy is modeled as an independent cell killing process using a uniform chemotherapy equivalent radiation dose (CERD) added to the entire organ at risk. We estimate the risk of grade 3 or higher RP (G3RP) using the critical volume model. RESULTS: The mean risk of clinical G3RP at zero CERD is 5% for tomotherapy (range: 1-18 %) and 14% for 3D-CRT (range 2-49%). When the CERD exceeds 9 Gy, however, the risk of RP with the tomotherapy plans become higher than the 3D-CRT plans. The IMPT plans are less toxic both at zero CERD (mean 2%, range 1-5%) and at CERD = 10 Gy (mean 7%, range 1-28%). Tomotherapy yields a lower risk of RP than 3D-CRT for 17/18 patients at zero CERD, but only for 7/18 patients at CERD = 10 Gy. IMPT gives the lowest risk of all plans for 17/18 patients at zero CERD and for all patients with CERD = 10 Gy. CONCLUSIONS: The low dose bath from highly conformal photon techniques may become relevant for lung toxicity when radiation is combined with cytotoxic chemotherapy as shown here. Proton therapy allows highly conformal delivery while minimizing the low dose bath potentially interacting with chemotherapy. Thus, intensive drug-radiation combinations could be an interesting indication for selecting patients for proton therapy. It is likely that the IMRT plans would perform better if the CERD was accounted for during optimization, but more clinical data is required to facilitate evidence-based plan optimization in the multi-modality setting.