Production and separation of positron emitters for hadron therapy at FRS-Cave M.

The FRagment Separator FRS at GSI is a versatile spectrometer and separator for experiments with relativistic in-flight separated short-lived exotic beams. One branch of the FRS is connected to the target hall where the bio-medical cave (Cave M) is located. Recently a joint activity between the experimental groups of the FRS and the biophysics at the GSI and Department of physics at LMU was started to perform biomedical experiments relevant for hadron therapy with positron emitting carbon and oxygen beams. This paper presents the new ion-optical mode and commissioning results of the FRS-Cave M branch where positron emitting 15O-ions were provided to the medical cave for the first time. An overall conversion efficiency of 2.9±0.2×10-4 15O fragments per primary 16O ion accelerated in the synchrotron SIS18 was reached.

Neutron shielding assessment of a16O hadron therapy room by means of Monte Carlo simulations with the PHITS code.

Hadron radiation therapy is of great interest worldwide. Heavy-ion beams provide ideal therapeutic conditions for deep-seated local tumours. At the Heidelberg Ion Beam Therapy Center (HIT, Germany), protons and carbon ions are already integrated into the clinical routine, while16O ions are still used for research only. To ensure the protection of the technical staff and members of the public, it is required to estimate the neutron dose distribution for optimal working conditions and at different locations. The Particle and Heavy Ion Transport Code System (PHITS) is used in this work to evaluate the dose rate distribution of secondary neutrons in a treatment room at HIT where16O ions are used: an equivalent target in soft tissue is considered in the shielding assessment to simulate the interaction of the beam with patients. The angular dependence of neutron fluences and energy spectra around the considered phantom were calculated. Alongside the spatial distribution of the neutron and photon fluence, a map of the effective dose rate was estimated using the ICRP fluence-to-effective dose conversion coefficients, exploiting the PHITS code's built-in capabilities. The capability of the actual shielding design of the studied HIT treatment room was approved.

Characterisation and Quenching Correction for an Al2O3:C Optical Fibre Real Time System in Therapeutic Proton, Helium, and Carbon-Charged Beams.

Real time radioluminescence fibre-based detectors were investigated for application in proton, helium, and carbon therapy dosimetry. The Al2O3:C probes are made of one single crystal (1 mm) and two droplets of micro powder in two sizes (38 µm and 4 µm) mixed with a water-equivalent binder. The fibres were irradiated behind different thicknesses of solid slabs, and the Bragg curves presented a quenching effect attributed to the nonlinear response of the radioluminescence (RL) signal as a function of linear energy transfer (LET). Experimental data and Monte Carlo simulations were utilised to acquire a quenching correction method, adapted from Birks' formulation, to restore the linear dose-response for particle therapy beams. The method for quenching correction was applied and yielded the best results for the '4 µm' optical fibre probe, with an agreement at the Bragg peak of 1.4% (160 MeV), and 1.5% (230 MeV) for proton-charged particles; 2.4% (150 MeV/u) for helium-charged particles and of 4.8% (290 MeV/u) and 2.9% (400 MeV/u) for the carbon-charged particles. The most substantial deviations for the '4 µm' optical fibre probe were found at the falloff regions, with ~3% (protons), ~5% (helium) and 6% (carbon).

Optimization of treatment planning for hypoxic tumours and re-modulation of radiation intensity in heavy-ion radiotherapy.

AIM: The purpose of this study is to optimize treatment planning in carbon ion radiotherapy, taking into account the effect of tumour hypoxia. BACKGROUND: In conventional hadron therapy, the goal is to create a homogenous dose in the tumour area and, thus, achieve a uniform cell survival level. Since the induction of a specific damage to cells is directly influenced by the level of hypoxia in the tissue, the varying oxygen pressure in the different regions of hypoxic tumours would disrupt the uniformity of the cell survival level. MATERIALS AND METHODS: Using the Geant4 Monte Carlo Code, the physical dose profile and dose-averaged linear energy transfer were calculated in the tumour. Then, the oxygen enhancement ratio in different areas of the tumour were compared with different pressures. RESULTS: Modulations of radiation intensities as well as energies of ion beams were calculated, both considering and disregarding the effect of hypoxia, and the required dose profiles were compared with each other. Cell survival levels were also compared between the two methods. An equation was obtained for re-modulating the beams in the presence of hypoxia, and radiation weighting factors were extracted for the beam intensities. CONCLUSION: The results show that taking the effect of hypoxia into account would cause the reduction of average doses delivered to the tumour tissues up to 1.54 times. In this regard, the required dose is reduced by 1.63 times in the healthy tissues before the tumour. This will result in an effective protection of healthy tissues around the tumour.

Optimization of an ultra-fast silicon detector for proton and carbon beams using GEANT4 Monte Carlo toolkit.

AIM: The purpose of this study was to investigate the crosstalk effects between adjacent pixels in a thin silicon detector with 50 um thickness. BACKGROUND: There are some limitations in the applications of detectors in hadron therapy. So it is necessary to have a detector with concurrent excellent time and resolution. In this work, the GEANT4 toolkit was applied to estimate the best value for energy cutoff in the thin silicon detector in order to optimize the detector. MATERIALS AND METHODS: GEANT4 toolkit was applied to simulate the transport and interactions of particles. Calculations were performed for a thin silicon detector (2 cm × 2 cm×0.005 cm) irradiated by proton and carbon ion beams. A two-dimensional array of silicon pixels in the x-y plane with 100 um × 100 um × 50 um dimensions build the whole detector. In the end, the ROOT package is used to interpret and analyze the results. RESULTS: It is seen that by the presence of energy cutoff, pixels with small deposited energy are ignored. The best values for energy cutoff are 0.01 MeV and 0.7 MeV for proton and carbon ion beams, respectively. By applying these energy cutoff values, efficiency and purity values are maximized and also minimum output errors are achieved. CONCLUSIONS: The results are reasonable, good and useful to optimize the geometry of future silicon detectors in order to be used as beam monitoring in hadron therapy applications.

Design of spread-out Bragg peaks in hadron therapy with oxygen ions.

AIM: Design of a numerical method for creating spread-out Bragg peak (SOBP) and evaluation of the best parameter in Bortfeld Model to this aim in oxygen ion therapy. BACKGROUND: In radiotherapy, oxygen ions have more biological benefits than light beams. Oxygen ions have a higher linear energy transfer (LET) and larger relative biological effectiveness (RBE) than lighter ones. MATERIALS AND METHODS: For the design of the spread-out Bragg peak (SOBP) for oxygen beam, we designed a numerical method using the Geant4 Monte Carlo simulation code, along with matrix computations. RESULTS: The profiles of the Bragg Peak have been calculated for each section in the target area by the Geant4 tool. Then, in order to produce SOBP smoothly, a set of weighting factors for the intensity of oxygen ion radiation in each energy was extracted through a numerically designed method. This method was tested for producing SOBP at various widths and at different depths of a phantom. Also, weighting factors of intensity for producing a flat SOBP with oxygen ions were also obtained using the Bortfeld model in order to determine the best parameters. Then, the results of the Bortfeld model were compared with the outcomes of the method that was developed in this study. CONCLUSIONS: The results showed that while the SOBP designed by the Bortfeld model has a homogeneity of 92-97%, the SOBP designed by the numerical method in the present study is above 99%, which in some cases even closed to 100%.

OPTIma: simplifying calorimetry for proton computed tomography in high proton flux environments.

Objective.Proton computed tomography (pCT) offers a potential route to reducing range uncertainties for proton therapy treatment planning, however the current trend towards high current spot scanning treatment systems leads to high proton fluxes which are challenging for existing systems. Here we demonstrate a novel approach to energy reconstruction, referred to as 'de-averaging', which allows individual proton energies to be recovered using only a measurement of their integrated energy without the need for spatial information from the calorimeter.Approach.The method is evaluated in the context of the Optimising Proton Therapy through Imaging (OPTIma) system which uses a simple, relatively inexpensive, scintillator-based calorimeter that reports only the integrated energy deposited by all protons within a cyclotron period, alongside a silicon strip based tracking system capable of reconstructing individual protons in a high flux environment. GEANT4 simulations have been performed to examine the performance of such a system at a modern commercial cyclotron facility using aσ≈ 10 mm beam for currents in the range 10-50 pA at the nozzle.Main results.Apart from low-density lung tissue, a discrepancy of less than 1% on the Relative Stopping Power is found for all other considered tissues when embedded within a 150 mm spherical Perspex phantom in the 10-30 pA current range, and for some tissues even up to 50 pA.Significance.By removing the need for the calorimeter system to provide spatial information, it is hoped that the de-averaging approach can facilitate clinically relevant, cost effective and less complex calorimeter systems for performing high current pCTs.

Modeling hypoxia-induced radiation resistance and the impact of radiation sources.

Hypoxia contributes significantly to resistance in radiotherapy. Our research rigorously examines the influence of microvascular morphology on radiotherapy outcome, specifically focusing on how microvasculature shapes hypoxia within the microenvironment and affects resistance to a standard treatment regimen (30×2GyRBE). Our computational modeling extends to the effects of different radiation sources. For photons and protons, our analysis establishes a clear correlation between hypoxic volume distribution and treatment effectiveness, with vascular density and regularity playing a crucial role in treatment success. On the contrary, carbon ions exhibit distinct effectiveness, even in areas of intense hypoxia and poor vascularization. This finding points to the potential of carbon-based hadron therapy in overcoming hypoxia-induced resistance to RT. Considering that the spatial scale analyzed in this study is closely aligned with that of imaging data voxels, we also address the implications of these findings in a clinical context envisioning the possibility of detecting subvoxel hypoxia.

Gamma-ray sources imaging and test-beam results with MACACO III Compton camera.

Hadron therapy is a radiotherapy modality which offers a precise energy deposition to the tumors and a dose reduction to healthy tissue as compared to conventional methods. However, methods for real-time monitoring are required to ensure that the radiation dose is deposited on the target. The IRIS group of IFIC-Valencia developed a Compton camera prototype for this purpose, intending to image the Prompt Gammas emitted by the tissue during irradiation. The system detectors are composed of Lanthanum (III) bromide scintillator crystals coupled to silicon photomultipliers. After an initial characterization in the laboratory, in order to assess the system capabilities for future experiments in proton therapy centers, different tests were carried out in two facilities: PARTREC (Groningen, The Netherlands) and the CNA cyclotron (Sevilla, Spain). Characterization studies performed at PARTREC indicated that the detectors linearity was improved with respect to the previous version and an energy resolution of 5.2 % FWHM at 511 keV was achieved. Moreover, the imaging capabilities of the system were evaluated with a line source of 68Ge and a point-like source of 241Am-9Be. Images at 4.439 MeV were obtained from irradiation of a graphite target with an 18 MeV proton beam at CNA, to perform a study of the system potential to detect shifts at different intensities. In this sense, the system was able to distinguish 1 mm variations in the target position at different beam current intensities for measurement times of 1800 and 600 s.

Carbon ion radiotherapy of hepatocellular carcinoma provides excellent local control: The prospective phase I PROMETHEUS trial.

Background & Aims: Inoperable hepatocellular carcinoma (HCC) can be treated by stereotactic body radiotherapy. However, carbon ion radiotherapy (CIRT) is more effective for sparing non-tumorous liver. High linear energy transfer could promote therapy efficacy. Japanese and Chinese studies on hypofractionated CIRT have yielded excellent results. Because of different radiobiological models and the different etiological spectrum of HCC, applicability of these results to European cohorts and centers remains questionable. The aim of this prospective study was to assess safety and efficacy and to determine the optimal dose of CIRT with active raster scanning based on the local effect model (LEM) I. Methods: CIRT was performed every other day in four fractions with relative biological effectiveness (RBE)-weighted fraction doses of 8.1-10.5 Gy (total doses 32.4-42.0 Gy [RBE]). Dose escalation was performed in five dose levels with at least three patients each. The primary endpoint was acute toxicity after 4 weeks. Results: Twenty patients received CIRT (median age 74.7 years, n = 16 with liver cirrhosis, Child-Pugh scores [CP] A5 [n = 10], A6 [n = 4], B8 [n = 1], and B9 [n = 1]). Median follow up was 23 months. No dose-limiting toxicities and no toxicities exceeding grade II occurred, except one grade III gamma-glutamyltransferase elevation 12 months after CIRT, synchronous to out-of-field hepatic progression. During 12 months after CIRT, no CP elevation occurred. The highest dose level could be applied safely. No local recurrence developed during follow up. The objective response rate was 80%. Median overall survival was 30.8 months (1/2/3 years: 75%/64%/22%). Median progression-free survival was 20.9 months (1/2/3 years: 59%/43%/43%). Intrahepatic progression outside of the CIRT target volume was the most frequent pattern of progression. Conclusions: CIRT of HCC yields excellent local control without dose-limiting toxicity. Impact and implications: To date, safety and efficacy of carbon ion radiotherapy for hepatocellular carcinoma have only been evaluated prospectively in Japanese and Chinese studies. The optimal dose and fractionation when using the local effect model for radiotherapy planning are unknown. The results are of particular interest for European and American particle therapy centers, but also of relevance for all specialists involved in the treatment and care of patients with hepatocellular carcinoma, as we present the first prospective data on carbon ion radiotherapy in hepatocellular carcinoma outside of Asia. The excellent local control should encourage further use of carbon ion radiotherapy for hepatocellular carcinoma and design of randomized controlled trials. Clinical Trials Registration: The study is registered at ClinicalTrials.gov (NCT01167374).

Light flashes and other sensory illusions perceived in space travel and on ground, including proton and heavy ion therapies.

Most of the astronauts experience visual illusions, apparent flashes of light (LF) in absence of light. The first reported observation of this phenomenon was in July 1969 by Buzz Aldrin, in the debriefing following the Apollo 11 mission. Several ground-based experiments in the 1970s tried to clarify the mechanisms behind these light flashes and to evaluate possible related risks. These works were supported by dedicated experiments in space on the following Apollo flights and in Low Earth Orbit (LEO). It was soon demonstrated that the LF could be caused by charged particles (present in the space radiation) traveling through the eye, and, possibly, some other visual cortical areas. In the 1990s the interest in these phenomena increased again and additional experiments in Low Earth Orbit and others ground-based were started. Recently patients undergoing proton and heavy ion therapy for eye or head and neck tumors have reported the perception of light flashes, opening a new channel to investigate these phenomena. In this paper the many LF studies will be reviewed, presenting an historical and scientific perspective consistent with the combined set of observations, offering a single comprehensive summary aimed to provide further insights on these phenomena. While the light flashes appear not to be a risk by themselves, they might provide information on the amount of radiation induced radicals in the astronauts' eyes. Understanding their generation mechanisms might also support radiation countermeasures development. However, even given the substantial progress outlined in this paper, many questions related to their generation are still under debate, so additional studies are suggested. Finally, it is also conceivable that further LF investigations could provide evidence about the possible interaction of single particles in space with brain function, impacting with the crew ability to optimally perform a mission.

Few-seconds range verification with short-lived positron emitters in carbon ion therapy.

In-beam PET (Positron Emission Tomography) is one of the most precise techniques for in-vivo range monitoring in hadron therapy. Our objective was to demonstrate the feasibility of a short irradiation run for range verification before a carbon-ion treatment. To do so a PMMA target was irradiated with a 220 MeV/u carbon-ion beam and annihilation coincidences from short-lived positron emitters were acquired after irradiations lasting 0.6 s. The experiments were performed at the synchrotron-based facility CNAO (Italian National Center of Oncological Hadrontherapy) by using the INSIDE in-beam PET detector. The results show that, with 3·107 carbon ions, the reconstructed positron emitting nuclei distribution is in good agreement with the predictions of a detailed FLUKA Monte Carlo study. Moreover, the radio-nuclei production is sufficiently abundant to determine the average ion beam range with a σ of 1 mm with a 6 s measurement of the activity distribution. Since the data were acquired when the beam was off, the proposed rapid calibration method can be applied to hadron beams extracted from accelerators with very different time structures.

Feasibility of Using Distal Endpoints for In-room PET Range Verification of Proton Therapy.

In an effort to verify the dose delivery in proton therapy, Positron Emission Tomography (PET) scans have been employed to measure the distribution of ß+ radioactivity produced from nuclear reactions of the protons with native nuclei. Because the dose and PET distributions are difficult to compare directly, the range verification is currently carried out by comparing measured and Monte Carlo (MC) simulation predicted PET distributions. In order to reduce the reliance on MC, simulated PET (simPET) and dose distal endpoints were compared to explore the feasibility of using distal endpoints for in-room PET range verification. MC simulations were generated for six head and neck patients with corrections for radiological decay, biological washout, and PET resolution. One-dimensional profiles of the dose and simPET were examined along the direction of the beam and covering the cross section of the beam. The chosen endpoints of the simPET (x-intercept of the linear fit to the distal falloff) and planned dose (20-50% of maximum dose) correspond to where most of the protons are below the threshold energy for the nuclear reactions. The difference in endpoint range between the distal surfaces of the dose and MC-PET were compared and the spread of range differences were assessed. Among the six patients, the mean difference between MC-PET and dose depth was found to be -1.6 mm to +0.5 mm between patients, with a standard deviation of 1.1 to 4.0 mm across the individual beams. In clinical practice, regions with deviations beyond the safety margin need to be examined more closely and can potentially lead to adjustments to the treatment plan.

Evaluation of endocrinological sequelae following particle therapy performed on anterior skull base lesions in the adult population.

Background: Radiotherapy has increasingly assumed a central role in the multidisciplinary treatment of skull base lesions. Unfortunately, it is often burdened by relevant radio-induced damage to the pituitary function and the surrounding structures and systems. Patients who were treated with radiotherapy around the sellar region especially have a high risk of developing radio-induced hypopituitarism. Particle therapy has the potential advantage of delivering a higher radiation dose to the target while potentially sparing the sellar region and pituitary function. The aim of this study is to evaluate the pituitary function in adult patients who have undergone hadron therapy for anterior skull base lesions involving or surrounding the pituitary gland. Methods: This is a retrospective, observational, and noncontrolled study. We evaluated pituitary and peripheral hormone levels in all patients referring to National Center for Oncological Hadrontherapy, Pavia, Italy for anterior skull base tumors. Furthermore, we performed a magnetic resonance imaging for every follow-up to evaluate potential tumoral growth. Results: We evaluated 32 patients with different tumoral lesions with a mean follow-up of 27.9 months. The mean hadron therapy (HT) dose was 60 ± 14 Gray, with a mean dose per fraction of 2.3 ± 2.1 Gray. Six patients were treated with carbon ions and 26 with protons. Pituitary hormone alteration of some kind was reported for six patients. No patient experienced unexpected severe adverse events related to particle therapy. Conclusion: Particle radiotherapy performed on anterior skull base lesions has proved to cause limited damage to pituitary function in the adult population.

Range verification in heavy-ion therapy using a hadron tumour marker.

Objective.A new method to estimate the range of an ion beam in a patient during heavy-ion therapy was investigated, which was previously verified for application in proton therapy.Approach.The method consists of placing a hadron tumour marker (HTM) close to the tumour. As the treatment beam impinges on the HTM, the marker undergoes nuclear reactions. When the HTM material is carefully chosen, the activation results in the emission of several delayed, characteristicγrays, whose intensities are correlated with the remaining range inside the patient. When not just one but two reaction channels are investigated, the ratio between these twoγray emissions can be measured, and the ratio is independent of any beam delivery uncertainties.Main results.A proof-of-principle experiment with an16O ion beam and Ag foils as HTM was successfully executed. The107Ag(16O,x)112Sb and the107Ag(16O,x)114Sb reaction channels were identified as suitable for the HTM technique. When only oneγ-ray emission is measured, the resulting range-uncertainty estimation is at the 0.5 mm scale. When both channels are considered, a theoretical limit on the range uncertainty of a clinical fiducal marker was found to be ±290µm.Significance.Range uncertainty of a heavy-ion beam limits the prescribed treatment plan for cancer patients, especially the direction of the ion beam in relation to any organ at risk. An easy to implement range-verification technique which can be utilized during clinical treatment would allow treatment plans to take full advantage of the sharp fall-off of the Bragg peak without the risk of depositing excessive dose into healthy tissue.

Development of a more accurate Geant4 quantum molecular dynamics model for hadron therapy.

Objective. Although in heavy-ion therapy, the quantum molecular dynamics (QMD) model is one of the most fundamental physics models providing an accurate daughter-ion production yield in the final state, there are still non-negligible differences with the experimental results. The aim of this study is to improve fragment production in water phantoms by developing a more accurate QMD model in Geant4.Approach. A QMD model was developed by implementing modern Skyrme interaction parameter sets, as well as by incorporating with an ad hocα-cluster model in the initial nuclear state. Two adjusting parameters were selected that can significantly affect the fragment productions in the QMD model: the radius to discriminate a cluster to which nucleons belong after the nucleus-nucleus reaction, denoted byR, and the squared standard deviation of the Gaussian packet, denoted byL. Squared Mahalanobis's distance of fragment yields and angular distributions with 1, 2, and the higher atomic number for the produced fragments were employed as objective functions, and multi-objective optimization (MOO), which make it possible to compare quantitatively the simulated production yields with the reference experimental data, was performed.Main results. The MOO analysis showed that the QMD model with modern Skyrme parameters coupled with the proposedα-cluster model, denoted as SkM*α, can drastically improve light fragments yields in water. In addition, the proposed model reproduced the kinetic energy distribution of the fragments accurately. The optimizedLin SkM*αwas confirmed to be realistic by the charge radii analysis in the ground state formation.Significance. The proposed framework using MOO was demonstrated to be very useful in judging the superiority of the proposed nuclear model. The optimized QMD model is expected to improve the accuracy of heavy-ion therapy dosimetry.

A systematic study of the contribution of counting statistics to the final lineal energy uncertainty in microdosimetry.

Objectives.Microdosimetry is proving to be a reliable and powerful tool to be applied in different fields such as radiobiology, radiation protection and hadron therapy. However, accepted standard protocols and codes of practice are still missing. With this regard, a systematic and methodical uncertainty analysis is fundamental to build an accredited uncertainty budget of practical use. This work studied the contribution of counting statistics (i.e. number of events collected) to the final frequency-mean and dose-mean lineal energy uncertainties, aiming at providing guidelines for good experimental and simulation practice. The practical limitation of current technologies and the non-negligible probability of nuclear reactions require careful considerations and nonlinear approaches.Approach.Microdosimetric data were obtained by means of the particle tracking Monte Carlo code Geant4. The uncertainty analysis was carried out relying on a Monte Carlo based numerical analysis, as suggested by the BIPM's 'Guide to the expression of uncertainty in measurement'. Final uncertainties were systematically investigated for proton, helium and carbon ions at an increasing number of detected events, for a range of different clinical-relevant beam energies.Main results.Rare events generated by nuclear interactions in the detector sensitive volume were found to massively degrade microdosimetric uncertainties unless a very high statistics is collected. The study showed an increasing impact of such events for increasing beam energy and lighter ions. For instance, in the entrance region of a 250 MeV proton beam, about 5 ∗ 107events need to be collected to obtain a dose-mean lineal energy uncertainty below 10%.Significance.The results of this study help define the necessary conditions to achieve appropriate statistics in computational microdosimetry, pointing out the importance of properly taking into account nuclear interaction events. Their impact on microdosimetric quantities and on their uncertainty is significant and cannot be overlooked, particularly when characterising clinical beams and radiobiological response. This work prepared the ground for deeper investigations involving dedicated experiments and for the development of a method to properly evaluate the counting statistics uncertainty contribution in the uncertainty budget, whose accuracy is fundamental for the clinical transition of microdosimetry.

Accumulation of sublethal radiation damage and its effect on cell survival.

Objective.Determine the extent of sublethal radiation damage (SRD) in a cell population that received a given dose of radiation and the impact of this damage on cell survival.Approach.We developed a novel formalism to account for accumulation of SRD with increasing dose. It is based on a very general formula for cell survival that correctly predicts the basic properties of cell survival curves, such as the transition from the linear-quadratic to a linear dependence at high doses. Using this formalism we analyzed extensive experimental data for photons, protons and heavy ions to evaluate model parameters, quantify the extent of SRD and its impact on cell survival.Main results.Significant accumulation of SRD begins at doses below 1 Gy. As dose increases, so does the number of damaged cells and the amount of SRD in individual cells. SRD buildup in a cell increases the likelihood of complex irrepairable damage. For this reason, during a dose fraction delivery, each dose increment makes cells more radiosensitive. This gradual radosensitization is evidenced by the increasing slope of survival curves observed experimentally. It continues until the fraction is delivered, unless radiosensitivity reaches its maximum first. The maximum radiosensitivity is achieved when SRD accumulated in most cells is the maximum damage they can repair. After this maximum is reached, the slope of a survival curve, logarithm of survival versus dose, becomes constant, dose independent. The survival curve becomes a straight line, as experimental data at high doses show. These processes are random. They cause large cell-to-cell variability in the extent of damage and radiosensitivity of individual cells.Significance.SRD is in effect a radiosensitizer and its accumulation is a significant factor affecting cell survival, especially at high doses. We developed a novel formalism to study this phenomena and reported pertinent data for several particle types.

Particle Therapy: Clinical Applications and Biological Effects.

Particle therapy is a developing area of radiotherapy, mostly involving the use of protons, neutrons and carbon ions for cancer treatment. The reduction of side effects on healthy tissues in the peritumoral area is an important advantage of particle therapy. In this review, we analyze state-of-the-art particle therapy, as compared to conventional photon therapy, to identify clinical benefits and specify the mechanisms of action on tumor cells. Systematization of published data on particle therapy confirms its successful application in a wide range of cancers and reveals a variety of biological effects which manifest at the molecular level and produce the particle therapy-specific molecular signatures. Given the rapid progress in the field, the use of particle therapy holds great promise for the near future.

Effect of overdispersion of lethal lesions on cell survival curves.

The linear-quadratic (LQ) model is the most commonly used mechanism to predict radiobiological outcomes. It has been used extensively to describe dose-responsein vitroandin vivo. There are, however, some questions about its applicability in terms of its capacity to represent some profound mechanistic behaviour. Specifically, empirical evidence suggests that the LQ model underestimates the survival of cells at low doses while overestimating cell death at higher doses. It is believed to be driven from the usual LQ model assumption that radiogenic lesions are Poisson distributed. In this context, we use a negative binomial (NB) distribution to study the effect of overdispersion on the shapes and the possibility of reducing dose-response curvature at higher doses. We develop an overdispersion model for cell survival using the non-homologous end-joining (NHEJ) pathway double-strand break (DSB) repair mechanism to investigate the effects of the overdispersion on probabilities of repair of DSBs. The error distribution is customised to ensure that the refined overdispersion parameter depends on the mean of the distribution. The predicted cell survival responses for V79, AG and HSG cells exposed to protons, helium and carbon ions are compared with the experimental data in low and high dose regions at various linear energy transfer (LET) values. The results indicate straightening of dose-response and approaching a log-linear behaviour at higher doses. The model predictions with the measured data show that the NB modelled survival curves agree with the data following medium and high doses. Model predictions are not validated at very tiny and very high doses; the approach presented provides an analysis of mechanisms at the microscopic level. This may help improve the understanding of radiobiological responses of survival curves and resolve discrepancies between experimental and theoretical predictions of cell survival models.