Modelling the influence of radiosensitivity on development of second primary cancer in out-of-field organs following proton therapy for paediatric cranial cancer.

OBJECTIVE: Radiobiological modelling the risks of second primary cancer (SPC) after proton therapy (PT) for childhood cranial cancer remains largely unknown. Organ-specific dose-response risk factors such as radiosensitivity require exploration. This study compared the influence of radiosensitivity data (slope of ßEAR) on children's lifetime attributable risks (LAR) of SPC development in out-of-field organs following cranial scattering and scanning PT. METHODS: Out-of-field radiosensitivity parameter estimates for organs (α/ß and ßEAR) were sourced from literature. Physical distances for 13 out-of-field organs were measured and input into Schneider's SPC model. Sensitivity analyses were performed as a function of radiosensitivity (α/ß of 1-10 Gy) and initial slope (ßEAR) from Japanese/UK data to estimate the influence on the risk of radiation-induced SPC following scattering and scanning PT. RESULTS: Models showed similar LAR of SPC estimates for age and sex-matched paediatric phantoms, however, for breast there was a significant increase using Japanese ßEAR data. For most organs, scattering PT demonstrated a larger risk of LAR for SPC which increased with α/ß. CONCLUSION: Breast tissue exhibited the highest susceptibility in calculated LAR risk, demonstrating the importance for accurate data input when estimating LAR of SPC. ADVANCES IN KNOWLEDGE: The findings of this study demonstrated younger female patients undergoing cranial proton therapy have a higher risk of developing second primary cancer of the breast tissue. Long-term multicenter registries are important to improve predictive radiobiological modelling studies of side effects.

Lifetime attributable risk of radiation induced second primary cancer from scattering and scanning proton therapy - A model for out-of-field organs of paediatric patients with cranial cancer.

BACKGROUND AND PURPOSE: Proton therapy (PT) can reduce side effects for paediatric cranial malignancies. Despite the high number of paediatric patients treated with PT, radiation induced risk factors for second primary cancer (SPC) in out-of-field organs are unknown. This study estimated lifetime attributable risk (LAR) of SPC as a function of age and sex for out-of-field organs following passive scattering and scanning beam PT in paediatric brain tumours. MATERIALS AND METHODS: Measured neutron dose equivalent spectra for scattered and scanning PT were sourced from literature. The physical distance of 12 measured organs from paediatric CT dataset-based phantoms (5, 9 and 13 years-of-age) were applied to Schneider et al.'s analytical model using MATLAB (R2020B) to calculate the organ-specific LAR of SPC. RESULTS: Scanning beam PT demonstrated smaller LAR (per 10,000 person years) of SPC compared to scattering. This was prominent for more radiosensitive organs, including the lung (320 vs 50), breast (1000 vs 150) and thyroid (350 vs 75), but not for all (i.e., rectum and reproductive organs were <10). For most organs, LAR was highest for 5-year-old females (i.e., breast LAR was 1,000 higher than for 13-year-olds), however, outliers existed for distal organs (i.e., stomach and lung). CONCLUSION: There was large variation in LAR estimates of out-of-field organs based on measured neutron dose equivalents. Younger female cranial paediatric patients were found at higher risk compared to males, especially for passive scattering PT. Not all organs had improved LAR using scanning beam PT for younger age groups.

Translational Research in FLASH Radiotherapy-From Radiobiological Mechanisms to In Vivo Results.

FLASH radiotherapy, or the administration of ultra-high dose rate radiotherapy, is a new radiation delivery method that aims to widen the therapeutic window in radiotherapy. Thus far, most in vitro and in vivo results show a real potential of FLASH to offer superior normal tissue sparing compared to conventionally delivered radiation. While there are several postulations behind the differential behaviour among normal and cancer cells under FLASH, the full spectra of radiobiological mechanisms are yet to be clarified. Currently the number of devices delivering FLASH dose rate is few and is mainly limited to experimental and modified linear accelerators. Nevertheless, FLASH research is increasing with new developments in all the main areas: radiobiology, technology and clinical research. This paper presents the current status of FLASH radiotherapy with the aforementioned aspects in mind, but also to highlight the existing challenges and future prospects to overcome them.

Modelling Spatial Scales of Dose Deposition and Radiolysis Products from Gold Nanoparticle Sensitisation of Proton Therapy in A Cell: From Intracellular Structures to Adjacent Cells.

Gold nanoparticle (GNP) enhanced proton therapy is a promising treatment concept offering increased therapeutic effect. It has been demonstrated in experiments which provided indications that reactive species play a major role. Simulations of the radiolysis yield from GNPs within a cell model were performed using the Geant4 toolkit. The effect of GNP cluster size, distribution and number, cell and nuclear membrane absorption and intercellular yields were evaluated. It was found that clusters distributed near the nucleus increased the nucleus yield by 91% while reducing the cytoplasm yield by 7% relative to a disperse distribution. Smaller cluster sizes increased the yield, 200 nm clusters had nucleus and cytoplasm yields 117% and 35% greater than 500 nm clusters. Nuclear membrane absorption reduced the cytoplasm and nucleus yields by 8% and 35% respectively to a permeable membrane. Intercellular enhancement was negligible. Smaller GNP clusters delivered near sub-cellular targets maximise radiosensitisation. Nuclear membrane absorption reduces the nucleus yield, but can damage the membrane providing another potential pathway for biological effect. The minimal effect on adjacent cells demonstrates that GNPs provide a targeted enhancement for proton therapy, only effecting cells with GNPs internalised. The provided quantitative data will aid further experiments and clinical trials.

Gold nanoparticle enhanced proton therapy: A Monte Carlo simulation of the effects of proton energy, nanoparticle size, coating material, and coating thickness on dose and radiolysis yield.

PURPOSE: Radiosensitizer enhanced radiotherapy provides the possibility of improved treatment outcomes by preferentially increasing the effectiveness of radiation within the tumor. Proton therapy offers improved sparing of tissue distal of the tumor along the beam path and reduced integral dose compared to conventional photon therapy. The combination of proton therapy with radiosensitizers offers the potential for an enhanced therapy with increased effect within the tumor and low integral dose. The simulations performed in this work determine the effect of nanoparticle characteristics and proton energy on the nanoscale dose and radiolysis yield enhancement for a single gold nanoparticle irradiated with a proton beam. This data can be used to determine optimal nanoparticle characteristics to enhance proton therapy. METHODS: A two-stage Monte Carlo simulation was performed using Geant4. In the first stage of the simulation, the physical interactions of protons within a gold nanoparticle were modeled and the secondary electrons escaping the nanoparticle's surface were scored in a phase space file. In the second stage of the simulation, the phase space file was used as an input to model the physical interactions of the secondary electrons in water and the resulting production and chemical interactions of reactive species. By comparing a gold nanoparticle with an equivalent water nanoparticle, the nanoscale enhancement of dose and radiolysis yield was calculated. RESULTS: A large nanoscale enhancement of both the dose and radiolysis yield of up to a factor of 11 due to gold nanoparticles was found for most simulated conditions. For 50 nm gold nanoparticles, a large enhancement factor of 9-11 was observed for high proton energies; however, the enhancement was reduced for proton energies below 10 MeV. For 5 MeV incident protons, it was found that the enhancement factor was approximately 9 for gold nanoparticles of sizes 5-25 nm with a reduction in enhancement observed for nanoparticle sizes outside this range. Additionally, it was found that larger nanoparticle sizes resulted in greater total energy deposition and radiolysis yields per proton flux but with reduced efficiency per nanoparticle mass. It was observed that a large loss of enhancement occurred for thick nanoparticle coatings. However, for polyethylene glycol (PEG) coatings, coating density had a minimal effect on enhancement. CONCLUSIONS: A large enhancement in dose and radiolysis yield was observed. However, the low-energy secondary electrons produced within the gold for lower energy protons are susceptible to self-absorption and result in the loss of enhancement observed for larger nanoparticles and thicker coatings. The radiolysis yield and dose increase with nanoparticle size; however, the yield and dose per gold mass decrease due to self-absorption. Therefore, an intermediate nanoparticle size of approximately 10-25 nm maximizes both the radiolysis yield and dose as well as the enhancement. Coatings should be kept to the minimum effective thickness to limit the loss of enhancement. For molecular coatings such as PEG, coating density should be maximized as this increases the coating's effectiveness with only a minimal effect on enhancement.

Gold Nanoparticle Enhanced Proton Therapy: Monte Carlo Modeling of Reactive Species' Distributions Around a Gold Nanoparticle and the Effects of Nanoparticle Proximity and Clustering.

Gold nanoparticles (GNPs) are promising radiosensitizers with the potential to enhance radiotherapy. Experiments have shown GNP enhancement of proton therapy and indicated that chemical damage by reactive species plays a major role. Simulations of the distribution and yield of reactive species from 10 ps to 1 µs produced by a single GNP, two GNPs in proximity and a GNP cluster irradiated with a proton beam were performed using the Geant4 Monte Carlo toolkit. It was found that the reactive species distribution at 1 µs extended a few hundred nm from a GNP and that the largest enhancement occurred over 50 nm from the nanoparticle. Additionally, the yield for two GNPs in proximity and a GNP cluster was reduced by up to 17% and 60% respectively from increased absorption. The extended range of action from the diffusion of the reactive species may enable simulations to model GNP enhanced proton therapy. The high levels of absorption for a large GNP cluster suggest that smaller clusters and diffuse GNP distributions maximize the total radiolysis yield within a cell. However, this must be balanced against the high local yields near a cluster particularly if the cluster is located adjacent to a biological target.

Validation and investigation of reactive species yields of Geant4-DNA chemistry models.

PURPOSE: Indirect biological damage due to reactive species produced in water radiolysis reactions is responsible for the majority of biological effect for low linear energy transfer (LET) radiation. Modeling water radiolysis and the subsequent interactions of reactive species, as well as track structures, is essential to model radiobiology on the microscale. Recently, chemistry models have been developed for Geant4-DNA to be used in combination with the comprehensive existing physics models. In the current work, the first detailed, independent, in silico validation of all species yields with published experimental observations and comparison with other radiobiological simulations is presented. Additionally, the effect of LET of protons and heavier ions on reactive species yield in the model was examined, as well as the completeness of the chemical reactions following the radiolysis within the time after physical interactions simulated in the model. METHODS: Yields over time of reactive species were simulated for water radiolysis by incident electrons, protons, alpha particles, and ions with various LETs using Geant4 and RITRACKS simulation tools. Water dissociation and recombination was simulated using Geant4 to determine the completeness of chemical reactions at the end of the simulation. Yield validation was performed by comparing yields simulated using Geant4 with experimental observations and other simulations. Validation was performed for all species for low LET radiation and the solvated electron and hydroxyl radical for high LET ions. RESULTS: It was found that the Geant4-DNA chemistry yields were generally in good agreement with experimental observations and other simulations. However, the Geant4-DNA yields for the hydroxyl radical and hydrogen peroxide at the end of the chemistry stage were found to be respectively considerably higher and lower than the experimentally observed yields. Increasing the LET of incident hadrons increased the yield of secondary species and decreased the yield of primary species. The effect of LET on the yield of the hydroxyl radical at 100 ns simulated with Geant4 was in good agreement with experimental measurements. Additionally, by the end of the simulation only 40% of dissociated water molecules had been recombined and the rate of recombination was slowing. CONCLUSIONS: The yields simulated using Geant4 are within reasonable agreement with experimental observations. Higher LET radiation corresponds with increased yields of secondary species and decreased yields of primary species. These trends combined with the LET having similar effects on the 100 ns hydroxyl radical yield for Geant4 and experimental measurements indicate that Geant4 accurately models the effect of LET on radiolysis yields. The limited recombination within the modeled chemistry stage and the slowing rate of recombination at the end of the stage indicate potential long-range indirect biological damage.

Metallic nanoparticle radiosensitisation of ion radiotherapy: A review.

The use of gold nanoparticle (GNP) and other metal nanoparticle (MNP) radiosensitisers to enhance radiotherapy offers the potential of improved treatment outcomes. Originally intended for use with X-ray therapy, the possibility of enhanced hadron therapy is desirable due to the superior sparing of healthy tissue in hadron therapy compared to conventional X-ray therapy. While MNPs were not expected to be effective radiosensitisers for hadron therapy due to the limited Z dependence of interactions, recent experimental measurements have contradicted this expectation. Key experimental measurements and Monte Carlo simulations of MNP radiosensitisation for hadron irradiation are reviewed in the current work. Numerous experimental measurements have found a large radiosensitisation effect due to MNPs for proton and carbon ion irradiation. Experiments have also indicated that the radiosensitisation is due in large part to enhanced reactive oxygen species (ROS) production. Simulations have found a large radial dose and ROS enhancement on the nanoscale around a single MNP. However, the short range of the dose enhancement is insufficient for a large macroscale dose enhancement or enhanced biological effect in a cell model considering dose to the nucleus from GNPs in the cytoplasm (a distribution observed in most experiments).