[en] Purpose: To assess the impact of approximations in current analytical dose calculation methods (ADCs) on tumor control probability (TCP) in proton therapy. Methods: Dose distributions planned with ADC were compared with delivered dose distributions as determined by Monte Carlo simulations. A total of 50 patients were investigated in this analysis with 10 patients per site for 5 treatment sites (head and neck, lung, breast, prostate, liver). Differences were evaluated using dosimetric indices based on a dose-volume histogram analysis, a γ-index analysis, and estimations of TCP. Results: We found that ADC overestimated the target doses on average by 1% to 2% for all patients considered. The mean dose, D95, D50, and D02 (the dose value covering 95%, 50% and 2% of the target volume, respectively) were predicted within 5% of the delivered dose. The γ-index passing rate for target volumes was above 96% for a 3%/3 mm criterion. Differences in TCP were up to 2%, 2.5%, 6%, 6.5%, and 11% for liver and breast, prostate, head and neck, and lung patients, respectively. Differences in normal tissue complication probabilities for bladder and anterior rectum of prostate patients were less than 3%. Conclusion: Our results indicate that current dose calculation algorithms lead to underdosage of the target by as much as 5%, resulting in differences in TCP of up to 11%. To ensure full target coverage, advanced dose calculation methods like Monte Carlo simulations may be necessary in proton therapy. Monte Carlo simulations may also be required to avoid biases resulting from systematic discrepancies in calculated dose distributions for clinical trials comparing proton therapy with conventional radiation therapy

[en] The objective of this paper is to evaluate the clinical impact of biological uncertainties in small field proton therapy due to the assumption of using a constant relative biological effectiveness (RBE) value of 1.1 (RBE-fixed) compared to a variable RBE (RBE-weighted). In this context the impact of the applied range margin was investigated.

Eight patients with arteriovenous malformation (AVM) treated with proton radiosurgery were selected due to the small target volume. Dose distributions were compared for RBE-weighted and RBE-fixed. The impact of RBE was assessed using Monte Carlo (MC) dose calculations for stereotactic doses and doses of 2 Gy(RBE). Four different α/β ratios were investigated. Additionally, dose distributions were recalculated with reduced range margins.

Applying variable RBE values for stereotactic doses resulted in an increase in the mean dose of 1.6% for a low α/β of 2 Gy, but a decrease of 2.6% for an α/β of 10 Gy. However, the mean dose increased to 17.1% and 2.1% for doses of 2 Gy(RBE) and α/β of 2 Gy and 10 Gy, respectively. Reducing range margins from 3.5%  +  1 mm to 2.5%  +  1 mm resulted in negligible difference in the mean RBE within the target, or 0.1% for stereotactic doses and 0.3% for doses of 2 Gy(RBE). Larger differences were seen for a range reduction to 0%  +  1 mm, i.e. 1.1% and 3.0% for stereotactic doses and doses of 2 Gy(RBE), respectively.

Because potential RBE effects are typically more pronounced in the distal part of a field, a bigger clinical impact of RBE uncertainties in small fields is expected. Our study shows that this could be significant for tissues with low α/β and a small dose per fraction. The uncertainty in RBE due to the uncertainty associated with the α/β ratio seems larger than the impact of the applied range uncertainty margin on RBE. (paper)

[en] Gold nanoparticles (GNPs) have been demonstrated as radiation dose enhancing agents. Kilovoltage external photon beams have been shown to yield the largest enhancement due to the high interaction probability with gold. While orthovoltage irradiations are feasible and promising, they suffer from a reduced tissue penetrating power. This study quantifies the effect of varying photon beam energies on various beam arrangements, body, tumor, and cellular GNP uptake geometries. Cell survival was modeled based on our previously developed GNP-local effect model with radial doses calculated using the TOPAS-nBio Monte Carlo code. Cell survival curves calculated for tumor sites with GNPs were used to calculate the relative biological effectiveness (RBE)-weighted dose. In order to evaluate the plan quality, the ratio of the mean dose between the tumor and normal tissue for 50–250 kVp beams with GNPs was compared to the standard of care using 6 MV photon beams without GNPs for breast and brain tumors. For breast using a single photon beam, kV  +  GNP was found to yield up to 2.73 times higher mean RBE-weighted dose to the tumor than two tangential megavoltage beams while delivering the same dose to healthy tissue. For irradiation of brain tumors using multiple photon beams, the GNP dose enhancement was found to be effective for energies above 50 keV. A small tumor at shallow depths was found to be the most effective treatment conditions for GNP enhanced radiation therapy. GNP uptake distributions in the cell (with or without nuclear uptake) and the beam arrangement were found to be important factors in determining the optimal photon beam energy. (paper)

[en] Gold nanoparticles (GNPs) have shown potential as a radiosensitizer for radiation therapy using photon beams. Recently, experimental studies have been carried out using proton beams showing the GNP enhanced responses in proton therapy. In this work, we established a biological model to investigate the change in survival of irradiated cells due to the radiosensitizing effect of gold nanoparticles. Results for proton, megavoltage (MV) photon and kilovoltage (kV) photon beams are compared. For each particle source, we assessed various treatment depths, GNP cellular uptakes and sizes. We showed that kilovoltage photons caused the highest enhancement due to the high interaction probability between GNPs and kV photons. The cell survival fraction can be significantly reduced for both proton and MV photon irradiations if GNPs accumulate in the cell. For instance, the sensitizer enhancement ratio (SER) is 1.33 for protons in the middle of a spread out Bragg peak for 1 µM of internalized 50 nm GNPs. If the GNPs can all be internalized into the cell nucleus, the SER for proton therapy increases from 1.33 to 1.81. The results also show that for the same mass of GNPs in the cells, one can expect the greatest sensitization by smaller GNPs, i.e. a SER of 1.33 for 1 µM of internalized 50 nm GNPs and a SER of 3.98 for the same mass of 2 nm GNPs. We concluded that if the GNPs cannot be internalized into the cytoplasm, no GNP enhancement will be observed for proton treatment. Meanwhile, proton radiotherapy can potentially be enhanced with GNPs if they can be internalized into cells, and especially the cell nucleus. (paper)

[en] The purpose of this study was to compare the radiation-induced second cancer risks for in-field and out-of-field organs and tissues for pencil beam scanning (PBS) and passive scattering proton therapy (PPT) and assess the impact of adding patient-specific apertures to sharpen the penumbra in pencil beam scanning for pediatric brain tumor patients. Five proton therapy plans were created for each of three pediatric patients using PPT as well as PBS with two spot sizes (average sigma of ∼17 mm and ∼8 mm at isocenter) and choice of patient-specific apertures. The lifetime attributable second malignancy risks for both in-field and out-of-field tissues and organs were compared among five delivery techniques. The risk for in-field tissues was calculated using the organ equivalent dose, which is determined by the dose volume histogram. For out-of-field organs, the organ-specific dose equivalent from secondary neutrons was calculated using Monte Carlo and anthropomorphic pediatric phantoms. We find that either for small spot size PBS or for large spot size PBS, a patient-specific aperture reduces the in-field cancer risk to values lower than that for PPT. The reduction for large spot sizes (on average 43%) is larger than for small spot sizes (on average 21%). For out-of-field organs, the risk varies only marginally by employing a patient-specific aperture (on average from  −2% to 16% with increasing distance from the tumor), but is still one to two orders of magnitude lower than that for PPT. In conclusion, when pencil beam spot sizes are large, the addition of apertures to sharpen the penumbra decreases the in-field radiation-induced secondary cancer risk. There is a slight increase in out-of-field cancer risk as a result of neutron scatter from the aperture, but this risk is by far outweighed by the in-field risk benefit from using an aperture with a large PBS spot size. In general, the risk for developing a second malignancy in out-of-field organs for PBS remains much lower compared to PPT even if apertures are being applied. (paper)

[en] Gold nanoparticles (GNPs) have shown potential to be used as a radiosensitizer for radiation therapy. Despite extensive research activity to study GNP radiosensitization using photon beams, only a few studies have been carried out using proton beams. In this work Monte Carlo simulations were used to assess the dose enhancement of GNPs for proton therapy. The enhancement effect was compared between a clinical proton spectrum, a clinical 6 MV photon spectrum, and a kilovoltage photon source similar to those used in many radiobiology lab settings. We showed that the mechanism by which GNPs can lead to dose enhancements in radiation therapy differs when comparing photon and proton radiation. The GNP dose enhancement using protons can be up to 14 and is independent of proton energy, while the dose enhancement is highly dependent on the photon energy used. For the same amount of energy absorbed in the GNP, interactions with protons, kVp photons and MV photons produce similar doses within several nanometers of the GNP surface, and differences are below 15% for the first 10 nm. However, secondary electrons produced by kilovoltage photons have the longest range in water as compared to protons and MV photons, e.g. they cause a dose enhancement 20 times higher than the one caused by protons 10 μm away from the GNP surface. We conclude that GNPs have the potential to enhance radiation therapy depending on the type of radiation source. Proton therapy can be enhanced significantly only if the GNPs are in close proximity to the biological target. (paper)

[en] Proton therapy treatments are currently planned and delivered using the assumption that the proton relative biological effectiveness (RBE) relative to photons is 1.1. This assumption ignores strong experimental evidence that suggests the RBE varies along the treatment field, i.e. with linear energy transfer (LET) and with tissue type. A recent review study collected over 70 experimental reports on proton RBE, providing a comprehensive dataset for predicting RBE for cell survival. Using this dataset we developed a model to predict proton RBE based on dose, dose average LET (LET_d) and the ratio of the linear-quadratic model parameters for the reference radiation (α/β)_x, as the tissue specific parameter.The proposed RBE model is based on the linear quadratic model and was derived from a nonlinear regression fit to 287 experimental data points. The proposed model predicts that the RBE increases with increasing LET_d and decreases with increasing (α/β)_x. This agrees with previous theoretical predictions on the relationship between RBE, LET_d and (α/β)_x. The model additionally predicts a decrease in RBE with increasing dose and shows a relationship between both α and β with LET_d. Our proposed phenomenological RBE model is derived using the most comprehensive collection of proton RBE experimental data to date. Previously published phenomenological models, based on a limited data set, may have to be revised. (paper)

[en] Purpose: A method to refine the implementation of an in vivo, adaptive proton therapy range verification methodology was investigated. Simulation experiments and in-phantom measurements were compared to validate the calibration procedure of a time-resolved diode dosimetry technique. Methods: A silicon diode array system has been developed and experimentally tested in phantom for passively scattered proton beam range verification by correlating properties of the detector signal to the water equivalent path length (WEPL). The implementation of this system requires a set of calibration measurements to establish a beam-specific diode response to WEPL fit for the selected ‘scout’ beam in a solid water phantom. This process is both tedious, as it necessitates a separate set of measurements for every ‘scout’ beam that may be appropriate to the clinical case, as well as inconvenient due to limited access to the clinical beamline. The diode response to WEPL relationship for a given ‘scout’ beam may be determined within a simulation environment, facilitating the applicability of this dosimetry technique. Measurements for three ‘scout’ beams were compared against simulated detector response with Monte Carlo methods using the Tool for Particle Simulation (TOPAS). Results: Detector response in water equivalent plastic was successfully validated against simulation for spread out Bragg peaks of range 10 cm, 15 cm, and 21 cm (168 MeV, 177 MeV, and 210 MeV) with adjusted R² of 0.998. Conclusion: Feasibility has been shown for performing calibration of detector response for a given ‘scout’ beam through simulation for the time resolved diode dosimetry technique.

[en] Gold nanoparticles (GNPs) have been shown to greatly increase the efficacy of radiation. Low-energy photons have high interaction probability with gold. Generated substantial number of secondary electrons deposits highly localized dose near the GNPs. To describe cell survival with GNPs, high dose spikes around GNPs were simulated and used for development of GNP-local effect model (LEM). Previous researches simply assumed uniformly distributed individual GNPs at certain GNP-exposure time. However, we present radiobiological modelling depending on clustered behavior of GNPs and different GNP-exposure time observed by optical diffraction tomography (ODT). Three-dimensional localization of clustered GNPs was assessed in the cells as times evolved using ODT.

[en] In radiopharmaceutical treatments α-particles are employed to treat tumor cells. However, the mechanism that drives the biological effect induced is not well known. Being ionizing radiation, α-particles can affect biological organisms by producing damage to the DNA, either directly or indirectly. Following the principle that microdosimetry theory accounts for the stochastic way in which radiation deposits energy in sub-cellular sized volumes via physical collisions, we postulate that microdosimetry represents a reasonable framework to characterize the statistical nature of direct damage induction by α-particles to DNA. We used the TOPAS-nBio Monte Carlo package to simulate direct damage produced by monoenergetic alpha particles to different DNA structures. In separate simulations, we obtained the frequency-mean lineal energy ($y_F$) and dose-mean lineal energy ($y_D$) of microdosimetric distributions sampled with spherical sites of different sizes. The total number of DNA strand breaks, double strand breaks (DSBs) and complex strand breaks per track were quantified and presented as a function of either $y_F$ or $y_D.$ The probability of interaction between a track and the DNA depends on how the base pairs are compacted. To characterize this variability on compactness, spherical sites of different size were used to match these probabilities of interaction, correlating the size-dependent specific energy ($z$) with the damage induced. The total number of DNA strand breaks per track was found to linearly correlate with $y_F$ and $z_F$ when using what we defined an effective volume as microdosimetric site, while the yield of DSB per unit dose linearly correlated with $y_D$ or $z_D,$ being larger for compacted than for unfolded DNA structures. The yield of complex breaks per unit dose exhibited a quadratic behavior with respect to $y_D$ and a greater difference among DNA compactness levels. Microdosimetric quantities correlate with the direct damage imparted on DNA. (paper)