Secondary neutron dosimetry for conformal FLASH proton therapy.

BACKGROUND: Cyclotron-based proton therapy systems utilize the highest proton energies to achieve an ultra-high dose rate (UHDR) for FLASH radiotherapy. The deep-penetrating range associated with this high energy can be modulated by inserting a uniform plate of proton-stopping material, known as a range shifter, in the beam path at the nozzle to bring the Bragg peak within the target while ensuring high proton transport efficiency for UHDR. Aluminum has been recently proposed as a range shifter material mainly due to its high compactness and its mechanical properties. A possible drawback lies in the fact that aluminum has a larger cross-section of producing secondary neutrons compared to conventional plastic range shifters. Accordingly, an increase in secondary neutron contamination was expected during the delivery of range-modulated FLASH proton therapy, potentially heightening neutron-induced carcinogenic risks to the patient. PURPOSE: We conducted neutron dosimetry using simulations and measurements to evaluate excess dose due to neutron exposure during UHDR proton irradiation with aluminum range shifters compared to plastic range shifters. METHODS: Monte Carlo simulations in TOPAS were performed to investigate the secondary neutron production characteristics with aluminum range shifter during 225 MeV single-spot proton irradiation. The computational results were validated against measurements with a pair of ionization chambers in an out-of-field region ( ≤ $\le$ 30 cm) and with a Proton Recoil Scintillator-Los Alamos rem meter in a far-out-of-field region (0.5-2.5 m). The assessments were repeated with solid water slabs as a surrogate for the conventional range shifter material to evaluate the impact of aluminum on neutron yield. The results were compared with the International Electrotechnical Commission (IEC) standards to evaluate the clinical acceptance of the secondary neutron yield. RESULTS: For a range modulation up to 26 cm in water, the maximum simulated and measured values of out-of-field secondary neutron dose equivalent per therapeutic dose with aluminum range shifter were found to be ( 0.57 ± 0.02 ) mSv/Gy $(0.57\pm 0.02)\ \text{mSv/Gy}$ and ( 0.46 ± 0.04 ) mSv/Gy $(0.46\pm 0.04)\ \text{mSv/Gy}$ , respectively, overall higher than the solid water cases (simulation: ( 0.332 ± 0.003 ) mSv/Gy $(0.332\pm 0.003)\ \text{mSv/Gy}$ ; measurement: ( 0.33 ± 0.03 ) mSv/Gy $(0.33\pm 0.03)\ \text{mSv/Gy}$ ). The maximum far out-of-field secondary neutron dose equivalent was found to be ( 8.8 ± 0.5 $8.8 \pm 0.5$ )  µ Sv / Gy $\umu {\rm Sv/Gy}$ and ( 1.62 ± 0.02 $1.62 \pm 0.02$ )  µ Sv / Gy $\umu {\rm Sv/Gy}$ for the simulations and rem meter measurements, respectively, also higher than the solid water counterparts (simulation: ( 3.3 ± 0.3 $3.3 \pm 0.3$ )  µ Sv / Gy $\umu {\rm Sv/Gy}$ ; measurement: ( 0.63 ± 0.03 $0.63 \pm 0.03$ )  µ Sv / Gy $\umu {\rm Sv/Gy}$ ). CONCLUSIONS: We conducted simulations and measurements of secondary neutron production under proton irradiation at FLASH energy with range shifters. We found that the secondary neutron yield increased when using aluminum range shifters compared to conventional materials while remaining well below the non-primary radiation limit constrained by the IEC regulations.

Model studies of the role of oxygen in the FLASH effect.

Current radiotherapy facilities are standardized to deliver dose rates around 0.1-0.4 Gy/s in 2 Gy daily fractions, designed to deliver total accumulated doses to reach the tolerance limit of normal tissues undergoing irradiation. FLASH radiotherapy (FLASH-RT), on the other hand, relies on facilities capable of delivering ultrahigh dose rates in large doses in a single microsecond pulse, or in a few pulses given over a very short time sequence. For example, most studies to date have implemented 4-6 MeV electrons with intra-pulse dose rates in the range 106 -107  Gy/s. The proposed dependence of the FLASH effect on oxygen tension has stimulated several theoretical models based on three different hypotheses: (i) Radiation-induced transient oxygen depletion; (ii) cell-specific differences in the ability to detoxify and/or recover from injury caused by reactive oxygen species; (iii) self-annihilation of radicals by bimolecular recombination. This article focuses on the observations supporting or refuting these models in the frame of the chemical-biological bases of the impact of oxygen on the radiation response of cell free, in vitro and in vivo model systems.

Toward MR-integrated proton therapy: modeling the potential benefits for liver tumors.

Magnetic resonance imaging (MRI)-integrated proton therapy (MRiPT) is envisioned to improve treatment quality for many cancer patients. However, given the availability of alternative image-guided strategies, its clinical need is yet to be justified. This study aims to compare the expected clinical outcomes of MRiPT with standard of practice cone-beam CT (CBCT)-guided PT, and other MR-guided methods, i.e. offline MR-guided PT and MR-linac, for treatment of liver tumors. Clinical outcomes were assessed by quantifying the dosimetric and biological impact of target margin reduction enabled by each image-guided approach. Planning target volume (PTV) margins were calculated using random and systematic setup, delineation and motion uncertainties, which were quantified by analyzing longitudinal MRI data for 10 patients with liver tumors. Proton treatment plans were created using appropriate PTV margins for each image-guided PT method. Photon plans with margins equivalent to MRiPT were generated to represent MR-linac. Normal tissue complication probabilities (NTCP) of the uninvolved liver were compared. We found that PTV margin can be reduced by 20% and 40% for offline MR-guided PT and MRiPT, respectively, compared with CBCT-guided PT. Furthermore, clinical target volume expansion could be largely alleviated when delineating on MRI rather than CT. Dosimetric implications included decreased equivalent mean dose of the uninvolved liver, i.e. up to 24.4 Gy and 27.3 Gy for offline MR-guided PT and MRiPT compared to CBCT-guided PT, respectively. Considering Child-Pugh score increase as endpoint, NTCP of the uninvolved liver was significantly decreased for MRiPT compared to CBCT-guided PT (up to 48.4%,p < 0.01), offline MR-guided PT (up to 12.9%,p < 0.01) and MR-linac (up to 30.8%,p < 0.05). Target underdose was possible in the absence of MRI-guidance (D90 reduction up to 4.2 Gy in 20% of cases). In conclusion, MRiPT has the potential to significantly reduce healthy liver toxicities in patients with liver tumors. It is superior to other image-guided techniques currently available.

Thermoacoustic range verification during pencil beam delivery of a clinical plan to an abdominal imaging phantom.

PURPOSE: The purpose of this phantom study is to demonstrate that thermoacoustic range verification could be performed clinically. Thermoacoustic emissions generated in an anatomical multimodality imaging phantom during delivery of a clinical plan are compared to simulated emissions to estimate range shifts compared to the treatment plan. METHODS: A single-field 12-layerproton pencil beam scanning (PBS)treatment plancreated in Pinnacle prescribing6 Gy/fractionwas delivered by a superconducting synchrocyclotron to a triple modality (CT, MRI, and US) abdominal imaging phantom.Data was acquired by four acoustic receivers rigidly affixed to a linear ultrasound array. Receivers 1-2 were located distal to the treatment volume, whereas 3-4 were lateral. Receivers' room coordinates were computed relative to the ultrasound image plane after co-registration to the planning CT volume. For each prescribed beamlet, a set of thermoacoustic emissions corresponding to varied beam energies were computed. Simulated emissions were compared to measured emissions to estimate shifts of the Bragg peak. RESULTS: Shifts were small for high-dose beamlets that stopped in soft tissue. Signals acquired by channels 1-2 yielded shifts of -0.2±0.7mm relative to Monte Carlo simulations for high dose spots (~40 cGy) in the second layer. Additionally, for beam energy ≥125 MeV, thermoacoustic emissions qualitatively tracked lateral motion of pristine beams in a layered gelatin phantom, and time shifts induced by changing phantom layers were self-consistent within nanoseconds. CONCLUSIONS: Acoustic receivers tuned to spectra of thermoacoustic emissions may enable range verification during proton therapy.

A physicochemical model of reaction kinetics supports peroxyl radical recombination as the main determinant of the FLASH effect.

BACKGROUND AND PURPOSE: FLASH radiotherapy, a technique based on delivering large doses in a single fraction at the micro/millisecond timescale, spares normal tissues from late radiation-induced toxicity, in an oxygen-dependent process, whilst keeping full anti-tumor efficiency. We present a theoretical model taking into account the kinetics of formation and decay of reactive oxygen species, in particular of organic peroxyl radicals ROO. formed by addition of O2 to primary carbon-centred radicals R. and known to play a major role at the origin radio-induced complications. MATERIALS AND METHODS: The model focuses on the time-dependent evolution of radiolytic products in living matter exposed to continuous irradiation at dose-rates in the range 10-3-107Gy·s-1. The 9 differential rate equations resulting from the radiolytic and enzymatic reactions network were solved using the published values of these reactions rate constants in a cellular environment. RESULTS: The model suggests a correlation between the area-under-the-curve of time-evolving [ROO.] and the probability of normal tissue complications. The model does not lend weight to the hypothesis of transient oxygen depletion as a main determinant of FLASH but rather suggests a major role of radical-radical recombination. CONCLUSION: The model gives support to the reduction of ROO. lifetime as the main root of FLASH and compares favorably with published experimental results. We conclude that any process - in this case radical recombination - that shortens the lifetime or limits the radiolytic yield of ROO. is likely to protect normoxic tissues against the deleterious effects of radiation.

Estimation of respiratory phases during proton radiotherapy from a 4D-CT and Prompt gamma detection profiles.

Proton radiotherapy has a potential to provide an effective cancer treatment while sparing greater volume of healthy tissue than the conventional X-ray based radiotherapy. However, in lungs this potential is hindered by motion due to breathing. An important quantity in treatment verification is the correlation between the respiratory phases (RP) and the timing of pencil beam scanning (PBS). In this note, we demonstrate how the RP can be estimated using Prompt gamma (PG) detection profiles collected during a treatment. We utilized a 4D-CT of a patient with lung cancer, a treatment plan and a PG simulator. The treatment plan consisted of ten layers corresponding to ten proton energies. The RPs of the 4D-CT were interpolated using a deformable registration algorithm, so as to have fifty RPs in total. Deviations from regular breathing were introduced via time dependent frequency modulation. Fifty unique breathing patterns were generated, for which PG profiles were simulated for each pencil beam. Poisson noise was added to each PG profile to account for photon statistics. The RPs were estimated by comparing the PG profiles with and without Poisson noise via three different methods: the RP associated with each layer was estimated 1) independently of the other layers, 2) using a linear correlation between the layers, and 3) using a quadratic correlation between the layers. The best model, the quadratic model, yielded an average error in RP estimation relative to the breathing period of 5% of the breathing period or less with a 90% confidence interval.

Reassessment of stopping power ratio uncertainties caused by mean excitation energies using a water-based formalism.

PURPOSE: In proton therapy planning, the accuracy of the Stopping Power Ratios (SPR) calculated in the stoichiometric CT calibration is affected by, among others, uncertainties on the mean excitation energies (I-values) of human tissues and water. Traditionally, the contribution of these uncertainties on the SPR has been conservatively estimated of the order of 1% or more for a reference tissue of known composition. This study provides a methodology that enables a finer estimation of this uncertainty, eventually showing that the traditional estimates of the uncertainty are too conservative. METHODS: Since human tissues contain water, a correlation exists between the I-values of tissues and water. As the SPR is the ratio of the tissue stopping power to that of water, this correlation decreases the uncertainty of the SPR. Our formalism considers this by expressing the I-value of the tissue as a function of the water weight fraction and the I-value of water, while applying Bragg's additivity rule only to the nonaqueous mixture of the tissue. For 22 reference tissue compositions, the SPR uncertainty was estimated by randomly sampling Gaussian distributions, based on ICRU data, for the I-values of water and the nonaqueous mixture, as well as for the water weight fraction. RESULTS: The relative standard deviation of the SPR, estimated at 150 MeV, is in the range of 0.1%-0.3% for soft tissues with an average water weight percentage of at least 60%. For tissues with a low water content (e.g., adipose and bones), this uncertainty is in the range of 0.5%-0.7%. CONCLUSION: Uncertainties on the I-values of human tissues and water appear to have a significantly lower impact on the SPR uncertainty than traditionally expected. In the future, this may provide a rationale for using smaller distal and proximal margins on the target volume, provided that all other range uncertainty components are correctly estimated too.

Estimating patient specific uncertainty parameters for adaptive treatment re-planning in proton therapy using in vivo range measurements and Bayesian inference: application to setup and stopping power errors.

In proton therapy, quantification of the proton range uncertainty is important to achieve dose distribution compliance. The promising accuracy of prompt gamma imaging (PGI) suggests the development of a mathematical framework using the range measurements to convert population based estimates of uncertainties into patient specific estimates with the purpose of plan adaptation. We present here such framework using Bayesian inference. The sources of uncertainty were modeled by three parameters: setup bias m, random setup precision r and water equivalent path length bias u. The evolution of the expectation values E(m), E(r) and E(u) during the treatment was simulated. The expectation values converged towards the true simulation parameters after 5 and 10 fractions, for E(m) and E(u), respectively. E(r) settle on a constant value slightly lower than the true value after 10 fractions. In conclusion, the simulation showed that there is enough information in the frequency distribution of the range errors measured by PGI to estimate the expectation values and the confidence interval of the model parameters by Bayesian inference. The updated model parameters were used to compute patient specific lateral and local distal margins for adaptive re-planning.