Proton RBE Research Articles

2453: Dose and setup verification based on in vivo dosimetry for PBS proton RBE mice studies

2453: Dose and setup verification based on in vivo dosimetry for PBS proton RBE mice studies

2230: Beyond a constant proton RBE: Survey on clinical and research activities in Europe and United States

2230: Beyond a constant proton RBE: Survey on clinical and research activities in Europe and United States

3463: Preclinical imaging studies of proton RBE in normal tissue: What are the mechanisms?

3463: Preclinical imaging studies of proton RBE in normal tissue: What are the mechanisms?

RBE Model Based Proton Planning of Stereotactic Body Radiotherapy for Spine Metastasis: A Dosimetric Analysis

Study of proton stereotactic body radiotherapy (SBRT) for spine metastasis is limited, largely due to theorized increased risk of spinal cord injury with higher end of range RBE. Though the 1.1 RBE constant for proton beam is clinically used, data indicate that proton RBE is variable and dependent on technical-, tissue-, and patient-factors. To better understand safety of proton SBRT for spine metastasis, we performed a dosimetric analysis comparing plans delivered by photon robotic technique versus intensity modulated proton therapy (IMPT) and accounting for RBE weighted dose. A total of 9 patients with spine metastasis (3 cervical, 3 thoracic, 3 lumbar) previously treated with a frameless robotic radiosurgery system (Sunnyvale, CA) were identified. Each level contained a case with paraspinal extension, a reirradiation case, and a case with epidural extension (Bilsky grade ≥1c) as such cases in current practice often require planning target volume (PTV) under-coverage in order to meet organ at risk (OAR) dose constraints. Given these challenges, selected cases were clinically treated with 30 Gy in 5 fractions despite an institutional preference of further dose escalation. Comparative IMPT plans were generated using 30 GyE in 5 fractions and 1.1 RBE constant. IMPT plans were then made using 1.1 RBE and 45 GyE in 5 fractions: a prescription dose associated with a 2-yr local control rate of 95% on prior tumor control probability modelling. A treatment planning system was used to separately generate and optimize RBE weighted plans based on Carabe-, McNamara-, or Wedenberg models for prescription doses of 30 GyE and 45 GyE. IMPT plans used robust optimization parameters of ± 3.5% range and 2-mm setup uncertainties. PTV coverage and OAR sparing were compared using Wilcoxon signed-rank tests. PTV coverage (PTV volume receiving prescription dose) was significantly improved with IMPT at 30 GyE / 1.1 RBE (median PTV V30: 93%) compared to CK at 30 Gy (median: 88.5%, p = .02). PTV coverage was similar when comparing CK at 30 Gy with IMPT at 45 GyE / 1.1 RBE (median PTV V45: 90%, p = .23). When comparing maximum spinal cord dose (cord Dmax), there was improved OAR sparing with IMPT at 30 GyE / 1.1 RBE (median: 17.6 GyE, p = .04) and IMPT at 45 GyE / 1.1 RBE (median: 16.1 GyE, p = .04) when respectively compared to CK at 30 Gy (median: 18 Gy). No difference was seen in cord Dmax when comparing CK at 30 Gy to RBE weighted plans at 30 GyE using Carabe- (median: 17.3 GyE, p = .22), McNamara- (median: 17.4 GyE, p = .22), or Wedenberg (median: 17.0 GyE, p = .08) model. Median cord Dmax values for RBE weighted plans at 45 GyE were numerically equivalent. The average increase in variable RBE plans' maximum dose compared to fixed RBE plans was 105.3% +/- 3.5%. We report the first dosimetric analysis of proton SBRT for spine metastasis using variable RBE dose models. IMPT may provide improved target coverage and better sparing of adjacent OARs compared to CK though fixed RBE computation may underestimate maximum dose to adjacent OARs.

TOPAS simulations of the response of a mini-TEPC: benchmark with experimental data

Objective. Microdosimetry offers a fast tool for radiation quality (RQ) verification to be implemented in treatment planning systems in proton therapy based on variable LET or RBE to move forward from the use of a fixed RBE of 1.1. It is known that the RBE of protons can increase up to 50% higher than that value in the last few millimetres of their range. Microdosimetry can be performed both experimentally and by means of Monte Carlo (MC) simulations. This paper has the aim of comparing the two approaches. Approach. Experimental measurements have been performed using a miniaturized Tissue equivalent proportional counter developed at the Legnaro National Laboratories of the Italian National Institute for Nuclear Physics with the aim of being used as RQ monitors for high intensity beams. MC simulations have been performed using the microdosimetric extension of TOPAS which provides optimized parameters and scorers for this application. Main results. Simulations were compared with experimental microdosimetric spectra in terms of shape of the spectra and their average values. Moreover, the latter have been investigated as possible estimators of LET obtained with the same MC code. The shape of the spectra is in general consistent with the experimental distributions and the average values of the distributions in both cases can predict the RQ increase with depth. Significance. This study aims at the comparison of microdosimetric spectra obtained from both experimental measurements and the microdosimetric extension of TOPAS in the same radiation field.

Results of a prospective randomized trial on long-term effectiveness of protons and carbon ions in prostate cancer: LEM I and α/β = 2 Gy overestimates the RBE

AimTo analyze the long-term effectiveness of carbon ions relative to protons in the prospective randomized controlled ion prostate irradiation (IPI) trial. MethodsEffectiveness via PSA assessment in a randomized study on prostate irradiation with 20x3.3 Gy(RBE) protons versus carbon ions was analyzed in 92 patients. Proton RBE was based on a fixed RBE of 1.1 while the local effect model (LEM) I and an α/β = 2 Gy was used for carbon ions. The dose in the prostate was recalculated based on the delivered treatment plan using LEM I and LEM IV and different α/β values. ResultsFive-year overall and progression free survival was 98% and 85% with protons and 91% and 50% with carbon ions, respectively, with the latter being unexpectedly low compared to Japanese carbon ion data and rather corresponding to a photon dose <72 Gy in 2 Gy fractions. According to LEM I and the applied α/β-value of 2 Gy, the applied carbon ion dose in 2 Gy(RBE) fractions (EQD2) was 87.46 Gy(RBE). Recalculations confirmed a strong dependence of RBE-weighted dose on the α/β ratio as well as on the RBE-model. ConclusionThe data demonstrate a significant lower effectiveness of the calculated RBE-weighted dose in the carbon ion as compared to the proton arm. LEM I and an α/β = 2 Gy overestimates the RBE for carbon ions in prostate cancer treatment. Adjusting the biological dose calculation by using LEM I with α/β = 4 Gy could be a pragmatic way to safely escalate dose in carbon ion radiotherapy for prostate cancer.

PO-1725 An approach for obtaining Monte Carlo computed variable proton RBE from a treatment planning system

PO-1725 An approach for obtaining Monte Carlo computed variable proton RBE from a treatment planning system

DNA Damage Response Inhibitors of DNA-PKcs, PARP, RAD51, ATR and ATM All Sensitize Cancer Cells to X-Rays and Protons

<h3>Purpose/Objective(s)</h3> Radiotherapy (RT) controls tumors primarily by inducing DNA damage. However, some tumor cells can repair RT-induced DNA damage and are thus radioresistant. RT could be made more effective by combining it with inhibitors of DNA damage response proteins (DDRi) to selectively render tumor cells more susceptible to RT-induced DNA damage. There are several DDRi currently approved by the FDA or in clinical trials for use as monotherapy, including inhibitors of DNA-PKcs, PARP, Rad 51, ATR and ATM. These proteins function in non-homologous end-joining (classical and alternative), homologous recombination, base excision repair or cell cycle checkpoint and disrupting any of which may enhance RT effectiveness. Because protons produce much more complex DNA lesion compared to x-rays, protons may amplify the effect of DDRis and further enhance potential activation of anti-tumor immune signaling. Our hypothesis is that DDRis sensitize cancer cells to RT and the sensitization effect is amplified by protons more so than x-rays with an enhancement in upstream immune signaling. <h3>Materials/Methods</h3> We used 4 cancer cell lines: H460, H1299, PANC-1 and Panc 10.05 and 5 DDRis targeting DNA-PKcs (NU7441), PARP (AZD2281), Rad 51 (B02), ATR (AZD6738) and ATM (KU55933) at various concentrations (0.1-10 µM). We irradiated cells with 6 MV x-rays or 9.9 keV/µm protons (dose-weighted LET in water) alone or with DDRis at various dose levels to assess cell survival via clonogenic assay, DNA damage via gH2AX and 53BP1 foci, micronuclei (MN) and cGAS-positive micronuclei (NM-cGAS⁺), the latter two being precursors of antitumor immunity. <h3>Results</h3> We observed that DDRis sensitized both x-rays and protons. Protons+ATMi (10 µM) sensitization relative to x-rays alone was increased 3.51-fold (± 0.09). The RBE ranged from 0.79 ± 0.03 to 1.54 ± 0.09 and were negatively correlated with x-rays sensitivity (r = -0.6160), suggesting that the greater the DDRi-induced sensitization, the less benefit there will be from the proton LET effect. Nonetheless, the sensitization relative to x-rays alone from combining DDRi with protons was generally larger (30 ± 3% on average). Generally, the combination of DDRi with RT increased gH2AX and 53BP1 foci at 24 h after radiation, and MN and MN-cGAS⁺ at 24 and 72 h after radiation with protons+DDRi having a higher increase relative to x-rays alone than x-rays+DDRi. <h3>Conclusion</h3> Inhibition of DNA-PKcs, PARP, Rad 51, ATR and ATM substantially sensitized several cancer cell lines to x-rays and protons. Although protons+DDRi reduced proton RBE, the inhibitor-induced sensitization outweighs the RBE loss, resulting in a net sensitization beyond x-rays+DDRi. The increased MN number indicates that pairing RT with DDRis may provide an additional benefit of antitumor immune stimulation. Additional preclinical work is warranted to elucidate the complex interaction of DDRi and RT in vivo.

OC-0283 LET dependence of proton RBE in early normal tissue damage in vivo

OC-0283 LET dependence of proton RBE in early normal tissue damage in vivo

OC-0418 European multi-centric study on variable proton RBE dose calculations for multiple anatomical sites

OC-0418 European multi-centric study on variable proton RBE dose calculations for multiple anatomical sites

OC-0417 Is a variable proton RBE considered in clinical practice? - ESTRO survey among 25 proton centres

OC-0417 Is a variable proton RBE considered in clinical practice? - ESTRO survey among 25 proton centres

In Vivo Validation of the BIANCA Biophysical Model: Benchmarking against Rat Spinal Cord RBE Data.

(1) Background: Cancer ion therapy is constantly growing thanks to its increased precision and, for heavy ions, its increased biological effectiveness (RBE) with respect to conventional photon therapy. The complex dependence of RBE on many factors demands biophysical modeling. Up to now, only the Local Effect Model (LEM), the Microdosimetric Kinetic Model (MKM), and the “mixed-beam” model are used in clinics. (2) Methods: In this work, the BIANCA biophysical model, after extensive benchmarking in vitro, was applied to develop a database predicting cell survival for different ions, energies, and doses. Following interface with the FLUKA Monte Carlo transport code, for the first time, BIANCA was benchmarked against in vivo data obtained by C-ion or proton irradiation of the rat spinal cord. The latter is a well-established model for CNS (central nervous system) late effects, which, in turn, are the main dose-limiting factors for head-and-neck tumors. Furthermore, these data have been considered to validate the LEM version applied in clinics. (3) Results: Although further benchmarking is desirable, the agreement between simulations and data suggests that BIANCA can predict RBE for C-ion or proton treatment of head-and-neck tumors. In particular, the agreement with proton data may be relevant if the current assumption of a constant proton RBE of 1.1 is revised. (4) Conclusions: This work provides the basis for future benchmarking against patient data, as well as the development of other databases for specific tumor types and/or normal tissues.

Redefine End-of-range RBE of Protons Based on Long-term Clinical Outcome

Redefine End-of-range RBE of Protons Based on Long-term Clinical Outcome

Systematic microdosimetric data for protons of therapeutic energies calculated with Geant4-DNA

The purpose of this study was to generate physical data needed for microdosimetry-based models of proton RBE. Our focus was on the frequency and dose average lineal energies, y F and y D. We report data for proton energies from 0.1 to 100 MeV, for spherical volumes 2–103 nm in diameter. These data were calculated using Geant4-DNA Monte Carlo software. The physics implemented in Geant4-DNA has been extensively tested for this type of calculations but data on y F and y D for protons generated with this code have been very limited. An innovative aspect of our study is that we introduced a straightforward procedure for calculation of y F and y D for polyenergetic beams and presented the data in a format that simplifies these calculations. We compared our data with previous studies that used different Monte Carlo codes and with experimental data.

The impact of proton LET/RBE modeling and robustness analysis on base-of-skull and pediatric craniopharyngioma proton plans relative to VMAT

Purpose: Pediatric craniopharyngioma, adult base-of-skull sarcoma and chordoma cases are all regarded as priority candidates for proton therapy. In this study, a dosimetric comparison between volumetric modulated arc therapy (VMAT) and intensity modulated proton therapy (IMPT) was first performed. We then investigated the impact of physical and biological uncertainties. We assessed whether IMPT plans remained dosimetrically superior when such uncertainty estimates were considered, especially with regards to sparing organs at risk (OARs).Methodology: We studied 10 cases: four chondrosarcoma, two chordoma and four pediatric craniopharyngioma. VMAT and IMPT plans were created according to modality-specific protocols. For IMPT, we considered (i) variable RBE modeling using the McNamara model for different values of (α/β)x, and (ii) robustness analysis with ±3 mm set-up and 3.5% range uncertainties.Results: When comparing the VMAT and IMPT plans, the dosimetric advantages of IMPT were clear: IMPT led to reduced integral dose and, typically, improved CTV coverage given our OAR constraints. When physical robustness analysis was performed for IMPT, some uncertainty scenarios worsened the CTV coverage but not usually beyond that achieved by VMAT. Certain scenarios caused OAR constraints to be exceeded, particularly for the brainstem and optical chiasm. However, variable RBE modeling predicted even more substantial hotspots, especially for low values of (α/β)x. Variable RBE modeling often prompted dose constraints to be exceeded for critical structures.Conclusion: For base-of-skull and pediatric craniopharyngioma cases, both physical and biological robustness analyses should be considered for IMPT: these analyses can substantially affect the sparing of OARs and comparisons against VMAT. All proton RBE modeling is subject to high levels of uncertainty, but the clinical community should remain cognizant possible RBE effects. Careful clinical and imaging follow-up, plus further research on end-of-range RBE mitigation strategies such as LET optimization, should be prioritized for these cohorts of proton patients.

Радиобиологические эффекты протонов

The article contains an analysis of literature data and the author’s own results on the radiobiological effects of protons at the cellular, systemic (intercellular) and organismic levels, as applied to the practical tasks of radiation therapy of oncological diseases and the protons effects on the astronauts’ organism.&#x0D; It is established that the proton RBE is a variable value, depending on the LET of the particles, the amount and dose rate, the presence or absence of oxygen. Proton RBE varies depending on the object of study, the type of tissue, proton energy and particle penetration depth, as well as the method for evaluating the biological efficiency of protons. which corresponds to general radiobiology.&#x0D; In particular, it has been shown that the RBE of protons adopted in radiation therapy at the level of 1.1 is conditional. A firmly established and repeatedly confirmed is an increase in RBE with a decrease in proton energy and, accordingly, an increase in LET.&#x0D; The use of elements of the physical protection of a spacecraft during exposure to protons with an energy of 170 MeV leads to an increase in LET and RBE of protons in terms of the cellularity of the bone marrow. &#x0D; Pharmacological agents effective in photon irradiation are also effective when exposed to a proton beam. It has been shown that natural melanin pigment and recombinant manganese superoxide dismutase helps to preserve and accelerate the resumption of blood formation in animals irradiated by protons. The Grippol vaccine increases radioresistance during proton irradiation. Neuropeptide Semax has a positive effect on the central nervous system and the strength of the forepaws of animals irradiated with protons at Bragg’s peak.

SP-0015 RBE of protons: what can we learn from preclinical models?

SP-0015 RBE of protons: what can we learn from preclinical models?

EP-1919 Voxel-based assessment of proton RBE in paediatric brain cancer radiotherapy from multimodal imaging

EP-1919 Voxel-based assessment of proton RBE in paediatric brain cancer radiotherapy from multimodal imaging

PREDICTING BIOLOGICAL EFFECTS ALONG HADRONTHERAPY DOSE PROFILES BY THE BIANCA BIOPHYSICAL MODEL.

The BIANCA biophysical model of cell death and chromosome aberrations was further refined and applied to predict the biological effectiveness along Spread-Out Bragg Peaks used in hadrontherapy. The simulation outcomes were compared with in vitro survival data on protons, He-ions and C-ions over a wide LET range, and the particle- and LET-dependence of the DNA Cluster Lesions (CLs) yields used as input parameters was investigated. For each particle type, the CL yield was found to increase with LET in a linear-quadratic fashion; fitting the CL yields allowed to predict cell death and chromosome aberrations in principle at any depth along a longitudinal proton dose profile used at CNAO. A clear increase in effectiveness was found in the SOBP distal region, supporting the idea that, in some cases, the constant proton RBE usually applied in clinics may be a sub-optimal solution.

Targeted Inhibition of Rad51 Renders Non–small Cell Lung Cancer Cells More Sensitive to Proton Therapy

Radiation therapy using proton beams is an emerging therapy that is being used for cancer treatment due to its superior physical dose distribution, higher RBE and increased effectiveness, leading to greater clinical gains. A recent study has shown a preferential involvement of the homologous recombination (HR) pathway in proton mediated radiosensitization. Rad51, a key protein in the HR pathway of DNA double-strand break repair, is overexpressed in various cancers and plays an essential role in radioresistance. Therefore, this study was designed to evaluate the impact of targeting Rad51on the RBE of protons and photons in NSCLC cell lines. The effects of Rad51 inhibition by genetic (Rad51 siRNA) and pharmacologic (BO2, a small molecule Rad51 inhibitor) approaches on radiosensitization of H1299 and A549 NSCLC cells were determined in vitro. The RBE of protons and photons following siRad51 treatment was compared using clonogenic cell survival assay when protons were delivered with doses of 2, 4 and 6 Gy at the mid-spread out Bragg peak (SOBP) using a reference beam of 15 g/cm2 range and 10 g/cm2modulation. Involvement of the DNA damage response was assessed by western blot analysis for DNA repair proteins and immunofluorescence staining for g-H2AX foci. Rad51 depletion by siRNA sensitized H1299 and A549 cells to protons and photons. However, both H1299 and A549 cell lines were significantly more sensitive to proton irradiation compared to photon. Survival fraction at 2 Gy (SF2) for H1299 cells exposed to proton beam was reduced from (53.7 ± 0.49) % in siScr to (21.8 ± 2.28) % in siRad51-treated group. Similarly, SF2 for A549 cells was reduced from (59.1 ± 1.16) % in siScr to (29.6 ± 4.9) % following siRad51-treatment. Survival enhancement ratios (SER) were calculated at 10% cell survival by dividing proton radiation dose of the siScr to that of siRad51 for that survival. The SER for H1299 cells at 10% survival was 1.9 and for A549 was 1.33, respectively. Similar results were obtained with the Rad51 small molecule inhibitor, BO2. Our results reveal that this enhanced efficacy of protons is associated with increased ATM and Chk1 phosphorylation as well as increased H2AX phosphorylation. Further, Rad51 knockdown led to persistent radiation-induced DNA damage as reflected by γ-H2AX foci staining. Our results demonstrate that Rad51 inhibition significantly increased the radiosensitivity of NSCLC cells, and that this increased radiosensitivity was mediated by the suppression of DNA repair. The effect of siRad51 on radiosensitization to protons was more significant than to photons.