Determinants of radiation dose to immune cells during breast radiotherapy.

BACKGROUND: The immune system has been identified as an organ at risk in esophageal and lung cancers. However, the dosimetric impact of radiotherapy on immune system exposure in patients treated for breast cancer has never been studied. METHODS: A monocentric retrospective dosimetric study included 163 patients treated at the Institut Curie (Paris, France) between 2010 and 2016 with locoregional helical tomotherapy after conservative surgery or total mastectomy. The effective dose to the immune system (EDIC) was calculated based on diverse dosimetric parameters. The clinical and volumetric determinants of EDIC in adjuvant radiotherapy of breast cancer were analyzed. RESULTS: The median EDIC for the population was 4.23 Gy, ranging from 1.82 to 6.19 Gy. Right-sided radiotherapy and regional lymph node irradiation were associated with significantly higher EDIC in univariate (4.38 Gy vs. 3.94 Gy, p < 0.01, and 4.27 Gy vs. 3.44 Gy, p < 0.01, respectively) and multivariate analyses (p < 0.01 and p < 0.01). Liver overexposure was the main contributor to EDIC increase in right-sided breast cancer patients (+0.38 Gy [95%CI: +0.30; +0.46]), while the integral total dose increase was the main contributor to EDIC increase in cases of regional node irradiation (+0.63 Gy [95%CI: +0.42; +0.85]). CONCLUSION: The EDIC score during adjuvant radiotherapy after breast cancer was statistically significantly higher in the case of right-sided radiotherapy and regional lymph node irradiation. Liver irradiation is the main contributor to immune system exposure in adjuvant irradiation of right-sided breast cancer. Populations in which an association between EDIC and survival would exist have yet to be identified but could potentially include patients treated for triple-negative breast cancer with a poor response to neoadjuvant chemoimmunotherapy.

Thoracic Proton Minibeam Radiation Therapy: Tissue Preservation and Survival Advantage Over Conventional Proton Therapy.

PURPOSE: Proton minibeam radiation therapy (pMBRT) is an innovative radiation therapy approach that highly modulates the spatial dimension of the dose delivery using narrow, parallel, and submillimetric proton beamlets. pMBRT has proven its remarkable healthy tissue preservation in the brain and skin. This study assesses the potential advantages of pMBRT for thoracic irradiations compared with conventional radiation therapy in terms of normal tissue toxicity. The challenge here was the influence of respiratory motion on the typical peak and valley dose patterns of pMBRT and its potential biologic effect. METHODS AND MATERIALS: The whole thorax of naïve C57BL/6 mice received one fraction of high dose (18 Gy) pMBRT or conventional proton therapy (CPT) without any respiratory control. The development of radiation-induced pulmonary fibrosis was longitudinally monitored using cone beam computed tomography. Anatomopathologic analysis was carried out at 9 months postirradiation and focused on the reaction of the lungs' parenchyma and the response of cell types involved in the development of radiation-induced fibrosis and lung regeneration as alveolar type II epithelial cells, club cells, and macrophages. RESULTS: pMBRT has milder effects on survival, skin reactions, and lung fibrosis compared with CPT. The pMBRT-induced lung changes were more regional and less severe, with evidence of potential reactive proliferation of alveolar type II epithelial cells and less extensive depletion of club cells and macrophage invasion than the more damaging effects observed in CPT. CONCLUSIONS: pMBRT appears suitable to treat moving targets, holding a significant ability to preserve healthy lung tissue, even without respiratory control or precise targeting.

Oxygen supplementation in anesthesia can block FLASH effect and anti-tumor immunity in conventional proton therapy.

BACKGROUND: Radiation-induced neurocognitive dysfunction is a major adverse effect of brain radiation therapy and has specific relevance in pediatric oncology, where serious cognitive deficits have been reported in survivors of pediatric brain tumors. Moreover, many pediatric patients receive proton therapy under general anesthesia or sedation to guarantee precise ballistics with a high oxygen content for safety. The present study addresses the relevant question of the potential effect of supplemental oxygen administered during anesthesia on normal tissue toxicity and investigates the anti-tumor immune response generated following conventional and FLASH proton therapy. METHODS: Rats (Fischer 344) were cranially irradiated with a single high dose of proton therapy (15 Gy or 25 Gy) using FLASH dose rate proton irradiation (257 ± 2 Gy/s) or conventional dose rate proton irradiation (4 ± 0.02 Gy/s), and the toxicities in the normal tissue were examined by histological, cytometric and behavioral analysis. Glioblastoma-bearing rats were irradiated in the same manner and tumor-infiltrating leukocytes were quantified by flow cytometry. RESULTS: Our findings indicate that supplemental oxygen has an adverse impact on both functional and anatomical evaluations of normal brain following conventional and FLASH proton therapy. In addition, oxygen supplementation in anesthesia is particularly detrimental for anti-tumor immune response by preventing a strong immune cell infiltration into tumoral tissues following conventional proton therapy. CONCLUSIONS: These results demonstrate the need to further optimize anesthesia protocols used in radiotherapy with the goal of preserving normal tissues and achieving tumor control, specifically in combination with immunotherapy agents.

Proton therapy is a type of precise radiotherapy that can have reduced side effects. Children undergoing proton therapy are often given a general anesthetic, supplemented with high oxygen levels as a measure of safety. However, the consequences of modifying the oxygen concentration in the treatment have not been studied. In this study, we evaluated the consequences of adding oxygen in the anesthesia in a model of brain tumor after conventional proton therapy and a new radiotherapy technique, FLASH proton therapy. We observed that oxygen supplementation can cause more brain damage in FLASH proton therapy and block anti-tumor immune cell infiltration into the tumor in conventional proton therapy. Overall, this study should be taken into consideration when designing new protocols of radiotherapy, specifically those including FLASH proton therapy and combinations with immune-targeted treatments.

Very high-energy electron dose calculation using the Fermi-Eyges theory of multiple scattering and a simplified pencil beam model.

BACKGROUND: Very high-energy electrons (VHEE) radiotherapy, in the energy range of 100-200 MeV is currently considered a promising technique for the future of radiation therapy and could benefit from the promises of ultra-high dose rate FLASH therapy. However, to our knowledge, no analytical calculation models have been tested for this type of application and the approximations proposed for multiple scattering with electron beams have not been extensively evaluated at these high energies. PURPOSE: In this work, we discuss the derivation of a simple and fast algorithm based on the Fermi-Eyges theory of multiple Coulomb scattering for fast dose calculation for VHEE beams (up to 200 MeV). Similar to the Gaussian pencil beam models used for electron or proton beams, this pencil beam kernel is separated into a central and an off-axis term. Monte Carlo simulations are performed to compare the analytical calculations with simulations and to determine the parametrizations used in the model at the highest electron energies. METHODS: The normalized electron planar fluence distribution is described in water according to the Fermi-Eyges theory of multiple Coulomb scattering and a double Gaussian distribution model. The main quantities used in the model and their calculation (mass angular scattering power, mean energy, range straggling) are discussed and tested for electron energies up to 200 MeV. The TOPAS/Geant4 Monte Carlo (MC) toolkit is used to compare analytical calculations with MC simulations for a theoretical pencil beam irradiation and to find the best parameters describing the range straggling. The model is then tested on a realistic simulation of a pencil beam scanning beamline with treatment field dimensions up to 15 × 15 cm2  and for deep-seated targets. RESULTS: Radial dose distributions of a pencil beam in water were calculated with the model and compared with the results of a complete Monte Carlo simulation. A good agreement (within 2%/2 mm gamma passing rate superior to 90%, and a mean deviation between calculated and simulated pencil beam radial spread smaller than 0.6 mm) was observed between analytical dose distributions and simulations for energies up to 200 MeV and field sizes up to 15 × 15 cm2 . CONCLUSIONS: A parameterization of an electron source and an analytical pencil beam model were proposed in this work, thereby allowing a suitable reproduction of the lateral fluence of a VHEE beam and good agreement between calculations and simulated data. Further improvement of the method would require the consideration of a model describing the large-angle scattering of the electrons. The results of this work could support future research into VHEE radiotherapy and might be of interest for use together with VHEE broad beams produced by scanned narrow pencil beams.

Secondary radiation dose modeling in passive scattering and pencil beam scanning very high energy electron (VHEE) radiation therapy.

BACKGROUND: Electrons with kinetic energy up to a few hundred MeV, also called very high energy electrons (VHEE), are currently considered a promising technique for the future of radiation therapy (RT) and in particular ultra-high dose rate (UHDR) therapy. However, the feasibility of a clinical application is still being debated and VHEE therapy remains an active area of research for which the optimal conformal technique is also yet to be determined. PURPOSE: In this work, we will apply two existing formalisms based on analytical Gaussian multiple-Coulomb scattering theory and Monte Carlo (MC) simulations to study and compare the electron and bremsstrahlung photon dose distributions arising from two beam delivery systems (passive scattering with or without a collimator or active scanning). METHODS: We therefore tested the application of analytical and MC models to VHEE beams and assessed their performance and parameterization in the energy range of 6-200 MeV. The optimized electron beam fluence, the bremsstrahlung, an estimation of central-axis and off-axis x-ray dose at the practical range and neutron contributions to the total dose, along with an extended parameterization for the photon dose model were developed, together with a comparison between double scattering (DS) and pencil beam scanning (PBS) techniques. MC simulations were performed with the TOPAS/Geant4 toolkit to verify the dose distributions predicted by the analytical calculations. RESULTS: The results for the clinical energy range (between 6 and 20 MeV) as well as for higher energies (VHEE range between 20 and 200 MeV) and for two treatment field sizes (5 × 5 and 10 × 10 cm2 ) are reported, showing a reasonable agreement with MC simulations with mean differences below 2.1%. The relative contributions of photons generated in the medium or by the scattering system along the central-axis (up to 50% of the total dose) are also illustrated, along with their relative variations with electron energy. CONCLUSIONS: The fast analytical models parametrized in this study allow an estimation of the amount of photons produced behind the practical range by a DS system with an accuracy lower than 3%, providing important information for the eventual design of a VHEE system. The results of this work could support future research on VHEE radiotherapy.

Proton minibeam radiation therapy for treating metastases: A treatment plan study.

BACKGROUND: Proton minibeam radiation therapy (pMBRT) is a new radiotherapy approach that has shown a significant increase in the therapeutic window in glioma-bearing rats compared to conventional proton therapy. Such preclinical results encourage the preparation of clinical trials. PURPOSE: In this study, the potential of pMBRT for treating clinical indications candidates for the first clinical trials (i.e., brain, lung, and liver metastases) was evaluated. METHODS: Four clinical cases, initially treated with stereotactic radiotherapy (SRT), were selected for this study. pMBRT, SRT, and conventional proton therapy (PT) dose distributions were compared by using three main criteria: (i) the tumor coverage, (ii) the mean dose to organs-at-risk, and (iii) the possible adverse effects in normal tissues by considering valley doses as the responsible for tissue sparing. pMBRT plans consisted of one fraction and one-two fields. Dose calculations were computed by means of Monte Carlo simulations. RESULTS: pMBRT treatments provide a similar or superior target coverage than SRT, even using fewer fields. pMBRT also significantly reduces the biologically effective dose (BED) to organs-at-risk. In addition, valley and mean doses to normal tissues remain below tolerance limits when treatments are delivered in a single fraction, contrary to PT treatments. CONCLUSIONS: This work provides a first insight into the possibility of treating metastases with pMBRT. More favorable dose distributions and treatment delivery regimes may be expected from this new approach than SRT. The advantages of pMBRT would need to be confirmed by means of Phase I clinical trials.

Proton FLASH Radiation Therapy and Immune Infiltration: Evaluation in an Orthotopic Glioma Rat Model.

PURPOSE: FLASH radiation therapy (FLASH-RT) is a promising radiation technique that uses ultrahigh doses of radiation to increase the therapeutic window of the treatment. FLASH-RT has been observed to provide normal tissue sparing at high dose rates and similar tumor control compared with conventional RT, yet the biological processes governing these radiobiological effects are still unknown. In this study, we sought to investigate the potential immune response generated by FLASH-RT in a high dose of proton therapy in an orthotopic glioma rat model. METHODS AND MATERIALS: We cranially irradiated rats with a single high dose (25 Gy) using FLASH dose rate proton irradiation (257 ± 2 Gy/s) or conventional dose rate proton irradiation (4 ± 0.02 Gy/s). We first assessed the protective FLASH effect that resulted in our setup through behavioral studies in naïve rats. This was followed by a comprehensive analysis of immune cells in blood, healthy tissue of the brain, and tumor microenvironment by flow cytometry. RESULTS: Proton FLASH-RT spared memory impairment produced by conventional high-dose proton therapy and induced a similar tumor infiltrating lymphocyte recruitment. Additionally, a general neuroinflammation that was similar in both dose rates was observed. CONCLUSIONS: Overall, this study demonstrated that FLASH proton therapy offers a neuro-protective effect even at high doses while mounting an effective lymphoid immune response in the tumor.

First experimental measurements of 2D microdosimetry maps in proton therapy.

BACKGROUND: Empirical data in proton therapy indicate that relative biological effectiveness (RBE) is not constant, and it is directly related to the linear energy transfer (LET). The experimental assessment of LET with high resolution would be a powerful tool for minimizing the LET hot spots in intensity-modulated proton therapy, RBE- or LET-guided evaluation and optimization to achieve biologically optimized proton plans, verifying the theoretical predictions of variable proton RBE models, and so on. This could impact clinical outcomes by reducing toxicities in organs at risk. PURPOSE: The present work shows the first 2D LET maps obtained at a proton therapy facility using the double scattering delivery mode in clinical conditions by means of new silicon 3D-cylindrical microdetectors. METHODS: The device consists of a matrix of 121 independent silicon-based detectors that have 3D-cylindrical electrodes of 25-µm diameter and 20-µm depth, resulting each one of them in a well-defined micrometric radiation sensitive volume etched inside the silicon. They have been specifically designed for a hadron therapy, improving the performance of current silicon-based microdosimeters. Microdosimetry spectra were obtained at different positions of the Bragg curve by using a water-equivalent phantom along an 89-MeV pristine proton beam generated in the Y1 proton passive scattering beamline of the Orsay Proton Therapy Centre (Institut Curie, France). RESULTS: Microdosimetry 2D-maps showing the variation of the lineal energy with depth in the three dimensions were obtained in situ during irradiation at clinical fluence rates (∼108  s-1  cm-2 ) for the first time with a spatial resolution of 200 µm, the highest achieved in the transverse plane so far. The experimental results were cross-checked with Monte Carlo simulations and a good agreement between the spectra shapes was found. The experimental frequency-mean lineal energy values in silicon were 1.858 ± 0.019 keV µm-1 at the entrance, 2.61 ± 0.03 keV µm-1 at the proximal distance, 4.97 ± 0.05 keV µm-1 close to the Bragg peak, and 8.6 ± 0.1 keV µm-1 at the distal edge. They are in good agreement with the expected trends in the literature in clinical proton beams. CONCLUSIONS: We present the first 2D microdosimetry maps obtained in situ during irradiation at clinical fluence rates in proton therapy. Our results show that the arrays of 3D-cylindrical microdetectors are a reliable microdosimeter to evaluate LET maps not only in the longitudinal axis of the beam, but also in the transverse plane allowing for LET characterization in three dimensions. This work is a proof of principle showing the capacity of our system to deliver LET 2D maps. This kind of experimental data is needed to validate variable proton RBE models and to optimize LET-guided plans.

Cardiotoxicity model-based patient selection for Hodgkin lymphoma proton therapy.

INTRODUCTION: Hodgkin lymphoma (HL) is a highly curable hematological malignancy. Consolidation radiation therapy techniques have made significant progresses to improve organ-at-risk sparing in order to reduce late radiation-induced toxicity. Recent technical breakthroughs notably include intensity modulated proton therapy (IMPT), which has demonstrated a major dosimetric benefit at the cardiac level for mediastinal HL patients. However, its implementation in clinical practice is still challenging, notably due to the limited access to proton therapy facilities. In this context, the purpose of this study was to estimate the benefit of IMPT for HL proton therapy for diverse cardiac adverse events and to propose a general frame for mediastinal HL patient selection strategy for IMPT based on cardiotoxicity reduction, patient clinical factors, and IMPT treatment availability. MATERIAL AND METHODS: This retrospective dosimetric study included 30 mediastinal HL patients treated with VMAT. IMPT plans were generated on the initial simulation scans. Dose to the heart, to the left ventricle and to the valves were retrieved to calculate the relative risk (RR) of ischemic heart disease (IHD), congestive heart failure (CHF) and valvular disease (VD). Composite relative risk reduction (cRRR) of late cardiotoxicity, between VMAT and IMPT, were calculated as the weighted mean of relative risk reduction for IHD, CHF and VD, calculated across a wide range of cardiovascular risk factor combinations. The proportion of mediastinal HL patients who could benefit from IMPT was estimated in European countries, based on the country population and on the number of active gantries, to propose country-specific cRRR thresholds for patient selection. RESULTS: Compared with VMAT, IMPT significantly reduced average mean doses to the heart (2.36 Gy vs 0.99 Gy, p < 0.01), to the left ventricle (0.67 Gy vs 0.03, p < 0.01) and to the valves (1.29 Gy vs. 0.06, p < 0.01). For a HL patient without cardiovascular risk factor other than anthracycline-based chemotherapy, the relative risks of late cardiovascular complications were significantly lower after IMPT compared with VMAT for ischemic heart disease (1.07 vs 1.17, p < 0.01), for congestive heart failure (2.84 vs. 3.00, p < 0.01), and for valvular disease (1.01 vs. 1.06, p < 0.01). The median cRRR of cardiovascular adverse events with IMPT was 4.8%, ranging between 0.1% and 30.5%, depending on the extent of radiation fields and on the considered cardiovascular risk factors. The estimated proportion of HL patients currently treatable with IMPT in European countries with proton therapy facilities ranged between 8.0% and 100% depending on the country, corresponding to cRRR thresholds ranging from 24.0% to 0.0%. CONCLUSION: While a statistically significant clinical benefit is theoretically expected for ischemic heart disease, cardiac heart failure and valvular disease for mediastinal HL patients with IMPT, the overall cardiotoxicity risk reduction is notable only for a minority of patients. In the context of limited IMPT availability, this study proposed a general model-based selection approach for mediastinal HL patient based on calculated cardiotoxicity reduction, taking into consideration patient clinical characteristics and IMPT facility availability.

Preclinical dosimetry in proton minibeam radiation therapy: Robustness analysis and guidelines.

PURPOSE: Proton minibeam radiation therapy (pMBRT) is a new radiotherapy approach that has shown a significant increase in the therapeutic window in glioma-bearing rats compared to conventional proton therapy. The dosimetry of pMBRT is challenging and error prone due to the submillimetric beamlet sizes used. The aim of this study was to perform a robustness analysis on the setup parameters utilized in current preclinical trials and provide guidelines for reproducible dosimetry. The results of this work are intended to guide upcoming implementations of pMBRT worldwide, as well as pave the way for future clinical implementations. METHODS: Monte Carlo simulations and experimental data were used to evaluate the impact of variations in setup parameters and uncertainties in collimator specifications on lateral pMBRT dose distributions. The value of each parameter was modified individually to evaluate their effect on dose distributions. Experimental dosimetry was performed by means of high-resolution detectors, that is, radiochromic films, the IBA Razor and the Microdiamond detector. New guidelines were proposed to optimize the experimental setup in pMBRT studies and perform reproducible dosimetry. RESULTS: The sensitivity of dose distributions to uncertainties and variations in setup parameters was quantified. Quantities that define pMBRT lateral profiles (i.e., the peak-to-valley dose ratio [PVDR], peak and valley doses, and peak width) are significantly influenced by small-scale fluctuations in several of those parameters. The setup implemented at the Orsay proton therapy center for pMBRT irradiation was optimized to increase PVDRs and peak symmetry. In addition, we proposed guidelines to perform accurate and reproducible dosimetry in preclinical studies. CONCLUSIONS: This study revealed the importance of adopting guidelines and protocols tailored to the distinct dose delivery method and dose distributions in pMBRT. This new methodology leads to reproducible dosimetry, which is imperative in preclinical trials. The results and guidelines presented in this manuscript can ease the initiation of pMBRT investigations in other centers.

Clinical and technical challenges of cancer reirradiation: Words of wisdom.

Since the development of new radiotherapy techniques that have improved healthy tissue sparing, reirradiation (reRT) has become possible. The selection of patients eligible for reRT is complex given that it can induce severe or even fatal side effects. The first step should therefore be to assess, in the context of multidisciplinary staff meeting, the patient's physical status, the presence of sequelae resulting from the first irradiation and the best treatment option available. ReRT can be performed either curatively or palliatively to treat a cancer-related symptom that is detrimental to the patient's quality of life. The selected techniques for reRT should provide the best protection of healthy tissue. The construction of target volumes and the evaluation of constraints regarding the doses that can be used in this context have not yet been fully codified. These points raised in the literature suggest that randomized studies should be undertaken to answer pending questions.

A Comprehensive Analysis of the Relationship Between Dose Rate and Biological Effects in Preclinical and Clinical Studies, From Brachytherapy to Flattening Filter Free Radiation Therapy and FLASH Irradiation.

PURPOSE: For many years, the effect of dose rate (DR) was considered negligible in external beam radiation therapy (EBRT) until very-high DR (>10 Gy/min) became possible and ultrahigh DR (>40 Gy/s) showed dramatic protection of normal tissues in preclinical experiments. We propose a critical review of preclinical and clinical studies to investigate the biological and clinical effects of DR variation in the range covering brachytherapy to flattening filter free EBRT and FLASH. METHODS AND MATERIALS: Preclinical and clinical studies investigating biological and clinical DR effects were reviewed extensively. We also conducted an in silico study to assess the effect of pulse DR (DRp), taking into account the mean time between 2 tracks during the pulse. RESULTS: Preclinical studies have shown that an increase in DR in the range of 0.01 to 20 Gy/min (not including ultralow or ultrahigh DR) resulted in decreased survival of both normal and tumor cells. This effect was attributed primarily to increasingly unrepaired "sublethal" DNA damage with increasing the DR. However, the models and irradiation conditions have often been very different from one radiobiological study to another. Moreover, the physical parameters on the spatial and temporal microstructure of the beam were not considered systematically. In particular, the DRp was rarely mentioned. The in silico studies showed that for the same average DR, increasing DRp induced an increase of mean track rates. These results could explain the presence of more complex damage when the DRp was increased within the range of DR considered, in relation to the time-dependent probability of accumulating unrepaired, "sublethal" DNA lesions in close proximity. CONCLUSIONS: Knowledge of the beam microstructure is critical to understanding the biological impact and the clinical outcomes of radiation at the DR commonly used in radiation therapy.

Development of Simplified Auto-Segmentable Functional Cardiac Atlas.

PURPOSE: There is increasing evidence that radiation doses to cardiac substructures are associated with cardiac adverse events. Manual delineation of cardiac substructures is time-consuming, and auto-segmentation of cardiac substructure atlases has consequently been evaluated. However, proper automatic delineation of small substructures, such as the left anterior descending coronary artery, is challenging, and auto-segmentation of cardiac conduction system substructures has never been evaluated, despite multiple reports of radiation-induced arrhythmia after thoracic irradiations. The aim of this study was to propose and evaluate a simplified auto-segmentable functional cardiac atlas. METHODS AND MATERIALS: We created a cardiac substructure atlas based on 20 computed tomography scans from patients with breast cancer comprising the 4 cardiac cavities, a high-risk cardiac zone as a left anterior descending coronary artery surrogate, and the 2 cardiac conduction nodes. Automatic delineation of this atlas by an atlas-based auto-segmentation algorithm was evaluated on a validation data set, consisting of 20 additional computed tomography scans. Dice similarity coefficients were used to evaluate the concordance level between the manual and the automatic contours; a dosimetric comparison between mean and maximum doses to the manual and to the auto-segmented substructures was additionally performed, based on intensity modulated radiation therapy treatment plans of the patients of the validation set. RESULTS: Average dice similarity coefficient values were 0.78 for the 4 cardiac cavities, 0.65 for the high-risk cardiac zones, 0.56 for the sinoatrial node, and 0.15 for the atrioventricular node. Compared with manual contours, auto-segmented substructures were slightly smaller but the dosimetric parameters were similar. CONCLUSIONS: We proposed a simplified functional cardiac atlas that included the cardiac conduction system and circumvented coronary delineation difficulties by using a surrogate high-risk cardiac zone. Most cardiac substructures were associated with acceptable atlas-based auto-segmentation properties. Such an atlas could be used for epidemiologic studies and for clinical practice.

Towards harmonizing clinical linear energy transfer (LET) reporting in proton radiotherapy: a European multi-centric study.

BACKGROUND: Clinical data suggest that the relative biological effectiveness (RBE) in proton therapy (PT) varies with linear energy transfer (LET). However, LET calculations are neither standardized nor available in clinical routine. Here, the status of LET calculations among European PT institutions and their comparability are assessed. MATERIALS AND METHODS: Eight European PT institutions used suitable treatment planning systems with their center-specific beam model to create treatment plans in a water phantom covering different field arrangements and fulfilling commonly agreed dose objectives. They employed their locally established LET simulation environments and procedures to determine the corresponding LET distributions. Dose distributions D1.1 and DRBE assuming constant and variable RBE, respectively, and LET were compared among the institutions. Inter-center variability was assessed based on dose- and LET-volume-histogram parameters. RESULTS: Treatment plans from six institutions fulfilled all clinical goals and were eligible for common analysis. D1.1 distributions in the target volume were comparable among PT institutions. However, corresponding LET values varied substantially between institutions for all field arrangements, primarily due to differences in LET averaging technique and considered secondary particle spectra. Consequently, DRBE using non-harmonized LET calculations increased inter-center dose variations substantially compared to D1.1 and significantly in mean dose to the target volume of perpendicular and opposing field arrangements (p < 0.05). Harmonizing LET reporting (dose-averaging, all protons, LET to water or to unit density tissue) reduced the inter-center variability in LET to the order of 10-15% within and outside the target volume for all beam arrangements. Consequentially, inter-institutional variability in DRBE decreased to that observed for D1.1. CONCLUSION: Harmonizing the reported LET among PT centers is feasible and allows for consistent multi-centric analysis and reporting of tumor control and toxicity in view of a variable RBE. It may serve as basis for harmonized variable RBE dose prescription in PT.

Hadrontherapy techniques for breast cancer.

Radiotherapy plays a key role in breast cancer treatment, and recent technical advances have been made to improve the therapeutic window by limiting the risk of radiation-induced toxicity or by increasing tumor control. Hadrontherapy is a form a radiotherapy relying on particle beams; compared with photon beams, particle beams have specific physical, radiobiological and immunological properties, which can be valuable in diverse clinical situations. To date, available hadrontherapy techniques for breast cancer irradiation include proton therapy, carbon ion radiation therapy, fast neutron therapy and boron neutron capture therapy. This review analyzes the current rationale and level of evidence for each hadrontherapy technique for breast cancer.

Biological Rationale and Clinical Evidence of Carbon Ion Radiation Therapy for Adenoid Cystic Carcinoma: A Narrative Review.

Adenoid cystic carcinoma (ACC) is a rare, basaloid, epithelial tumor, arising mostly from salivary glands. Radiation therapy can be employed as a single modality for unresectable tumors, in an adjuvant setting after uncomplete resection, in case of high-risk pathological features, or for recurrent tumors. Due to ACC intrinsic radioresistance, high linear energy transfer (LET) radiotherapy techniques have been evaluated for ACC irradiation: while fast neutron therapy has now been abandoned due to toxicity concerns, charged particle beams such as protons and carbon ions are at present the beams used for hadron therapy. Carbon ion radiation therapy (CIRT) is currently increasingly used for ACC irradiation. The aim of this review is to describe the immunological, molecular and clinicopathological bases that support ACC treatment with CIRT, as well as to expose the current clinical evidence that reveal the advantages of using CIRT for treating ACC.

First Evaluation of Temporal and Spatial Fractionation in Proton Minibeam Radiation Therapy of Glioma-Bearing Rats.

(1) Background: Proton minibeam radiation therapy (pMBRT) is a new radiotherapy technique using spatially modulated narrow proton beams. pMBRT results in a significantly reduced local tissue toxicity while maintaining or even increasing the tumor control efficacy as compared to conventional radiotherapy in small animal experiments. In all the experiments performed up to date in tumor bearing animals, the dose was delivered in one single fraction. This is the first assessment on the impact of a temporal fractionation scheme on the response of glioma-bearing animals to pMBRT. (2) Methods: glioma-bearing rats were irradiated with pMBRT using a crossfire geometry. The response of the irradiated animals in one and two fractions was compared. An additional group of animals was also treated with conventional broad beam irradiations. (3) Results: pMBRT delivered in two fractions at the biological equivalent dose corresponding to one fraction resulted in the highest median survival time, with 80% long-term survivors free of tumors. No increase in local toxicity was noted in this group with respect to the other pMBRT irradiated groups. Conventional broad beam irradiations resulted in the most severe local toxicity. (4) Conclusion: Temporal fractionation increases the therapeutic index in pMBRT and could ease the path towards clinical trials.

Back to the Future: Very High-Energy Electrons (VHEEs) and Their Potential Application in Radiation Therapy.

The development of innovative approaches that would reduce the sensitivity of healthy tissues to irradiation while maintaining the efficacy of the treatment on the tumor is of crucial importance for the progress of the efficacy of radiotherapy. Recent methodological developments and innovations, such as scanned beams, ultra-high dose rates, and very high-energy electrons, which may be simultaneously available on new accelerators, would allow for possible radiobiological advantages of very short pulses of ultra-high dose rate (FLASH) therapy for radiation therapy to be considered. In particular, very high-energy electron (VHEE) radiotherapy, in the energy range of 100 to 250 MeV, first proposed in the 2000s, would be particularly interesting both from a ballistic and biological point of view for the establishment of this new type of irradiation technique. In this review, we examine and summarize the current knowledge on VHEE radiotherapy and provide a synthesis of the studies that have been published on various experimental and simulation works. We will also consider the potential for VHEE therapy to be translated into clinical contexts.

Hadrontherapy for Thymic Epithelial Tumors: Implementation in Clinical Practice.

Radiation therapy is part of recommendations in the adjuvant settings for advanced stage or as exclusive treatment in unresectable thymic epithelial tumors (TETs). However, first-generation techniques delivered substantial radiation doses to critical organs at risk (OARs), such as the heart or the lungs, resulting in noticeable radiation-induced toxicity. Treatment techniques have significantly evolved for TET irradiation, and modern techniques efficiently spare normal surrounding tissues without negative impact on tumor coverage and consequently local control or patient survival. Considering its dosimetric advantages, hadrontherapy (which includes proton therapy and carbon ion therapy) has proved to be worthwhile for TET irradiation in particular for challenging clinical situations such as cardiac tumoral involvement. However, clinical experience for hadrontherapy is still limited and mainly relies on small-size proton therapy studies. This critical review aims to analyze the current status of hadrontherapy for TET irradiation to implement it at a larger scale.