Double scattering and pencil beam scanning Monte Carlo workflows for proton therapy retrospective studies on radiation-induced toxicities.

PURPOSE: Monte Carlo (MC) simulations can be used to accurately simulate dose and linear energy transfers (LET) distributions, thereby allowing for the calculation of the relative biological effectiveness (RBE) of protons. We present hereby the validation and implementation of a workflow for the Monte Carlo modelling of the double scattered and pencil beam scanning proton beamlines at our institution. METHODS: The TOPAS/Geant4 MC model of the clinical nozzle has been comprehensively validated against measurements. The validation also included a comparison between simulated clinical treatment plans for four representative patients and the clinical treatment planning system (TPS). Moreover, an in-house tool implemented in Python was tested to assess the variable RBE-weighted dose in proton plans, which was illustrated for a patient case with a developing radiation-induced toxicity. RESULTS: The simulated range and modulation width closely matches the measurements. Gamma-indexes (3%/3mm 3D), which compare the TPS and MC computations, showed a passing rate superior to 98%. The calculated RBE-weighted dose presented a slight increase at the necrosis location, within the PTV margins. This indicates the need for reporting on the physical and biological effects of irradiation in high dose regions, especially at the healthy tissues and increased LET distributions location. CONCLUSION: The results demonstrate that the Monte Carlo method can be used to independently validate a TPS calculation, and to estimate LET distributions. The features of the in-house tool can be used to correlate LET and RBE-weighted dose distributions with the incidence of radiation-induced toxicities following proton therapy treatments.

Neutron brachytherapy in the modern era: Indications and evidence.

Hadrontherapy is a form of radiation therapy (RT) that relies on heavy particles, such as proton, heavy ions, or neutrons, to enhance anti-tumoral efficacy based on their specific dosimetric and radio-biological properties. Neutrons are characterized by specific radiobiological properties that might deserve greater consideration, including the high linear energy transfer and the low oxygen enhancement ratio. Neutron brachytherapy, relying on interstitial or intracavitary neutron sources, has been developed since the 1950s using Californium-252 (252Cf) as a mixed emitter of fission fast neutrons and γ-photos. However, the place of NBT in the era of modern radiation therapy is yet to be precisely defined. In this systematic review, we aim to provide an up-to-date analysis of current experience and clinical evidence of NBT in the XXI th century, by answering the following clinical questions: How is NBT currently delivered? What are the current efficacy data and tolerance profiles of NBT?

Ion recombination correction factors and detector comparison in a very-high dose rate proton scanning beam.

PURPOSE: Accurate dosimetry is paramount to study the FLASH biological effect since dose and dose rate are critical dosimetric parameters governing its underlying mechanisms. With the goal of assessing the suitability of standard clinical dosimeters in a very-high dose rate (VHDR) experimental setup, we evaluated the ion collection efficiency of several commercially available air-vented ionization chambers (IC) in conventional and VHDR proton irradiation conditions. METHODS: A cyclotron at the Orsay Proton Therapy Center was used to deliver VHDR pencil beam scanning irradiation. Ion recombination correction factors (ks) were determined for several detectors (Advanced Markus, PPC05, Nano Razor, CC01) at the entrance of the plateau and at the Bragg peak, using the Niatel model, the Two-voltage method and Boag's analytical formula for continuous beams. RESULTS: Mean dose rates ranged from 4 Gy/s to 385 Gy/s, and instantaneous dose rates up to 1000 Gy/s were obtained with the experimental set-up. Recombination correction factors below 2 % were obtained for all chambers, except for the Nano Razor, at VHDRs with variations among detectors, while ks values were significantly smaller (0.8 %) for conventional dose rates. CONCLUSIONS: While the collection efficiency of the probed ICs in scanned VHDR proton therapy is comparable to those in the conventional regime with recombination coefficiens smaller than 1 % for mean dose rates up to 177 Gy/s, the reduction in collection efficiency for higher dose rates cannot be ignored when measuring the absorbed dose in pre-clinical proton scanned FLASH experiments and clinical trials.

[The role of proton therapy in esophageal cancer]. / Le rôle de la protonthérapie dans les cancers de l'oesophage.

Because of the physical properties of proton beam radiation therapy (PT), which allows energy to be deposited at a specific depth with a rapid energy fall-off beyond that depth, PT has several theoretical advantages over photon radiation therapy for esophageal cancer (EC). Protons have the potential to reduce the dose to healthy tissue and to more safely allow treatment of tumors near critical organs, dose escalation, trimodal treatment, and re-irradiation. In recent years, larger multicenter retrospective studies have been published showing excellent survival rates, lower than expected toxicities and even better outcomes with PT than with photon radiotherapy even using IMRT or VMAT techniques. Although PT was associated with reduced toxicities, postoperative complications, and hospital stays compared to photon radiation therapy, these studies all had inherent biases in relation with patient selection for PT. These observations were recently confirmed by a randomized phase II study in locally advanced EC that showed significantly reduced toxicities with protons compared with IMRT. Currently, two randomized phase III trials (NRG-GI006 in the US and PROTECT in Europe) are being conducted to confirm whether protons could become the standard of care in locally advanced and resectable esophageal cancers.

Secondary neutron dose contribution from pencil beam scanning, scattered and spatially fractionated proton therapy.

The Orsay Proton therapy Center (ICPO) has a long history of intracranial radiotherapy using both double scattering (DS) and pencil beam scanning (PBS) techniques, and is actively investigating a promising modality of spatially fractionated radiotherapy using proton minibeams (pMBRT). This work provides a comprehensive comparison of the organ-specific secondary neutron dose due to each of these treatment modalities, assessed using Monte Carlo (MC) algorithms and measurements. A MC model of a universal nozzle was benchmarked by comparing the neutron ambient dose equivalent,H*(10), in the gantry room with measurements obtained using a WENDI-II counter. The secondary neutron dose was evaluated for clinically relevant intracranial treatments of patients of different ages, in which secondary neutron doses were scored in anthropomorphic phantoms merged with the patients' images. The MC calculatedH*(10) values showed a reasonable agreement with the measurements and followed the expected tendency, in which PBS yields the lowest dose, followed by pMBRT and DS. Our results for intracranial treatments show that pMBRT yielded a higher secondary neutron dose for organs closer to the target volume, while organs situated furthest from the target volume received a greater quantity of neutrons from the passive scattering beam line. To the best of our knowledge, this is the first study to compare MC secondary neutron dose estimates in clinical treatments between these various proton therapy modalities and to realistically quantify the secondary neutron dose contribution of clinical pMBRT treatments. The method established in this study will enable epidemiological studies of the long-term effects of intracranial treatments at ICPO, notably radiation-induced second malignancies.

Future technological developments in proton therapy - A predicted technological breakthrough.

In the current spectrum of cancer treatments, despite high costs, a lack of robust evidence based on clinical outcomes or technical and radiobiological uncertainties, particle therapy and in particular proton therapy (PT) is rapidly growing. Despite proton therapy being more than fifty years old (first proposed by Wilson in 1946) and more than 220,000 patients having been treated with in 2020, many technological challenges remain and numerous new technical developments that must be integrated into existing systems. This article presents an overview of on-going technical developments and innovations that we felt were most important today, as well as those that have the potential to significantly shape the future of proton therapy. Indeed, efforts have been done continuously to improve the efficiency of a PT system, in terms of cost, technology and delivery technics, and a number of different developments pursued in the accelerator field will first be presented. Significant developments are also underway in terms of transport and spatial resolution achievable with pencil beam scanning, or conformation of the dose to the target: we will therefore discuss beam focusing and collimation issues which are important parameters for the development of these techniques, as well as proton arc therapy. State of the art and alternative approaches to adaptive PT and the future of adaptive PT will finally be reviewed. Through these overviews, we will finally see how advances in these different areas will allow the potential for robust dose shaping in proton therapy to be maximised, probably foreshadowing a future era of maturity for the PT technique.

Metallic implants and CT artefacts in the CTV area: Where are we in 2020?

Radiation therapy (RT) is one of the main modalities of cancer treatment worldwide with computed tomography (CT), as the most commonly used imaging method for treatment planning system (TPS). Image reconstruction errors may greatly affect all the radiation therapy planning process, such as target delineation, dose calculation and delivery, particularly with particle therapy. Metallic implants, such as hip and spinal implants, and dental filling significantly deteriorate image quality. These hardware structures are often very complex in geometry leading to geometric complex artefacts in the clinical target volume (CTV) area, rendering the delineation of CTV challenging. In our review, we focus on the methods to overcome artefact consequences on CTV delineation: 1- medical approaches anticipating issues associated with imaging artefacts during preoperative multidisciplinary discussions while following standard recommendations; 2- common metal artefact reduction (MAR) methods such as manually override artefact regions, ballistics avoiding beam paths through implanted materials, megavoltage-CT (MVCT); 3- prospects with radiolucent implants, MAR algorithms and various methods of dual energy computed tomography (DECT). Despite substantial and broad evidence for their benefits, there is still no universal solution for cases involving implanted metallic devices. There is still a high need for research efforts to adapt technologies to our issue: "how do I accurately delineate the ideal CTV in a metal artefact area?"

Exploiting the full potential of proton therapy: An update on the specifics and innovations towards spatial or temporal optimisation of dose delivery.

Prescription and delivery of protons are somewhat different compared to photons and may influence outcomes (tumour control and toxicity). These differences should be taken into account to fully exploit the clinical potential of proton therapy. Innovations in proton therapy treatment are also required to widen the therapeutic window and determine appropriate populations of patients that would benefit from new treatments. Therefore, strategies are now being developed to reduce side effects to critical normal tissues using alternative treatment configurations and new spatial or temporal-driven optimisation approaches. Indeed, spatiotemporal optimisation (based on flash, proton minibeam radiation therapy or hypofractionated delivery methods) has been gaining some attention in proton therapy as a mean of improving (biological and physical) dose distribution. In this short review, the main differences in planning and delivery between protons and photons, as well as some of the latest developments and methodological issues (in silico modelling) related to providing scientific evidence for these new techniques will be discussed.

A diamond guard ring microdosimeter for ion beam therapy.

A single crystal chemical vapor deposition diamond-based microdosimeter prototype featuring an array of micro-sensitive volumes (µSVs) and surrounded by a so-called guard ring (GR) electrode has been fabricated using various microfabrication techniques available at Diamond Sensors Laboratory of CEA, Saclay. The GR microdosimeter was irradiated by a raster scanning method with 2 MeV proton microbeams. The charge transport properties of the GR sensor were determined with sub-micron spatial resolution by measuring the charge collection efficiency (CCE), the µSV geometry, and the pulse-height spectra. The response of the microdosimeter showed a well-defined and homogeneously active µSV. Appropriate biasing of the µSV structures led toward a full CCE for protons with lineal energies of ∼46 keV/µm. This shows the GR microdosimeter's great potential for applications in microdosimetry in clinical beam conditions.

First proton minibeam radiation therapy treatment plan evaluation.

Proton minibeam radiation therapy (pMBRT) is a novel dose delivery method based on spatial dose fractionation. pMBRT has been shown to be promising in terms of reduced side effects and superior tumour control in high-grade glioma-bearing rats compared to standard irradiation. These findings, together with the recent optimized implementation of pMBRT in a clinical pencil beam scanning system, have triggered reflection on the possible application to patient treatments. In this context, the present study was designed to conduct a first theoretical investigation of the clinical potential of this technique. For this purpose, a dedicated dose engine was developed and used to evaluate two clinically relevant patient treatment plans (high-grade glioma and meningioma). Treatment plans were compared with standard proton therapy plans assessed by means of a commercial treatment planning system (ECLIPSE-Varian Medical systems) and Monte Carlo simulations. A multislit brass collimator consisting of 0.4 mm wide slits separated by a centre-to-centre distance of 4 or 6 mm was placed between the nozzle and the patient to shape the planar minibeams. For each plan, spread-out Bragg peaks and homogeneous dose distributions (±7% dose variations) can be obtained in target volumes. The Peak-to-Valley Dose Ratios (PVDR) were evaluated between 9.2 and 12.8 at a depth of 20 mm for meningioma and glioma, respectively. Dose volume histograms (DVHs) for target volumes and organs at risk were quantitatively compared, resulting in a slightly better target homogeneity with standard PT than with pMBRT plans, but similar DVHs for deep-seated organs-at-risk and lower average dose for shallow organs. The proposed delivery method evaluated in this work opens the way to an effective treatment for radioresistant tumours and will support the design of future clinical research.

Independent 6D quality assurance of stereotactic radiotherapy repositioning on linacs.

PURPOSE: A high level of accuracy while positioning the patient is mandatory for frameless stereotactic radiotherapy (SRT), as large doses in multiple fractions can be delivered near organs at risk. The objective of this study is to propose an end-to-end quality assurance method to verify that submillimetre alignment can be achieved with stereotactic conventional linacs. METHODS: We used a TrueBeam® linear accelerator equipped with a 6DOF robotic couch. The "ISO Cube" phantom was used with a homemade stand designed to generate known translational and rotational offsets. A reference CT scan was performed with straight alignment of the phantom. The procedure introduced 1.6° angular offset for the couch pitch and roll, at various gantry angles. The couch base was also moved between 0° and 270°. We compared the results with the daily machine performance check tests (MPC, Varian). RESULTS: The mean isocentre size, MV and kV imager offsets were found to agree to within 0.1mm, 0.1mm and 0.3mm respectively, and were in close agreement between the methods. For a total four months data collection period, the mean deviation between requested and measured 6DOF couch shifts was 0.6mm and 0.2°. Errors on field size were smaller than 1mm for 97.7% of the 324 data points. CONCLUSION: Results demonstrate that the linac equipped with a 6DOF robotic positioner and CBCT imaging satisfies requirements for SRT. Our methodology, based on a modified Winston-Lutz quality control, allowed us to quantitatively assess end-to-end accuracy of a linac in order to safely deliver SRT.

Experimental characterisation of a proton kernel model for pencil beam scanning techniques.

The aim of this work is to perform Monte Carlo simulations of a proton pencil beam scanning machine, characterise the low-dose envelope of scanned proton beams and assess the differences between various approximations for nozzle geometry. Measurements and Monte Carlo simulations were carried out in order to describe the dose distribution of a proton pencil beam in water for energies between 100 and 220 MeV. Dose distributions were simulated by using a Geant4 Monte Carlo platform (TOPAS), and were measured in water using a two-dimensional ion chamber array detector. The beam source in air was adjusted for each configuration. Double Gaussian parameterisation was proposed for definition of the beam source model in order to improve simulations starting at the nozzle exit. Absolute dose distributions and field size factors were measured and compared with simulations. The influence of the high-density components present in the treatment nozzle was also investigated by analysis of proton phase spaces at the nozzle exit. An excellent agreement was observed between experimental dose distributions and simulations for energies higher than 160 MeV. However, minor differences were observed between 100 and 160 MeV, suggesting poorer modelling of the beam when the full treatment head was not taken into account. We found that the first ionisation chamber was the main cause of the tail component observed for low proton beam energies. In this work, various parameterisations of proton sources were proposed, thereby allowing reproduction of the low-dose envelope of proton beams and excellent agreement with measured data.

Spatial fractionation of the dose in proton therapy: Proton minibeam radiation therapy.

In radiation therapy, a renewed interest is emerging for the study of spatially fractionated irradiation. In this article, a few applications using spatial fractionation of the dose will be discussed with a focus on proton minibeam radiation therapy. Examples of calculated dose (1D profiles and 2D dose distributions) and biological evidence obtained so far will be presented for various spatially fractionated techniques GRID, micro- and minibeam radiation therapy. Recent results demonstrating that proton minibeam radiation therapy leads to an increase in normal tissues sparing will be discussed, which opens the door to a dose escalation in the tumour and a possibly efficient treatment of very radioresistant tumours.

Proton radiography with a commercial range telescope detector using dedicated post processing methods.

Proton transmission imaging uses protons with high enough energy to fully traverse the phantom/patient and to be captured in a suitable detector placed behind it. The measured residual energy or residual range provide a direct estimate of the water equivalent thickness (WET) of the image volume. Requirements for proton imaging to be exploitable in clinical practice include: sufficient WET accuracy and integrability into the treatment room and the clinical workflow, as well as an acceptably low dose to the patient and a sufficient spatial resolution. In this work, we report on experiments performed at the Institut Curie-Proton therapy center in Orsay (IC-CPO), France, using a commercial range telescope commonly employed for quality assurance measurements. The purpose was to keep the experimental set-up as simple as possible and to achieve nonetheless high WET accuracy radiographies by developing and applying dedicated post processing methods. We explain these methods in detail and discuss their performance. We assess the WET accuracy based on two different reference phantoms: a CIRS electron density phantom with tissue equivalent inserts and a homogeneous step phantom. We find an agreement between the measured and the reference WET values of 0.2-0.5 mm. The lowest investigated dose was 10 mGy per acquisition. It could be lowered by modifying the irradiation plan and lowering the beam current, though the latter would impose slight optimisations of the detector hardware. Our work suggests that proton radiographies with good WET accuracy can be obtained with a reasonable experimental effort that would facilitate integration into clinical routine.

Mechanisms of phosphene generation in ocular proton therapy as related to space radiation exposure.

Particle therapy provides an opportunity to study the human response to space radiation in ground-based facilities. On this basis, a study of light flashes analogous to astronauts' phosphenes reported by patients undergoing ocular proton therapy has been undertaken. The influence of treatment parameters on phosphene generation was investigated for 430 patients treated for a choroidal melanoma at the proton therapy centre of the Institut Curie (ICPO) in Orsay, France, between 2008 and 2011. 60% of them report light flashes, which are predominantly (74%) blue. An analysis of variables describing the patient's physiology, properties of the tumour and dose distribution shows that two groups of tumour and beam variables are correlated with phosphene occurrence. Physiology is found to have no influence on flash triggering. Detailed correlation study eventually suggests a possible twofold mechanism of phosphene generation based on (i) indirect Cerenkov light in the bulk of the eye due to nuclear interactions and radioactive decay and (ii) direct excitation of the nerve fibres in the back of the eye and/or radical excess near the retina.

Dosimetric characteristics of four PTW microDiamond detectors in high-energy proton beams.

Small diamond detectors are useful for the dosimetry of high-energy proton beams. However, linear energy transfer (LET) dependence has been observed in the literature with such solid state detectors. A novel synthetic diamond detector has recently become commercially available from the manufacturer PTW-Freiburg (PTW microDiamond type 60019). This study was designed to thoroughly characterize four microDiamond detectors in clinical proton beams, in order to investigate their response and their reproducibility in high LET regions. Very good dosimetric characteristics were observed for two of them, with good stability of their response (deviation less than 0.4% after a pre-irradiation dose of approximately 12 Gy), good repeatability (coefficient of variation of 0.06%) and a sensitivity of approximately 0.85 nC Gy(-1). A negligible dose rate dependence was also observed for these two microDiamonds with a deviation of the sensitivity less than 0.7% with respect to the one measured at the reference dose rate of 2.17 Gy min(-1), in the investigated dose rate range from 1.01 Gy min(-1) to 5.52 Gy min(-1). Lateral dose profile measurements showed the high spatial resolution of the microDiamond oriented with its stem perpendicular to the beam axis and with its small sensitive thickness of about 1 µm in the scanning profile direction. Finally, no significant LET dependence was found with these two diamond dosimeters in comparison to a reference ionization chamber (model IBA PPC05). These good results were in accordance to the literature. However, this study showed also a non reproducibility between the devices in terms of stability, sensitivity and LET dependence, since the two other microDiamonds characterized in this work showed different dosimetric characteristics making them not suitable for proton beam dosimetry with a maximum difference of the peak-to-plateau ratio of 6.7% relative to the reference ionization chamber in a clinical 138 MeV proton beam.

Influence of beam incidence and irradiation parameters on stray neutron doses to healthy organs of pediatric patients treated for an intracranial tumor with passive scattering proton therapy.

PURPOSE: In scattering proton therapy, the beam incidence, i.e. the patient's orientation with respect to the beam axis, can significantly influence stray neutron doses although it is almost not documented in the literature. METHODS: MCNPX calculations were carried out to estimate stray neutron doses to 25 healthy organs of a 10-year-old female phantom treated for an intracranial tumor. Two beam incidences were considered in this article, namely a superior (SUP) field and a right lateral (RLAT) field. For both fields, a parametric study was performed varying proton beam energy, modulation width, collimator aperture and thickness, compensator thickness and air gap size. RESULTS: Using a standard beam line configuration for a craniopharyngioma treatment, neutron absorbed doses per therapeutic dose of 63µGyGy(-1) and 149µGyGy(-1) were found at the heart for the SUP and the RLAT fields, respectively. This dose discrepancy was explained by the different patient's orientations leading to changes in the distance between organs and the final collimator where external neutrons are mainly produced. Moreover, investigations on neutron spectral fluence at the heart showed that the number of neutrons was 2.5times higher for the RLAT field compared against the SUP field. Finally, the influence of some irradiation parameters on neutron doses was found to be different according to the beam incidence. CONCLUSION: Beam incidence was thus found to induce large variations in stray neutron doses, proving that this parameter could be optimized to enhance the radiation protection of the patient.

An empirical model for calculation of the collimator contamination dose in therapeutic proton beams.

Collimators are used as lateral beam shaping devices in proton therapy with passive scattering beam lines. The dose contamination due to collimator scattering can be as high as 10% of the maximum dose and influences calculation of the output factor or monitor units (MU). To date, commercial treatment planning systems generally use a zero-thickness collimator approximation ignoring edge scattering in the aperture collimator and few analytical models have been proposed to take scattering effects into account, mainly limited to the inner collimator face component. The aim of this study was to characterize and model aperture contamination by means of a fast and accurate analytical model. The entrance face collimator scatter distribution was modeled as a 3D secondary dose source. Predicted dose contaminations were compared to measurements and Monte Carlo simulations. Measurements were performed on two different proton beam lines (a fixed horizontal beam line and a gantry beam line) with divergent apertures and for several field sizes and energies. Discrepancies between analytical algorithm dose prediction and measurements were decreased from 10% to 2% using the proposed model. Gamma-index (2%/1 mm) was respected for more than 90% of pixels. The proposed analytical algorithm increases the accuracy of analytical dose calculations with reasonable computation times.

Analytical linear energy transfer model including secondary particles: calculations along the central axis of the proton pencil beam.

In proton therapy, the relative biological effectiveness (RBE) depends on various types of parameters such as linear energy transfer (LET). An analytical model for LET calculation exists (Wilkens' model), but secondary particles are not included in this model. In the present study, we propose a correction factor, L sec, for Wilkens' model in order to take into account the LET contributions of certain secondary particles. This study includes secondary protons and deuterons, since the effects of these two types of particles can be described by the same RBE-LET relationship. L sec was evaluated by Monte Carlo (MC) simulations using the GATE/GEANT4 platform and was defined by the ratio of the LET d distributions of all protons and deuterons and only primary protons. This method was applied to the innovative Pencil Beam Scanning (PBS) delivery systems and L sec was evaluated along the beam axis. This correction factor indicates the high contribution of secondary particles in the entrance region, with L sec values higher than 1.6 for a 220 MeV clinical pencil beam. MC simulations showed the impact of pencil beam parameters, such as mean initial energy, spot size, and depth in water, on L sec. The variation of L sec with these different parameters was integrated in a polynomial function of the L sec factor in order to obtain a model universally applicable to all PBS delivery systems. The validity of this correction factor applied to Wilkens' model was verified along the beam axis of various pencil beams in comparison with MC simulations. A good agreement was obtained between the corrected analytical model and the MC calculations, with mean-LET deviations along the beam axis less than 0.05 keV µm(-1). These results demonstrate the efficacy of our new correction of the existing LET model in order to take into account secondary protons and deuterons along the pencil beam axis.

Use of gEUD for predicting ear and pituitary gland damage following proton and photon radiation therapy.

OBJECTIVE: To determine the relationship between the dose to the inner ear or pituitary gland and radiation-induced late effects of skull base radiation therapy. METHODS: 140 patients treated between 2000 and 2008 were considered for this study. Hearing loss and endocrine dysfunction were retrospectively reviewed on pre- and post-radiation therapy audiometry or endocrine assessments. Two normal tissue complication probability (NTCP) models were considered (Lyman-Kutcher-Burman and log-logistic) whose parameters were fitted to patient data using receiver operating characteristics and maximum likelihood analysis. The method provided an estimation of the parameters of a generalized equivalent uniform dose (gEUD)-based NTCP after conversion of dose-volume histograms to equivalent doses. RESULTS: All 140 patients had a minimum follow up of 26 months. 26% and 44% of patients experienced mild hearing loss and endocrine dysfunction, respectively. The fitted values for TD50 and γ50 ranged from 53.6 to 60.7 Gy and from 1.9 to 2.9 for the inner ear and were equal to 60.6 Gy and 4.9 for the pituitary gland, respectively. All models were ranked equal according to Akaike's information criterion. CONCLUSION: Mean dose and gEUD may be used as predictive factors for late ear and pituitary gland late complications after skull base proton and photon radiation therapy. ADVANCES IN KNOWLEDGE: In this study, we have reported mean dose effects and dose-response relationship of small organs at risk (partial volumes of the inner ear and pituitary gland), which could be useful to define optimal dose constraints resulting in an improved therapeutic ratio.