OBJECTIVE: Secondary breast cancer is a frequent late adverse event of mediastinal Hodgkin lymphoma radiotherapy. Secondary breast cancers overwhelmingly correspond to ductal carcinoma and develop from the glandular mammary tissue. In addition, during childhood, radiation overexposure of the glandular tissue may lead to a late breast hypotrophy at adult age. The aim of this study was to evaluate the radiation exposure to the glandular tissue in patients treated for mediastinal Hodgkin lymphoma with intensity-modulated proton therapy, in order to evaluate the potential dosimetric usefulness of its delineation for breast sparing.
METHODS: Sixteen consecutive intermediate-risk mediastinal female patients with Hodgkin lymphoma treated with consolidation radiation with deep inspiration breath hold intensity-modulated proton therapy to the total dose of 30Gy were included. Breasts were delineated according to the European Society for Radiotherapy and Oncology guidelines for treatment optimization (\"clinical organ at risk\"). The glandular tissue (\"glandular organ at risk\") was retrospectively contoured on the initial simulation CT scans based on Hounsfield unit (HU) values, using a range between -80HU and 500HU.
RESULTS: The mean and maximum doses delivered to the glandular organ at risk were significantly lower than the mean and maximum doses delivered to the clinical organ at risk, but were statistically correlated. Glandular organ at risk volumes were significantly smaller.
CONCLUSIONS: Optimizing the treatment plans on the clinical breast contours will systematically lead to overestimation of the dose received to the glandular tissue and, consequently, to an indistinct and involuntary improved glandular tissue sparing. As such, our findings do not support the consideration of the glandular tissue as an additional organ at risk when planning intensity-modulated proton therapy for mediastinal Hodgkin lymphoma in female patients.

OBJECTIVE: Radiation-induced optic neuropathy (RION) is rare but may lead to blindness. The mechanisms by which this occurs include endothelial and neuronal damage, but RION has been assessed very little in the case of extraocular tumors treated with high-energy proton therapy, the use of which is expanding worldwide. We assessed peripapillary microvascular changes by optical coherence tomography angiography (OCT-A) in patients undergoing high-energy proton therapy for para-optic intracranial or head and neck tumors.
METHODS: In this prospective institutional review board approved study, patients receiving>40Gy_RBE maximal PBT dose to their optic nerve between 2018 and 2020 underwent quantitative OCT-A analyses. ImageJ software was used to assess changes in the peripapillary superficial vascular complex (SVC) using vascular area density (VAD), vessel length density (VLD) and fractal dimension (FDsk). Uni- and multivariate analyses were performed.
RESULTS: Of 47 patients (78 eyes) with 29±6 months of follow-up (range 18-42), 29 patients (61.7%) had previously undergone surgery and 18 (32.1%) had microvascular abnormalities prior to proton therapy. Total radiotherapy dose was the most relevant factor in decreased peripapillary microvasculature. Duration of follow-up was associated with lower VAD (P=0.005) and mean retinal nerve fiber layer (RNFLm) thickness also decreased. There was no significant correlation between OCT-A changes and mean visual defect.
CONCLUSIONS: Peripapillary microvasculature changes may occur from tumor compression or surgery and proton therapy for extraocular tumors. OCT-A may provide quantitative and mechanistic insights into RION before the occurrence of clinical symptoms.

BACKGROUND: High energy proton therapy (HEP) is a form of radiation therapy using protons for extraocular tumors. Its ballistic properties are theoretically advantageous, but the real impact on the surrounding ocular tissues during cerebral and ENT irradiation is poorly documented. We describe three consecutive patients with corneal damage following such irradiation.
METHODS: Post-proton therapy neurotrophic keratitis (NK) is defined as corneal hypo/anesthesia responsible for an alteration of corneal trophicity and graded according to the Mackie classification, in terms of a prospective ophthalmological follow-up protocol for all patients with extraocular tumors treated with HEP.
RESULTS: Among 193 patients treated with HEP between 2018 and 2021 for extraocular tumors, three patients developed severe neurotrophic keratitis, i.e. 1.6% of treated patients. According to the Mackie classification, the three patients showed grade 3 NK less than one year after the conclusion of their HEP. These three patients underwent amniotic membrane grafting. They were placed on autologous serum eye drops. Two of the three patients had to be eviscerated. The dose to the cornea was greater than 50 Gray (Gy)_Relative biological effectiveness (RBE) in the three cases.
CONCLUSIONS: The diagnosis and etiological origin of neurotrophic keratitis are often difficult to establish. In these cases, the imputability of radiation therapy, proton therapy in our cases, in the development of neurotrophic keratitis was plausible based on the dosimetry of the patients, all of whom had anterior tumors with a poor prognosis requiring high tumoricidal doses.
CONCLUSIONS: Further studies to establish the impact of proton therapy on corneal sensitivity are necessary. However, this feedback and the multidisciplinary management of tumors can help to limit the risk of some complications of radiation therapy. Early diagnosis allows for appropriate management and could possibly minimize the anatomical and functional ocular complications of neurotrophic keratitis.

Rare central nervous system tumors are defined by an incidence rate of less than 6 cases per 100 000 individuals a year. It comprises a large panel of entities including medulloblastoma, glioneuronal tumors, solitary fibrous tumors, rare pituitary tumors, ependymal or embryonal tumors. The management of these tumors is not clearly defined and radiotherapy indications should be discussed at a multidisciplinary board. Image-guided and intensity-modulated radiation therapy should be proposed and MRI has a fundamental place in the treatment preparation. To avoid the occurrence of side effects, proton therapy is playing an increasingly role for the treatment of these tumors.

OBJECTIVE: 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.
CONCLUSIONS: 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.

Reirradiation of a tumor recurrence or second cancer in a previously irradiated area is challenging due to lack of high-quality physical, radiobiological, clinical data and inherent substantial risks of toxicity with cumulative dose and uncertain tissue recovery. Yet, major advances have been made in radiotherapy techniques, that have the potential to achieve cure while limiting severe toxicity rates, but still much research is necessary to better appraise the therapeutic index in such a complex situation.

OBJECTIVE: In radiotherapy, the dose and volumes of the irradiated normal tissues is correlated to the complication rate. We assessed the performances of low-energy proton therapy (ocular PT) with eye-dedicated equipment, high energy PT with pencil-beam scanning (PBS) or CyberKnifeR  -based stereotactic irradiation (SBRT).
METHODS: CT-based comparative dose distribution between external beam radiotherapy techniques was assessed using an anthropomorphic head phantom. The prescribed dose was 60Gy_RBE in 4 fractions to a typical posterior pole uveal melanoma. Clinically relevant structures were delineated, and doses were calculated using radiotherapy treatment planning softwares and measured using Gafchromic dosimetry films inserted at the ocular level.
RESULTS: Precision was significantly better with ocular PT than both PBS or SBRT in terms of beam penumbra (80%-20%: laterally 1.4 vs. ≥10mm, distally 0.8 vs. ≥2.5mm). Ocular PT duration was shorter, allowing eye gating and lid sparing more easily. Tumor was excellent with all modalities, but ocular PT resulted in more homogenous and conformal dose compared to PBS or SBRT. The maximal dose to ocular/orbital structures at risk was smaller and often null with ocular PT compared to other modalities. Mean dose to ocular/orbital structures was also lower with ocular PT. Structures like the lids and lacrimal punctum could be preserved with ocular PT using gaze orientation and lid retractors, which is easier to implement clinically than with the other modalities. The dose to distant organs was null with ocular PT and PBS, in contrast to SBRT.
CONCLUSIONS: ocular PT showed significantly improved beam penumbra, shorter treatment delivery time, better dose homogeneity, and reduced maximal/mean doses to critical ocular structures compared with other current external beam radiation modalities. Similar comparisons may be warranted for other tumor presentations.

OBJECTIVE: Radiotherapy with protons (PT) is a standard treatment of ocular tumors. It achieves excellent tumor control, limited toxicities, and the preservation of important functional outcomes, such as vision. Although PT may appear as one homogenous technique, it can be performed using dedicated ocular passive scattering PT or, increasingly, Pencil Beam Scanning (PBS), both with various degrees of patient-oriented customization.
UNASSIGNED: MEDICYC PT facility of Nice are detailed with respect to their technical, dosimetric, microdosimetric and radiobiological, patient and tumor-customization process of PT planning and delivery that are key. 6684 patients have been treated for ocular tumors (1991-2020). Machine characteristics (accelerator, beam line, beam monitoring) allow efficient proton extraction, high dose rate, sharp lateral and distal penumbrae, and limited stray radiation in comparison to beam energy reduction and subsequent straggling with high-energy PBS PT. Patient preparation before PT includes customized setup and image-guidance, CT-based planning, and ocular PT software modelling of the patient eye with integration of beam modifiers. Clinical reports have shown excellent tumor control rates (∼95%), vision preservation and limited toxicity rates (papillopathy, retinopathy, neovascular glaucoma, dry eye, madarosis, cataract).
RESULTS: Although demanding, dedicated ocular PT has proven its efficiency in achieving excellent tumor control, OAR sparing and patient radioprotection. It is therefore worth adaptations of the equipments and practice.
CONCLUSIONS: Some of these adaptations can be transferred to other PT centers and should be acknowledeged when using non-PT options.

We present the update of the recommendations of the French society of radiation oncology on soft tissue sarcomas. Currently, the initial management of sarcomas is very important as it may impact on patients\' quality of life, especially in limb soft tissue sarcomas, and on overall survival in trunk sarcomas. Radiotherapy has to be discussed within a multidisciplinary board meeting with results of biopsy, eventually reexamined by a dedicated sarcoma pathologist. The role of radiotherapy varies according to localization of soft tissue sarcoma. It is part of the standard treatment in grade 2 and 3 sarcomas of the extremities and superficial trunk>5cm. In case of R1 or R2 resection, reexcision should be discussed. In such cases, it may be delivered preoperatively (50Gy/25 fractions of 2Gy) or postoperatively. In retroperitoneal sarcomas, preoperative conformal radiotherapy with or without modulated intensity cannot be proposed systematically in daily practice. Concomitant chemoradiotherapy cannot be considered a standard treatment. Intensity-modulated radiotherapy has become widely available. Other soft tissue sarcoma sites such as trunk, head and neck and gynaecological soft tissue sarcomas will be addressed, as well as other techniques that may be used such as brachytherapy and proton therapy.

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.