In particle therapy, the uncertainty of the delivered particle range during the patient irradiation limits the optimization of the treatment planning. Therefore, an in vivo treatment verification device is required, not only to improve the plan robustness, but also to detect significant interfractional morphological changes during the treatment itself. In this article, an effective and robust analysis to detect regions with a significant range discrepancy is proposed. This study relies on an in vivo treatment verification by means of in-beam Positron Emission Tomography (PET) and was carried out with the INSIDE system installed at the National Center of Oncological Hadrontherapy (CNAO) in Pavia, which is under clinical testing since July 2019. Patients affected by head-and-neck tumors treated with protons have been considered. First, in order to tune the analysis parameters, a Monte Carlo (MC) simulation was carried out to reproduce a patient who required a replanning because of significant morphological changes found during the treatment. Then, the developed approach was validated on the experimental measurements of three patients recruited for the INSIDE clinical trial (ClinicalTrials.gov ID: NCT03662373), showing the capability to estimate the treatment compliance with the prescription both when no morphological changes occurred and when a morphological change did occur, thus proving to be a promising tool for clinicians to detect variations in the patients treatments.

Purpose: The electron linac ElectronFlash installed at Institut Curie (Orsay, France) is entirely dedicated to FLASH irradiation for radiobiological and pre-clinical studies. The system was designed to deliver an ultra-high-dose rate per pulse (UHDR) (above 106 Gy/s) and a very high average dose rate at different energies and pulse durations. A campaign of tests and measurements was performed to obtain a full reliable characterizations of the electron beam and of the delivered dose, which are necessary to the radiobiological experiments. Methods: A Faraday cup was used to measure the electron charges in a single RF pulse. The percentage depth dose (PDD) and the transverse dose profiles, at the energies of 5 MeV and 7 MeV, were evaluated employing Gafchromic films EBT-XD for two Poly-methylmethacrylate (PMMA) applicators with irradiation sizes of 30 mm and 120 mm, normally used for in vivo and in vitro experiments, respectively. The results were compared with Monte Carlo (MC) simulations. Results: The measurements were performed during a period of a few months in which the experimental set up was adapted and tuned in order to characterize the electron beam parameters and the values of delivered doses before the radiobiological experiments. The measurements showed that the dose parameters, obtained at the energy of 5 MeV and 7 MeV with different applicators, fulfill the FLASH regime, with a maximum value of an average dose rate of 4750 Gy/s, a maximum dose per pulse of 19 Gy and an instantaneous dose rate up to 4.75 ×106 Gy/s. By means of the PMMA applicators, a very good flatness of the dose profiles was obtained at the cost of a reduced total current. The flatness of the large field is reliable and reproducible in radiobiological experiments. The measured PDD and dose profiles are in good agreement with Monte Carlo simulations with more than 95% of the gamma-index under the thresholds of 3 mm/3%. Conclusions: The results show that the system can provide UHDR pulses totally satisfying the FLASH requirements with very good performances in terms of beam profile flatness for any size of the fields. The monitoring of electron beams and the measurement of the dose parameters played an important role in the in vivo and in vitro irradiation experiments performed at the Institut Curie laboratory.

The high dose conformity and healthy tissue sparing achievable in Particle Therapy when using C ions calls for safety factors in treatment planning, to prevent the tumor under-dosage related to the possible occurrence of inter-fractional morphological changes during a treatment. This limitation could be overcome by a range monitor, still missing in clinical routine, capable of providing on-line feedback. The Dose Profiler (DP) is a detector developed within the INnovative Solution for In-beam Dosimetry in hadronthErapy (INSIDE) collaboration for the monitoring of carbon ion treatments at the CNAO facility (Centro Nazionale di Adroterapia Oncologica) exploiting the detection of charged secondary fragments that escape from the patient. The DP capability to detect inter-fractional changes is demonstrated by comparing the obtained fragment emission maps in different fractions of the treatments enrolled in the first ever clinical trial of such a monitoring system, performed at CNAO. The case of a CNAO patient that underwent a significant morphological change is presented in detail, focusing on the implications that can be drawn for the achievable inter-fractional monitoring DP sensitivity in real clinical conditions. The results have been cross-checked against a simulation study.