Particle therapy exploits the energy deposition pattern of hadron beams. The narrow Bragg Peak at the end of range is a major advantage but range uncertainties can cause severe damage and require online verification to maximise the effectiveness in clinics. In-beam Positron Emission Tomography (PET) is a non-invasive, promising in-vivo technique, which consists in the measurement of the β+ activity induced by beam-tissue interactions during treatment, and presents the highest correlation of the measured activity distribution with the deposited dose, since it is not much influenced by biological washout. Here we report the first clinical results obtained with a state-of-the-art in-beam PET scanner, with on-the-fly reconstruction of the activity distribution during irradiation. An automated time-resolved quantitative analysis was tested on a lacrimal gland carcinoma case, monitored during two consecutive treatment sessions. The 3D activity map was reconstructed every 10 s, with an average delay between beam delivery and image availability of about 6 s. The correlation coefficient of 3D activity maps for the two sessions (above 0.9 after 120 s) and the range agreement (within 1 mm) prove the suitability of in-beam PET for online range verification during treatment, a crucial step towards adaptive strategies in particle therapy.

The quality assurance of particle therapy treatment is a fundamental issue that can be addressed by developing reliable monitoring techniques and indicators of the treatment plan correctness. Among the available imaging techniques, positron emission tomography (PET) has long been investigated and then clinically applied to proton and carbon beams. In 2013, the Innovative Solutions for Dosimetry in Hadrontherapy (INSIDE) collaboration proposed an innovative bimodal imaging concept that combines an in-beam PET scanner with a tracking system for charged particle imaging. This paper presents the general architecture of the INSIDE project but focuses on the in-beam PET scanner that has been designed to reconstruct the particles range with millimetric resolution within a fraction of the dose delivered in a treatment of head and neck tumors. The in-beam PET scanner has been recently installed at the Italian National Center of Oncologic Hadrontherapy (CNAO) in Pavia, Italy, and the commissioning phase has just started. The results of the first beam test with clinical proton beams on phantoms clearly show the capability of the in-beam PET to operate during the irradiation delivery and to reconstruct on-line the beam-induced activity map. The accuracy in the activity distal fall-off determination is millimetric for therapeutic doses.

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.

In vivo range monitoring techniques are necessary in order to fully take advantage of the high dose gradients deliverable in hadrontherapy treatments. Positron emission tomography (PET) scanners can be used to monitor beam-induced activation in tissues and hence measure the range. The INSIDE (Innovative Solutions for In-beam DosimEtry in Hadrontherapy) in-beam PET scanner, installed at the Italian National Center of Oncological Hadrontherapy (CNAO, Pavia, Italy) synchrotron facility, has already been successfully tested in vivo during a proton therapy treatment. We discuss here the system performance evaluation with carbon ion beams, in view of future in vivo tests. The work is focused on the analysis of activity images obtained with therapeutic treatments delivered to polymethyl methacrylate (PMMA) phantoms, as well as on the test of an innovative and robust Monte Carlo simulation technique for the production of reliable prior activity maps. Images are reconstructed using different integration intervals, so as to monitor the activity evolution during and after the treatment. Three procedures to compare activity images are presented, namely Pearson correlation coefficient, Beam's eye view and overall view. Images of repeated irradiations of the same treatments are compared to assess the integration time necessary to provide reproducible images. The range agreement between simulated and experimental images is also evaluated, so as to validate the simulation capability to provide sound prior information. The results indicate that at treatment end, or at most 20 s afterwards, the range measurement is reliable within 1-2 mm, when comparing both different experimental sessions and data with simulations. In conclusion, this work shows that the INSIDE in-beam PET scanner performance is promising towards its in vivo test with carbon ions.