Centre For Oncological Hadrontherapy Research Articles

Developing a trial design to establish BNCT as clinical application: insight for the national italian center for oncological hadrontherapy (CNAO)

PurposeBoron Neutron Capture Therapy (BNCT) represents an advanced radiation therapy capable of selectively killing tumor cells. It operates on a dual therapy approach, utilizing boronated agents that preferentially deliver boron-10 to tumors, followed by neutron irradiation. This leads to the emission of two ionizing particles. These particles expend all their energy over a distance comparable to the diameter of a cell and can cause irreparable damage to DNA when passing through the nucleus.MethodsThis paper outlines the approach taken by the Italian National Cancer Center for Oncological Hadrontherapy (CNAO) to achieve BNCT certification for clinical applications within the EU regulatory framework.ResultsThe existing literature reports excellent outcomes for many unresectable and recurrent tumors, especially in head and neck cancer (HNC).ConclusionsThe paper seeks to clarify the rationale and methods for formulating a clinical trial design to meet these objectives.

The clinical roadmap in a dual-beam hadrontherapy centre: tumour-based and patient-tailored selection criteria, management of range uncertainties and oncological patient pathway

PurposeIn the present short report, we encompass the radiobiological and dosimetric advantages of particle beam radiotherapy and we illustrate the oncological pathway for patients eligible for hadrontherapy being used at the National Center for Oncological Hadrontherapy (CNAO).MethodsWith a narrative approach, we examined the clinical and practical aspects of hadrontherapy compared to traditional photon beam radiotherapy. We described the need to select patients considering the intrinsic characteristics both of the tumour and the patient. Moreover, we described the decisional oncological tree and the patient pathway by our facility.ResultsConsidering the dosimetric and radiobiological characteristics of particle beam radiotherapy, the selection of patients can not be done regardless of the intrinsic tumour and patient hallmarks. In particular, the tumour radioresistance, the patient radiosensitivity and the need to avoid post-actinic toxicities in long-term survivors should guide the clinical indication. The finite range of particles should be considered to avoid treatment uncertainties. Multidisciplinary national and international collaboration is crucial to better manage patients to treat with hadrontherapy and to create robust clinical evidence.ConclusionHadrontherapy, with its distinctive physical and biological advantages, heralds a promising era in the field of precision radiotherapy. Patients’ radiosensitivity, tumour radioresistance, and treatment uncertainties should be considered to enhance the efficacy and to ameliorate the selection of patients.

The Role of Carbon Ion Therapy in the Changing Oncology Landscape-A Narrative Review of the Literature and the Decade of Carbon Ion Experience at the Italian National Center for Oncological Hadrontherapy.

Currently, 13 Asian and European facilities deliver carbon ion radiotherapy (CIRT) for preclinical and clinical activity, and, to date, 55 clinical studies including CIRT for adult and paediatric solid neoplasms have been registered. The National Center for Oncological Hadrontherapy (CNAO) is the only Italian facility able to accelerate both protons and carbon ions for oncological treatment and research. To summarise and critically evaluate state-of-the-art knowledge on the application of carbon ion radiotherapy in oncological settings, the authors conducted a literature search till December 2022 in the following electronic databases: PubMed, Web of Science, MEDLINE, Google Scholar, and Cochrane. The results of 68 studies are reported using a narrative approach, highlighting CNAO's clinical activity over the last 10 years of CIRT. The ballistic and radiobiological hallmarks of CIRT make it an effective option in several rare, radioresistant, and difficult-to-treat tumours. CNAO has made a significant contribution to the advancement of knowledge on CIRT delivery in selected tumour types. After an initial ramp-up period, CNAO has progressively honed its clinical, technical, and dosimetric skills. Growing engagement with national and international networks and research groups for complex cancers has led to increasingly targeted patient selection for CIRT and lowered barriers to facility access.

Implementation of a new hadrontherapy pediatric pathway: results from CNAO (National Centre for Oncological Hadrontherapy), Italy

Implementation of a new hadrontherapy pediatric pathway: results from CNAO (National Centre for Oncological Hadrontherapy), Italy

A randomized controlled phase III study comparing hadrontherapy with carbon ions versus conventional radiotherapy – including photon and proton therapy – for the treatment of radioresistant tumors: the ETOILE trial

BackgroundSome cancers such as sarcomas (bone and soft tissue sarcomas) and adenoid cystic carcinomas are considered as radioresistant to low linear energy transfer radiation (including photons and protons) and may therefore beneficiate from a carbon ion therapy. Despite encouraging results obtained in phase I/II trials compared to historical data with photons, the spread of carbon ions has been limited mainly because of the absence of randomized medical data. The French health authorities stressed the importance of having randomized data for carbon ion therapy.MethodsThe ETOILE study is a multicenter prospective randomized phase III trial comparing carbon ion therapy to either advanced photon or proton radiotherapy for inoperable or macroscopically incompletely resected (R2) radioresistant cancers including sarcomas and adenoid cystic carcinomas.In the experimental arm, carbon ion therapy will be performed at the National Center for Oncological Hadrontherapy (CNAO) in Pavia, Italy. In the control arm, photon or proton radiotherapy will be carried out in referent centers in France.The primary endpoint is progression-free survival (PFS). Secondary endpoints are overall survival and local control, toxicity profile, and quality of life. In addition, a prospective health-economic study and a radiobiological analysis will be conducted.To demonstrate an absolute improvement in the 5-year PFS rate of 20% in favor of carbon ion therapy, 250 patients have to be included in the study.DiscussionSo far, no clinical study of phase III has demonstrated the superiority of carbon ion therapy compared to conventional radiotherapy, including proton therapy, for the treatment of radioresistant tumors.Trial registrationClinicalTrials.gov identifier: NCT02838602. Date of registration: July 20, 2016. The posted information will be updated as needed to reflect protocol amendments and study progress.

IL CENTRO NAZIONALE DI ADROTERAPIA ONCOLOGICA: INNOVAZIONI TECNICO-SCIENTIFICHE E NUOVE PROSPETTIVE DELLA BNCT PER LA LOTTA AI TUMORI

Protons and carbon ions (hadrons) have useful properties for the treatments of patients affected by oncological pathologies. They are more precise than conventional X-rays and possess radiobiological characteristics suited for treating radio-resistant or inoperable tumors. This paper gives an overview of the status of hadron therapy around the world. It focusses on the Italian National Centre for Oncological Hadron therapy (CNAO), describing the centre and the expansion projects. There is growing evidence that supports safety and effectiveness of hadron therapy for a variety of clinical situations. However, there is still a lack of high-level evidence directly comparing hadron therapy with modern conventional radiotherapy techniques. The results give an overview of pre-clinical and clinical research studies and of the treatments of 3700 patients performed at CNAO. The success and development of hadron therapy is strongly associated with the creation of networks among hadron therapy facilities, clinics, universities and research institutions.

Hadron Therapy Achievements and Challenges: The CNAO Experience

Protons and carbon ions (hadrons) have useful properties for the treatments of patients affected by oncological pathologies. They are more precise than conventional X-rays and possess radiobiological characteristics suited for treating radio-resistant or inoperable tumours. This paper gives an overview of the status of hadron therapy around the world. It focusses on the Italian National Centre for Oncological Hadron therapy (CNAO), introducing operation procedures, system performance, expansion projects, methodologies and modelling to build individualized treatments. There is growing evidence that supports safety and effectiveness of hadron therapy for a variety of clinical situations. However, there is still a lack of high-level evidence directly comparing hadron therapy with modern conventional radiotherapy techniques. The results give an overview of pre-clinical and clinical research studies and of the treatments of 3700 patients performed at CNAO. The success and development of hadron therapy is strongly associated with the creation of networks among hadron therapy facilities, clinics, universities and research institutions. These networks guarantee the growth of cultural knowledge on hadron therapy, favour the efficient recruitment of patients and present available competences for R&D (Research and Development) programmes.

Current and Future Technologies of the CNAO Dose Delivery System

The aim of this paper is to review the Dose Delivery System (DDS), developed by the National Center for Oncological Hadrontherapy (CNAO), Pavia, Italy, in collaboration with a group at the National Institute of Nuclear Physics (INFN) of Turin, Italy. The DDS controls and monitors the delivery of clinical ion beams.

A facility for the research, development, and translation of advanced technologies for ion-beam therapies

This article describes the updated GSI radiotherapy research facility (Cave M) located at the GSI Helmholtz Center for Heavy Ion Research in Darmstadt, Germany. This facility was upgraded by modernizing the beamline that supported a pilot project in carbon ion cancer therapy in Europe from 1997 to 2008. Descriptions are provided of the modernized beamline, related hardware components and treatment delivery system. The performance specifications and general characteristics for each major component are described, along with example pre-clinical test results of selected components. These upgrades to Cave M allow for investigating novel therapy methods. The radiotherapy research facility is located on a beamline of the heavy ion synchrotron (Schwer-Ionen-Synchrotron, or SIS-18) accelerator complex, capable of delivering 0.1 to 2 GeV/u charged particle beams, ranging from protons to uranium. This beamline contains components for fast beam gating, aborting, focusing, scanning, monitoring, and shifting the range of the beam. The beam scanning magnets, position detectors, and beam monitors are described, along with tests of functionality and performance. A dose delivery system (DDS) was adapted from a clinical unit at the National Centre for Oncological Hadrontherapy (CNAO), Pavia, Italy, and consists of modular real-time hardware and software. The DDS was modified to enable research on adaptively-managed patient motion through the use of libraries of 4D-optimized radiation treatment plans, an unsolved problem of importance for treating moving tumors. The system is modular and is designed to support future research studies, such as high dose rate (Flash) radiotherapy and radioactive ion beams. A series of validation tests confirmed the functionality and performance of various key components and systems. For example, an end-to-end test revealed that dosimetric spatial homogeneity of over 95% was achieved for square treatment fields. More generally, all performance characteristics that were tested satisfied anticipated clinical requirements.

Beam loss monitoring with unfolding techniques

Since the first particle accelerator’s construction in 1931, an exponential spread of these machines occurred worldwide, in different kinds of applications. Nowadays, these are mainly used for industrial (60%) and medical (35%) purposes and for scientific research (5%). High energy secondary mixed fields produced by the particle beams interaction with matter imply a complex environmental dosimetry and special radiation protection regulations able to guarantee workers and population safety. In the medical field, this aspect is particularly emphasized in hadrontherapy centres, where high energy charged particles such as protons and carbon ions modify environmental doses, with a significant increase in the neutron contribution. This work proposes a technique to identify points of losses of the primary particle beam around an acceleration ring and has been developed within the radiation protection section at the National Centre for Oncological Hadrontherapy situated in Pavia. In the first part, the radiation field produced by protons and carbon ions interactions with structural materials at different energies was investigated. The main instrument of analysis is the Monte Carlo code for particle transport FLUKA, supported by experimental measurements in the treatment room carried out with the rem counter LUPIN, designed for pulsed neutron fields dosimetry. This first step allowed an analysis of both the angular and energetic instrumental response and a comparison of experimental results with simulations. The second part proposes a description of the technique for beam loss positions reconstruction around the acceleration ring at CNAO based on the application of unfolding codes.

The National Centre for Oncological Hadron therapy (CNAO): Present Status and Future Perspectives

Some elementary particles used for experiments of fundamental physics have properties useful to the treatments of patients affected by oncological pathologies. They are protons and carbon ions, collectively named hadrons, hence the term hadron therapy. Hadrons, in particular carbon ions, are more precise on the target than conventional X-rays and possess radiobiological characteristics suited to treat radioresistant or inoperable tumors. Italy is at the forefront of these techniques, and in Pavia a clinical facility called CNAO (Italian acronym that stands for National Centre for Oncological Hadron therapy) has treated so far more than 2800 patients with very good results. The CNAO was created by the Health Ministry and was realized by the CNAO Foundation in collaboration with the Italian Institute of Nuclear Physics (INFN), CERN, GSI and other institutions in Italy and abroad. The facility in Pavia delivers beams of hadrons in three treatment rooms with four fixed beam ports: three horizontal and one vertical. A new room, with an horizontal beamline and multiple isocenters, was completed and will be fully devoted to research applications. The CNAO has also launched a development programe to add a new single room for proton therapy with a gantry and a dedicated accelerator. Attention is also devoted to the most interesting aspects of research and development in the hadron therapy domain, like the creation of a new BNCT (Boron Neutron Capture Therapy) facility and the design of a novel gantry for carbon ions.

Outcome and Toxicity of Carbon Ion Radiotherapy for Axial Bone and Soft Tissue Sarcomas.

Definitive radiotherapy for bone and soft tissues sarcomas benefits patients deemed unfit for surgery; poor outcomes have been reported with conventional photons, while interesting preliminary results have been described with particle in single-Institution experiences. The aim of the study was to retrospectively evaluate preliminary results of carbon ion radiotherapy (CIRT) in patients with axial bone and soft tissue sarcomas (BSTS) treated with curative intent at the National Center for Oncological Hadrontherapy (CNAO). From January 2013 to September 2018, 54 patients with axial BSTS were treated with CIRT at CNAO. Their median age was 50 years (range=19-79 years), males/females=1.4:1. Tumor site was the pelvis in 50% of cases (n=27), thoracic region in 24% (n=13), cervical spine in 15% (n=8) and lumbar in 11% (n=6). A total of 76% (n=41) of patients had primary disease, while 24% (n=13) had recurrent disease. Before CIRT, surgery was performed in 47% of cases, including positive margins (R1) in 8 patients, and macroscopic residual disease (R2) in 17. Histological subtypes were mainly represented by chondrosarcomas in 39% (n=21) of patients and osteosarcomas in 24% (n=13). Pre-treatment chemotherapy was administered in 40% of cases (n=22); no patient received previous radiotherapy. All treatments were performed with active scanning CIRT for a median total dose of 73.6 Gy (range=70.4-76.8 Gy), in 16 fractions (4 fractions per week). Median follow-up was 24 months (range=4-61 months). Four patients were lost to follow-up. Acute toxicities were mild, no >G2 event was reported and no treatment interruption was required. For late toxicity, only G3 neuropathy was detected in 4% of cases (n=2). With a median time to local progression of 13 months (3-35), 15 local failures were observed, resulting in 2- and 3-year local control rates of 67.4% for both. Distant progression occurred in 12 patients, with 1-year progression-free survival (PFS) rate of 97.5%; 2- and 3-year rates were 92.2%. Fifteen patients died resulting in 1- 2- and 3-years overall survival (OS) rates of 87.1%, 75.4% and 64%, respectively. At log-rank test, gross total volume (GTV) >1,000 ml was found to be predictive of local failure (p=0.04), pre-treatment chemotherapy was found to be significantly related to PFS and OS (p=0.02 and p=0.016); also, recurrent disease and distant progression were significantly related to OS (p=0.019 and p=0.0013). Cox proportional-hazards model confirmed that GTV >1,000 ml was related to worse local control (p=0.0010). CIRT for axial BSTS resulted in mild toxicity, showing promising results in terms of clinical outcomes. A longer follow-up is warranted.

A GEMPix-based integrated system for measurements of 3D dose distributions in water for carbon ion scanning beam radiotherapy.

PurposeCommercially available systems for ion beam reference dosimetry in water are mainly based on ionization chambers. In those systems, a large number of small detectors are typically arranged in a two‐dimensional (2D) array or matrix to achieve high spatial resolution (order of several millimeters) and large field coverage at the same time. The goal of this work was to investigate the reliability of a detector of superior spatial resolution to perform three‐dimensional (3D) ionization measurements in carbon ion pencil beams.MethodsThe GEMPix is a small gaseous detector with a highly pixelated readout, consisting of a drift region (with 2.8 cm3 × 2.8 cm3 × 0.3 cm3 volume), three gas electron multipliers (GEMs) for signal amplification and four Timepix ASICs with 55 µm pixel pitch and a total of 262,144 pixels. An integrated system was designed and built, which consists of a commercial water phantom with a three‐axis motorized arm, a reference large‐area ionization chamber for signal normalization to the beam output and the GEMPix itself. Measurements at different depths in water have been performed at the Italian National Centre for Oncological Hadrontherapy (CNAO) with three carbon ion beam energies. Lateral beam profiles measured with the GEMPix at the shallowest depth were compared to those measured with radiochromic EBT3 films in air in the position of the reference ionization chamber. The Timepix readout was calibrated in energy by using one independent depth scan with carbon ions of 150 mm range. Bragg peak curves were also simulated using the Monte Carlo FLUKA code as a reference.ResultsBeam profiles measured with the GEMPix were smooth and showed similar shape and full width at half maximum when compared to those measured with radiochromic EBT3 films. Smooth, reproducible Bragg curves were obtained with statistical uncertainties of about 2%, matching FLUKA simulations of the Bragg curves within 15% for most data points. This difference is partially explained for the measurement with carbon ions of 150 mm range by a saturation effect in the GEMs. The high granularity of the readout allowed to produce 2D images of the deposited dose at different depths, as well as 3D data distributions.ConclusionsThis paper demonstrates the capability of the GEMPix detector to measure the 3D dose distribution of carbon ions in water for a clinical pencil beam reliably. In the future, the detector area will be increased to cover fields of scanned beams. Measurements at higher beam intensities and with protons are planned.

A nano-microdosimetric characterization of a therapeutic carbon ion beam at CNAO

A nano-microdosimetric tissue-equivalent proportional counter (TEPC) capable of measuring microdosimetric spectra of ionizing radiation in the range 500–25 nm was designed, constructed and deeply characterized in order to fill the gap between nanodosimetry and experimental microdosimetry. This work describes the first microdosimetric characterization at nanometric level of a 195.2 MeV/u carbon ion beam available at CNAO (National Centre for Oncological Hadron Therapy). The detector was properly placed at different depths in PMMA phantom across the depth-dose profile of the primary beam for measuring microdosimetric distributions for different simulated site sizes down to 25 nm at different depths.The acquired spectra show that this TEPC is capable of reproducing the beam slowing down, showing a shift towards higher lineal energies as the primary particles slow-down. Moreover, the distributions at different simulated site sizes for the same depth are influenced by secondary electrons: smaller site size spectra exhibit a shift towards higher lineal energies as the site decreases, while this is not the case for more distal positions, where the edge of the spectra is almost independent of the simulated site size. Monte Carlo simulations performed with the FLUKA code show a good agreement with the experimental results obtained in the present paper.

Dose intercomparison at Italian hadrontherapy centers

PurposeTo perform the first dosimetric intercomparison for proton beams in Italy using ionization chambers, according to the IAEA TRS-398 code of practice. MethodsMeasurement sites included: National Center for Oncological Hadron Therapy (CNAO, Pavia), Center for Proton Therapy (CTP, Trento) and Center for Hadron Therapy and for advanced Nuclear Applications (CATANA, Catania). For comparison we also included a 6 MV photon beam produced at Istituti Clinici Scientifici Maugeri (ICSM, Pavia). For proton beams, both single pseudo-monoenergetic layers (in order to obtain a planned dose of 2 Gy at the reference depth of 2 cm in a water phantom) and Spread-out Bragg peaks (SOBP) have been delivered. Measurements were performed with a PTW Farmer 30010-1 and a PTW Advanced Markus type 34,045 ionization chamber. ResultsData obtained at CATANA, CNAO and CPT in terms of absorbed dose to water depth show good consistency within the experimental uncertainties, with a weighted mean of 1.99 ± 0.01 Gy and a standard error of 0.003 Gy, with reference to a nominal dose of 2 Gy as designed by the treatment planning system. ConclusionsThe results showed a standard deviation of less than 1% for single layer and SOBP beams, for all chambers and a percent deviation less than 1.5% for single layer measurements. The weighted means of the absorbed doses for clinical proton beams (118.19 MeV and 173.61 MeV) are consistent within less than 1%. These results agree within the 1.5% difference considered acceptable for national dose intercomparison.

Long-time clinical experience in patient setup for several particle therapy clinical indications: management of patient positioning and evaluation of setup reproducibility and stability.

Accurate patient positioning is crucial in particle therapy due to the geometrical selectivity of particles. We report and discuss the National Center for Oncological Hadrontherapy (CNAO) experience in positioning accuracy and stability achieved with solid thermoplastic masks fixed on index base plates and assessed by daily orthogonal X-ray imaging. Positioning data were retrospectively collected (between 2012 and 2018) and grouped according to the treated anatomical site. 19696 fractions of 1325 patients were evaluated.The study was designed to assess:(i) the number of fractions in which a single correction vector was applied(SCV);(ii) the number of fractions in which further setup verification was performed (SV);(iii) the number of fractions in which SV lead to an additional correction within (MCV<5min) or after (MCV>5min) 5 minutes from the first setup correction;(iv) the systematic (Σ) and random (σ) error components of the correction vectors applied. A SCV was applied in 71.5% of fractions, otherwise SV was required. In 30.6% of fractions with SV, patient position was not further revised. In the remaining fractions, MCV<5min and MCV>5min were applied mainly in extracranial and cranial sites respectively.Interfraction Σ was ≤ 1.7 mm/0.7° and σ was ≤ 1.2 mm/0.6° in cranial sites while in extracranial sites Σ was ≤ 5.5 mm/0.9° and σ was ≤4.4 mm/0.9°. Setup residuals were submillimetric in all sites. In cranial patients, maximum intrafractional Σ was 0.8 mm/0.4°. This report extensively quantifies inter- and intrafraction setup accuracy on an institutional basis and confirms the need of image guidance to fully benefit from the geometrical selectivity of particles. The reported analysis provides a board institutional data set on the evaluation of patient immobilization and bony anatomy alignment for several particle therapy clinical indications.

Design and commissioning of the non-dedicated scanning proton beamline for ocular treatment at the synchrotron-based CNAO facility.

Only few centers worldwide treat intraocular tumors with proton therapy, all of them with a dedicated beamline, except in one case in the USA. The Italian National Center for Oncological Hadrontherapy (CNAO) is a synchrotron-based hadrontherapy facility equipped with fixed beamlines and pencil beam scanning modality. Recently, a general-purpose horizontal proton beamline was adapted to treat also ocular diseases. In this work, the conceptual design and main dosimetric properties of this new proton eyeline are presented. A 28 mm thick water-equivalent range shifter (RS) was placed along the proton beamline to shift the minimum beam penetration at shallower depths. FLUKA Monte Carlo (MC) simulations were performed to optimize the position of the RS and patient-specific collimator, in order to achieve sharp lateral dose gradients. Lateral dose profiles were then measured with radiochromic EBT3 films to evaluate the dose uniformity and lateral penumbra width at several depths. Different beam scanning patterns were tested. Discrete energy levels with 1 mm water-equivalent step within the whole ocular energy range (62.7-89.8 MeV) were used, while fine adjustment of beam range was achieved using thin polymethylmethacrylate additional sheets. Depth-dose distributions (DDDs) were measured with the Peakfinder system. Monoenergetic beam weights to achieve flat spread-out Bragg Peaks (SOBPs) were numerically determined. Absorbed dose to water under reference conditions was measured with an Advanced Markus chamber, following International Atomic Energy Agency (IAEA) Technical Report Series (TRS)-398 Code of Practice. Neutron dose at the contralateral eye was evaluated with passive bubble dosimeters. Monte Carlo simulations and experimental results confirmed that maximizing the air gap between RS and aperture reduces the lateral dose penumbra width of the collimated beam and increases the field transversal dose homogeneity. Therefore, RS and brass collimator were placed at about 98 cm (upstream of the beam monitors) and 7 cm from the isocenter, respectively. The lateral 80%-20% penumbra at middle-SOBP ranged between 1.4 and 1.7 mm depending on field size, while 90%-10% distal fall-off of the DDDs ranged between 1.0 and 1.5 mm, as a function of range. Such values are comparable to those reported for most existing eye-dedicated facilities. Measured SOBP doses were in very good agreement with MC simulations. Mean neutron dose at the contralateral eye was 68 μSv/Gy. Beam delivery time, for 60 Gy relative biological effectiveness (RBE) prescription dose in four fractions, was around 3 min per session. Our adapted scanning proton beamline satisfied the requirements for intraocular tumor treatment. The first ocular treatment was delivered in August 2016 and more than 100 patients successfully completed their treatment in these 2 yr.

Monte Carlo simulation tool for online treatment monitoring in hadrontherapy with in-beam PET: A patient study

Hadrontherapy is a method for treating cancer with very targeted dose distributions and enhanced radiobiological effects. To fully exploit these advantages, in vivo range monitoring systems are required. These devices measure, preferably during the treatment, the secondary radiation generated by the beam-tissue interactions. However, since correlation of the secondary radiation distribution with the dose is not straightforward, Monte Carlo (MC) simulations are very important for treatment quality assessment.The INSIDE project constructed an in-beam PET scanner to detect signals generated by the positron-emitting isotopes resulting from projectile-target fragmentation. In addition, a FLUKA-based simulation tool was developed to predict the corresponding reference PET images using a detailed scanner model.The INSIDE in-beam PET was used to monitor two consecutive proton treatment sessions on a patient at the Italian Center for Oncological Hadrontherapy (CNAO). The reconstructed PET images were updated every 10 s providing a near real-time quality assessment. By half-way through the treatment, the statistics of the measured PET images were already significant enough to be compared with the simulations with average differences in the activity range less than 2.5 mm along the beam direction. Without taking into account any preferential direction, differences within 1 mm were found.In this paper, the INSIDE MC simulation tool is described and the results of the first in vivo agreement evaluation are reported. These results have justified a clinical trial, in which the MC simulation tool will be used on a daily basis to study the compliance tolerances between the measured and simulated PET images.

MICRODOSIMETRIC STUDY AT THE CNAO ACTIVE-SCANNING CARBON-ION BEAM

The Italian National Centre for Oncological Hadrontherapy (CNAO) has been treating patients since 2011 with carbon-ion beams using the active-scanning modality. In such irradiation modality, the beam spot, which scans the treatment area, is characterised by very high particle-fluence rates (more than 105 s-1 mm-2). Moreover, the Bragg-peak is only ~1 mm-FWHM. Commercial tissue-equivalent proportional counters (TEPC), like the Far West Technologies LET-½, are large, hence they have limited capability to measure at high counting fluence rates. In this study we have used two home-made detectors, a mini-TEPC 0.81 mm2 in sensitive area and a silicon telescope 0.125 mm2 in sensitive area, to perform microdosimetric measurements in the therapeutic carbon-ion beam of CNAO. A monoenergetic carbon-ion beam of 189.5 ± 0.3 MeV/u scanning a 3 × 3 cm2 area has been used. Spectral differences are visible in the low y-value region, but the mean microdosimetric values, measured with the two detectors, result to be pretty consistent, as well as the microdosimetric spectra in the high y-value region.

Uptake of 18F-FET and 18F-FCH in Human Glioblastoma T98G Cell Line after Irradiation with Photons or Carbon Ions.

The differential diagnosis between recurrence of gliomas or brain metastases and this phenomenon is important in order to choose the best therapy and predict the prognosis but is still a big problem for physicians. The new emerging MRI, CT, and PET diagnostic modalities still lack sufficient accuracy. Radiolabeled choline and amino acids have been reported to show great tumor specificity. We studied the uptake kinetics of [18F]fluoromethyl-choline (FCH) and O-(2-[18F]fluoroethyl)-L-tyrosine (FET) by the T98G human glioblastoma cells from 20 to 120 min after irradiation either with photons at 2-10-20 Gy or with carbon ions at 2 Gy (at the National Centre for Oncological Hadrontherapy (CNAO), Pavia, Italy). We also evaluated the cell death and morphology changes induced by radiation treatment. Both FET and FCH are able to trace tumor behavior in terms of higher uptake for increased doses of radiation treatment, due to the upregulation of cells attempts to repair nonlethal damage. Our data suggest that both FCH and FET could be useful to analyze the metabolic pathways of glioblastoma cells before and after radiotherapy. Physicians will have to consider the different kinetics pathways of uptake concerning the two radiopharmaceuticals.