Sensitivity of a mini-TEPC to radiation quality variations in clinical proton beams.

PURPOSE: This work aims at studying the sensitivity of a miniaturized Tissue-Equivalent Proportional Counter to variations of beam quality in clinical radiation fields, to further investigate its performances as radiation quality monitor. METHODS: Measurements were taken at the CATANA facility (INFN-LNS, Catania, Italy), in a monoenergetic and an energy-modulated proton beam with the same initial energy of 62 MeV. PMMA layers were placed in front of the detector to measure at different depths along the depth-dose profile. The frequency- and dose-mean lineal energy were compared to the track- and dose-averaged LET calculated by Monte Carlo simulations. A microdosimetric evaluation of the Relative Biological Effectiveness (RBE) was performed and compared with cell survival experiments. RESULTS: Microdosimetric distributions measured at identical depths in the two beams show spectral differences reflecting their different radiation quality. Discrepancies are most evident at depths corresponding to the Spread-Out Bragg Peak, while spectra at the entrance and in the dose fall-off regions are similar. This can be explained by the different energy components that compose the pristine and spread-out peaks at each depth. The trend of microdosimetric mean values matches that of calculated LET averages along the entire penetration depth, and the microdosimetric estimation of RBE is consistent with radiobiological data not only at 2 Gy but also at lower dose levels, such as those absorbed by healthy tissues. CONCLUSIONS: The mini-TEPC is sensitive to differences in radiation quality resulting from different modulations of the proton beam, confirming its potential for beam quality monitoring in proton therapy.

Microdosimetry of a 62-MeV clinical proton beam with five detectors.

In proton therapy, most treatment planning systems (TPS) use a fixed relative biological effectiveness (RBE) of 1.1 all along the depth-dose profile. Innovative TPS are now investigated considering the variability of RBE with radiation quality. New TPS need an experimental verification in the quality assurance (QA) routine in clinics, but RBE data are usually obtained with radiobiological measurements that are time consuming and not suitable for daily QA. Microdosimetry is a useful tool based on physical measurements which can monitor the radiation quality. Several microdosimeters are available in different research institutions, which could potentially be used for the QA in TPS. In this study, the response functions of five detectors in the same 62-MeV proton Spread Out Bragg Peak is compared in terms of spectral distributions and their average values and microdosimetric RBE. Their different response function has been commented and must be considered in the clinical practice.

Microdosimetric analysis of the radiation quality of two different proton beams in the distal edge of the depth-dose profile.

Proton-therapy exploits the advantageous depth-dose profile of protons to induce the highest damage to tumoral cells in the last millimetres of their range in sharp Bragg Peak. To cover the whole tumoral volume, beams of different energies are combined to create the Spread Out Bragg Peak (SOBP). In passive modulated beams, the energy spread is created with modulators in which the highest energy beam is degraded through different thicknesses of calibrated plastic materials. The highest energy is chosen depending on the deepest point that needs to be treated. This study aims to investigate differences in the radiation quality in the distal edge of SOBP beams with different initial energy and modulation techniques based on microdosimetric measurements with mini Tissue-Equivalent Proportional Counters. The beams investigated are the 62 MeV proton SOBP of the clinical facility of CATANA and the 148 MeV proton SOBP of the research beam line of the proton-therapy centre of Trento.

4He dose- and track-averaged linear energy transfer: Monte Carlo algorithms and experimental verification.

Objective.In the present hadrontherapy scenario, there is a growing interest in exploring the capabilities of different ion species other than protons and carbons. The possibility of using different ions paves the way for new radiotherapy approaches, such as the multi-ions treatment, where radiation could vary according to target volume, shape, depth and histologic characteristics of the tumor. For these reasons, in this paper, the study and understanding of biological-relevant quantities was extended for the case of4He ion.Approach.Geant4 Monte Carlo based algorithms for dose- and track-averaged LET (Linear Energy Transfer) calculations, were validated for4He ions and for the case of a mixed field characterised by the presence of secondary ions from both target and projectile fragmentation. The simulated dose and track averaged LETs were compared with the corresponding dose and frequency mean values of the lineal energy,yD¯andy¯F, derived from experimental microdosimetric spectra. Two microdosimetric experimental campaigns were carried out at the Italian eye proton therapy facility of the Laboratori Nazionali del Sud of Istituto Nazionale di Fisica Nucleare (INFN-LNS, Catania, I) using two different microdosimeters: the MicroPlus probe and the nano-TEPC (Tissue Equivalent Proportional Counter).Main results.A good agreement ofL¯dTotalandL¯tTotalwithy¯Dandy¯Texperimentally measured with both microdosimetric detectors MicroPlus and nano-TEPC in two configurations: full energy and modulated4He ion beam, was found.Significance.The results of this study certify the use of a very effective tool for the precise calculation of LET, given by a Monte Carlo approach which has the advantage of allowing detailed simulation and tracking of nuclear interactions, even in complex clinical scenarios.

Microdosimetry of an accelerator based thermal neutron field for Boron Neutron Capture Therapy.

The MUNES project (MUltidisciplinary NEutron Source) aims at the realization of an intense accelerator-based source of thermal neutrons, suitable for Boron Neutron Capture Therapy (BNCT). This exploits the interaction of 5 MeV protons onto a beryllium target, producing a fast neutron spectrum, which is moderated to the thermal range by a large assembly made of a Polytetrafluoroethylene (PTFE) tank filled with heavy water, surrounded by graphite blocks. The thermal neutron field is extracted through a bismuth beam port. The microdosimetric characterization of this field was performed using a cylindrical avalanche-confinement Tissue Equivalent Proportional Counter (TEPC) equipped with interchangeable cathode walls, positioned in front of the beam port. Measurements were taken both with a boron-doped wall and with an undoped one. The comparison of the two microdosimetric distributions allows to distinguish the relative dose contribution due to alpha particles and lithium ions from the BNC reaction from that of photons and other particles from neutron interactions on the cathode walls. The Relative Biological Effectiveness (RBE) was also calculated from the convolution of the measured spectra with a biological weighting function. This paper describes the experimental microdosimetric approach and the results of measurements with a boron-loaded cathode performed for the first time at an accelerator-based BNCT source.

Experimental investigation at CATANA facility of n-10B and p-11B reactions for the enhancement of proton therapy.

The aim of the NEPTUNE (Nuclear process-driven Enhancement of Proton Therapy UNravEled) project is to investigate in detail both the physical and radiobiological phenomena that could justify an increase of the proton-induced cytogenetic effects in cells irradiated in presence of an agent containing natural boron. In this work, a double-stage silicon telescope coupled to different boron converters was irradiated at the CATANA proton therapy facility (INFN-LNS) for studying the proton boron fusion and the neutron boron capture reactions by discriminating secondary particles from primary protons. Different boron targets were developed by depositing boric acid, enriched with a higher than 99% content of 10B or 11B, on a 50 µm thick PolyMethilMetacrylate (PMMA) substrate. The 10B target allows to evaluate the contribution of lithium and alpha particles produced by the boron neutron capture reaction triggered by secondary thermal neutrons, while the 11B target is exploited for studying the effect of the p + 11B → 3α nuclear reaction directly triggered by primary protons. Experimental results clearly show the presence of alpha particles from both the reactions. The silicon telescope is capable of discriminating, by means of the so-called "scatter plots", the contribution of alpha particles originated by thermal neutrons on 10B with respect to the ones produced by protons impinging on 11B. Although a reliable quantitative study of the alpha production rate has not been achieved yet, this work demonstrates that low energy and, therefore, high-LET particles from both the reactions can be measured.

Monte Carlo implementation of new algorithms for the evaluation of averaged-dose and -track linear energy transfers in 62 MeV clinical proton beams.

We exploited the power of the Geant4 Monte Carlo toolkit to study and validate new approaches for the averaged linear energy transfer (LET) calculation in 62 MeV clinical proton beams. The definitions of the averaged LET dose and LET track were extended, so as to fully account for the contribution of secondary particles generated by target fragmentation, thereby leading to a more general formulation of the LET total. Moreover, in the proposed new strategies for the LET calculation, we minimised the dependencies in respect to the transport parameters adopted during the Monte Carlo simulations (such as the production cut of secondary particles, voxel size and the maximum steplength). The new proposed approach was compared against microdosimetric experimental spectra of clinical proton beams, acquired at the Italian eye proton therapy facility of the Laboratori Nazionali del Sud, Istituto Nazionale di Fisica Nucleare (INFN-LNS, Catania, I) from two different detectors: a mini-tissue equivalent proportional chamber (TEPC), developed at the Legnaro National Laboratories of the National Institute for Nuclear Physics (LNL-INFN) and a silicon-on-insulator (SOI) microdosimeter with 3D sensitive volumes developed by the Centre for Medical Radiation Physics of Wollongong University (CMRP-UoW). A significant increase of the LET in the entrance region of the spread out Bragg peak (SOBP) was observed, when the contribution of the generated secondary particles was included in the calculation. This was consistent with the experimental results obtained.

Microdosimetry of a therapeutic proton beam with a mini-TEPC and a MicroPlus-Bridge detector for RBE assessment.

Proton beams are widely used worldwide to treat localized tumours, the lower entrance dose and no exit dose, thus sparing surrounding normal tissues, being the main advantage of this treatment modality compared to conventional photon techniques. Clinical proton beam therapy treatment planning is based on the use of a general relative biological effectiveness (RBE) of 1.1 along the whole beam penetration depth, without taking into account the documented increase in RBE at the end of the depth dose profile, in the Bragg peak and beyond. However, an inaccurate estimation of the RBE can cause both underdose or overdose, in particular it can cause the unfavourable situation of underdosing the tumour and overdosing the normal tissue just beyond the tumour, which limits the treatment success and increases the risk of complications. In view of a more precise dose delivery that takes into account the variation of RBE, experimental microdosimetry offers valuable tools for the quality assurance of LET or RBE-based treatment planning systems. The purpose of this work is to compare the response of two different microdosimetry systems: the mini-TEPC and the MicroPlus-Bridge detector. Microdosimetric spectra were measured across the 62 MeV spread out Bragg peak of CATANA with the mini-TEPC and with the Bridge microdosimeter. The frequency and dose distributions of lineal energy were compared and the different contributions to the spectra were analysed, discussing the effects of different site sizes and chord length distributions. The shape of the lineal energy distributions measured with the two detectors are markedly different, due to the different water-equivalent sizes of the sensitive volumes: 0.85 µm for the TEPC and 17.3 µm for the silicon detector. When the Loncol's biological weighting function is applied to calculate the microdosimetric assessment of the RBE, both detectors lead to results that are consistent with biological survival data for glioma U87 cells. Both the mini-TEPC and the MicroPlus-Bridge detector can be used to assess the RBE variation of a 62 MeV modulated proton beam along its penetration depth. The microdosimetric assessment of the RBE based on the Loncol's weighting function is in good agreement with radiobiological results when the 10% biological uncertainty is taken into account.

Microdosimetry at the CATANA 62 MeV proton beam with a sealed miniaturized TEPC.

A new mini-TEPC with cylindrical sensitive volume of 0.9 mm in diameter and height, and with external diameter of 2.7 mm, has been developed to work without gas flow. With such a mini counter we have measured the physical quality of the 62 MeV therapeutic proton beam of CATANA (Catania, Italy). Measurements were performed at six precise positions along the Spread-Out Bragg Peak (SOBP): 1.4, 19.4, 24.6, 29.0, 29.7 and 30.8 mm, corresponding to positions of clinical relevance (entrance, proximal, central, and distal-edge of the SOBP) or of high lineal energy transfer (LET) increment (distal-dose drop off). Without refilling the microdosimeter with new gas, the measurements were repeated at the same positions 4 months later, in order to study the stability of the response in sealed-mode operation. From the microdosimetric spectra the frequency-mean lineal energy y-F and the dose-mean lineal energy y-D were derived and compared with average LET values calculated by means of Geant4 simulations. The comparison points out, in particular, a good agreement between microdosimetric y-D and the total dose-average LET¯d, which is the average LET of the mixed radiation field, including the contribution by nuclear reactions.

Intracorporeal versus extracorporeal anastomosis after laparoscopic gastrectomy for gastric cancer. A systematic review with meta-analysis.

AIM: To perform a systematic review and meta-analyses of studies comparing the totally laparoscopic procedures with intracorporeal anastomosis (IA) to laparoscopic-assisted surgery with extracorporeal anastomosis (EA) in gastric resections. METHODS: We performed a systematic search in the electronic databases. Outcomes analysed were: intraoperative (operative time and intraoperative blood loss), oncologic (harvested nodes, distance of the tumour from proximal and distal margin), postoperative complications (gastric stasis, intraluminal and extraluminal bleeding, leakage and wound infection) recovery (time to first flatus, time to first oral intake and hospital stay). We performed meta-regression analyses after implementing a regression model with the analysed outcomes as dependent variables (y) and the demographic and pathologic covariates as independent variables (x). RESULTS: A total of 26 studies (20 on distal gastrectomy and 6 on total gastrectomy) were included in the final analysis. Regarding distal gastrectomy, there was no statistical difference between the two groups in the above-mentioned outcomes, except for intraoperative blood loss (less in IA group, P=0.003), number of harvested nodes (better in the IA group, P=0.022) and length of hospital stay (shorter in the IA group, P=0.037). Regarding total gastrectomy, there was no statistical difference for all outcomes, except for the distal margin (further in the EA group, P=0.040). Meta-regression analysis showed that a lot of variables influenced results in distal gastric resections, but not in total gastric resections. CONCLUSION: We can state laparoscopic gastric resections with IA are safe and feasible when performed by expert surgeons. However, new well-designed studies comparing the two techniques are needed to confirm the benefits of laparoscopic IA.

TOWARDS THE USE OF NANODOSIMETRY TO PREDICT CELL SURVIVAL.

Experimental nanodosimetry aims to develop a new concept of radiation quality, based on the correlation between initial features of particle tracks and late biological outcome. A direct proportionality has been observed between the cumulative probability of measuring at least k ionisations within a nanometric volume and inactivation cross sections at specific survival levels. Based on this proportionality, physical quantities which are measurable at the nanometre level can be used to estimate the alpha and beta parameters of the linear-quadratic dose-response model, provided that two proportionality factors are determined in a reference radiation field. This work describes the procedure and first results applied to published data for V79 cell survival after irradiation with protons and carbon ions.

MICRODOSIMETRY AT NANOMETRIC SCALE WITH AN AVALANCHE-CONFINEMENT TEPC: RESPONSE AGAINST A HELIUM ION BEAM.

The tissue-equivalent proportional counter (TEPC) is the most accurate device for measuring the microdosimetric properties of a particle beam but, since the lower operation limit of common TEPCs is ~0.3 µm, no detailed information on the track structure of the impinging particles can be obtained. The pattern of particle interactions at the nanometric level is measured directly by only three different nanodosimeters worldwide: practical instruments are not yet available. In order to partially fill the gap between microdosimetry and track-nanodosimetry, a low-pressure avalanche-confinement TEPC was designed and constructed for simulating tissue-equivalent sites down to the nanometric region. The present paper aims at describing the response of this TEPC in the range 0.3 µm-25 nm to a 62 MeV/n 4He ion beam. The experimental results, for depths near the Bragg peak, show good agreement with FLUKA simulations and suggest that, for smaller depths, the distribution is highly influenced by secondary electrons.

Miniaturized microdosimeters as LET monitors: First comparison of calculated and experimental data performed at the 62 MeV/u 12C beam of INFN-LNS with four different detectors.

PURPOSE: The aim of this paper is to investigate the limits of LET monitoring of therapeutic carbon ion beams with miniaturized microdosimetric detectors. METHODS: Four different miniaturized microdosimeters have been used at the 62 MeV/u 12C beam of INFN Southern National Laboratory (LNS) of Catania for this purpose, i.e. a mini-TEPC and a GEM-microdosimeter, both filled with propane gas, and a silicon and a diamond microdosimeter. The y-D (dose-mean lineal energy) values, measured at different depths in a PMMA phantom, have been compared withLET¯D (dose-mean LET) values in water, calculated at the same water-equivalent depth with a Monte Carlo simulation setup based on the GEANT4 toolkit. RESULTS: In these first measurements, no detector was found to be significantly better than the others as a LET monitor. The y-D relative standard deviation has been assessed to be 13% for all the detectors. On average, the ratio between y-D and LET¯D values is 0.9 ±â€¯0.3, spanning from 0.73 ±â€¯0.08 (in the proximal edge and Bragg peak region) to 1.1 ±â€¯0.3 at the distal edge. CONCLUSIONS: All the four microdosimeters are able to monitor the dose-mean LET with the 11% precision up to the distal edge. In the distal edge region, the ratio of y-D to LET¯D changes. Such variability is possibly due to a dependence of the detector response on depth, since the particle mean-path length inside the detectors can vary, especially in the distal edge region.

A MONTE CARLO TOOL FOR MULTI-TARGET NANODOSIMETRY.

A Monte Carlo simulation tool has been developed, based on the physical models of the Geant4-DNA extension of Geant4, to study the ionisation pattern of charged particles in a multi-target environment. The tool allows to code easily the geometry to build a simulation with multiple targets, since several parameters can be changed interactively and independently via macro commands. In this work a set of nanometric target spheres is embedded in a cylindrical water phantom 20 nm in height and 40 nm in diameter. The targets are randomly distributed in such a way that they do not overlap and are contained within a smaller cylindrical volume 20 nm in diameter and height. The water phantom is irradiated by ions which are shot parallel to the central axis and randomly distributed over the cross section of the inner cylinder. Two different types of simulations are performed. In one, the penumbra of secondary electrons is fully simulated, in the other the transport of secondary electrons is carried out only if they are produced inside one of the targets, and the electron track is terminated when it leaves the sphere of production. First results are presented and discussed.

State of The Art of Instrumentation in Experimental Nanodosimetry.

Nanodosimetry is a branch of dosimetry for investigation and modeling of the interaction pattern of ionizing radiation in nanometre site-sizes (at unit density), which dates back to the 1970's (Pszona S. A track ion counter. Proceedings of Fifth Symposium on Microdosimetry EUR 5452 d-e-f, Published by the Commission of the European Communities, Luxemburg, pp. 1107-1122 (1976)). To date, the different experimental approaches have lead to developing of three fully functional nanodosimeters: the Jet Counter operated at NCBJ, the Ion Counter operated at PTB and Startrack Counter operated at INFN-LNL. Descriptions of each nanodosimeter as well as of the techniques used to investigate the track structure of ionizing particles are presented.

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.

NANODOSIMETRY: TOWARDS A NEW CONCEPT OF RADIATION QUALITY.

The biological action of ionizing charged particles is initiated at the DNA level, and the effectiveness with which the initial physical effect changes into measurable biological damage is likely ruled by the stochastics of ionizations produced by the incident ions in subcellular nanometric volumes. Based on this hypothesis, experimental nanodosimetry aims at establishing a new concept of radiation quality that builds on measurable characteristics of the particle track structure at the nanometer scale. Three different nanodosimetric detection systems have been developed to date that allow measurements of the number of ionizations produced by the passage of a primary particle in a nanometer-size gas volume (in unit density scale). Within the Italian project MITRA (MIcrodosimetry and TRAck structure), funded by the Italian Istituto Nazionale di Fisica Nucleare (INFN) and the EMRP Joint Research Project 'BioQuaRT' (Biologically Weighted Quantities in Radiotherapy), experiments have been carried out, in which the frequency distribution of ionizations produced by proton and carbon ion beams of given energy was measured with the three nanodosimetric detectors. Descriptors of the track structure can be derived from these distributions. In particular, the first moment M1, representing the mean number of ionizations produced in the target volume, and the cumulative probability Fk of measuring a number ν ≥ k of ionizations. The correlation between measured nanodosimetric quantities and experimental radiobiological data available in the literature is here presented and discussed.

MICRODOSIMETRIC SIMULATIONS OF CARBON IONS USING THE MONTE CARLO CODE FLUKA.

Therapeutic carbon ion beams produce a complex and variable radiation field that changes along the penetration depth due to the high density of energy loss along the particle track together with the secondary particles produced by nuclear fragmentation reactions. An accurate physical characterisation of such complex mixed-radiation fields can be performed by measuring microdosimetric spectra with mini tissue-equivalent proportional counters (mini-TEPCs), which are one of the most accurate devices used in experimental microdosimetry. Numerical calculations with Monte Carlo codes such as FLUKA can be used to supplement experimental microdosimetric measurements performed with TEPCs, but the nuclear cross sections and fragmentation models need to be benchmarked with experimental data for different energies and scenarios. The aim of this work is to compare experimental carbon microdosimetric data measured with the mini TEPC with calculated microdosimetry spectra obtained with FLUKA for 12C ions of 189.5 MeV/u in the Bragg peak region.

A NOVEL TEPC FOR MICRODOSIMETRY AT NANOMETRIC LEVEL: RESPONSE AGAINST DIFFERENT NEUTRON FIELDS.

Tissue equivalent proportional counter (TEPC) is the most accurate device for measuring the microdosimetric properties of a particle beam, nevertheless no detailed information on the track structure of the impinging particles can be obtained, since the lower operation limit of common TEPCs is ~0.3 µm. On the other hand, the pattern of particle interactions at the nanometer level is measured by only three different nanodosimeters worldwide: practical instruments are not yet available. In order to partially fill the gap between microdosimetry and track-nanodosimetry, a low-pressure avalanche-confinement TEPC was recently designed and constructed for simulating tissue-equivalent sites down to the nanometric region. The present article aims at describing the response of this newly developed TEPC in the range 0.3 µm-25 nm against a fast neutron field from a 241Am-Be source and a quasi-monoenergetic neutron beam. The experimental results are in good agreement with Monte Carlo simulations carried out with the FLUKA code.