Consistency of Faraday cup and ionization chamber dosimetry of proton fields and the role of nuclear interactions.

BACKGROUND: A Faraday cup (FC) facilitates a quite clean measurement of the proton fluence emerging from clinical spot-scanning nozzles with narrow pencil-beams. The utilization of FCs appears to be an attractive option for high dose rate delivery modes and the source models of Monte-Carlo (MC) dose engines. However, previous studies revealed discrepancies of 3%-6% between reference dosimetry with ionization chambers (ICs) and FC-based dosimetry. This has prevented the widespread use of FCs for dosimetry in proton therapy. PURPOSE: The current study aims at bridging the gap between FC dosimetry and IC dosimetry of proton fields delivered with spot-scanning treatment heads. Particularly, a novel method to evaluate FC measurements is introduced. METHODS: A consistency check is formulated, which makes use of the energy balance and the reciprocity theorem. The measurement data comprise central-axis depth distributions of the absorbed dose of quasi-monochromatic fields with a width of about 28.5 cm and FC measurements of the reciprocal fields with a single spot. These data are complemented by a look-up of energy-range tables, the average Q-value of transmutations, and the escape energy carried away by neutrons and photons. The latter data are computed by MC simulations, which in turn are validated with measurements of the distal dose tail and neutron out-of-field doses. For comparison, the conventional approach of FC evaluation is performed, which computes absorbed dose from the product of fluence and stopping power. The results from the FC measurements are compared with the standard dosimetry protocols and improved reference dosimetry methods. RESULTS: The deviation between the conventional FC-based dosimetry and the IC-based one according to standard dosimetry protocols was -4.7 ( ± $\pm$ 3.3)% for a 100 MeV field and -3.6 ( ± $\pm$ 3.5)% for 200 MeV, thereby agreeing within the reported uncertainties. The deviations could be reduced to -4.0 ( ± $\pm$ 2.9)% and -3.0 ( ± $\pm$ 3.1)% by adopting state-of-the-art reference dosimetry methods. The alternative approach using the energy balance gave deviations of only -1.9% (100 MeV) and -2.6% (200 MeV) using state-of-the-art dosimetry. The standard uncertainty of this novel approach was estimated to be about 2%. CONCLUSIONS: An alternative concept has been established to determine the absorbed dose of monoenergetic proton fields with an FC. It eliminates the strong dependence of the conventional FC-based approach on the MC simulation of the stopping-power and of the secondary ions, which according to the study at hand is the major contributor to the underestimation of the absorbed dose. Some contributions to the uncertainty of the novel approach could potentially be reduced in future studies. This would allow for accurate consistency tests of conventional dosimetry procedures.

Preclinical Dosimetry for Small Animal Radiation Research in Proton Therapy: A Feasibility Study.

Purpose: To evaluate the feasibility of the three-dimensional (3D) printed small animal phantoms in dosimetric verification of proton therapy for small animal radiation research. Materials and Methods: Two different phantoms were modeled using the computed-tomography dataset of real rat and tumor-bearing mouse, retrospectively. Rat phantoms were designed to accommodate both EBT3 film and ionization chamber. A subcutaneous tumor-bearing mouse phantom was only modified to accommodate film dosimetry. All phantoms were printed using polylactic-acid (PLA) filament. Optimal printing parameters were set to create tissue-equivalent material. Then, proton therapy plans for different anatomical targets, including whole brain and total lung irradiation in the rat phantom and the subcutaneous tumor model in the mouse phantom, were created using the pencil-beam scanning technique. Point dose and film dosimetry measurements were performed using 3D-printed phantoms. In addition, all phantoms were analyzed in terms of printing accuracy and uniformity. Results: Three-dimensionally printed phantoms had excellent uniformity over the external body, and printing accuracy was within 0.5 mm. According to our findings, two-dimensional dosimetry with EBT3 showed acceptable levels of γ passing rate for all measurements except for whole brain irradiation (γ passing rate, 89.8%). In terms of point dose analysis, a good agreement (<0.1%) was found between the measured and calculated point doses for all anatomical targets. Conclusion: Three-dimensionally printed small animal phantoms show great potential for dosimetric verifications of clinical proton therapy for small animal radiation research.

Biophysical characterization of collimated and uncollimated fields in pencil beam scanning proton therapy.

Objective. The lateral dose fall-off in proton pencil beam scanning (PBS) technique remains the preferred choice for sparing adjacent organs at risk as opposed to the distal edge due to the proton range uncertainties and potentially high relative biological effectiveness. However, because of the substantial spot size along with the scattering in the air and in the patient, the lateral penumbra in PBS can be degraded. Combining PBS with an aperture can result in a sharper dose fall-off, particularly for shallow targets.Approach. The aim of this work was to characterize the radiation fields produced by collimated and uncollimated 100 and 140 MeV proton beams, using Monte Carlo simulations and measurements with a MiniPIX-Timepix detector. The dose and the linear energy transfer (LET) were then coupled with publishedin silicobiophysical models to elucidate the potential biological effects of collimated and uncollimated fields.Main results. Combining an aperture with PBS reduced the absorbed dose in the lateral fall-off and out-of-field by 60%. However, the results also showed that the absolute frequency-averaged LET (LETF) values increased by a maximum of 3.5 keVµm-1in collimated relative to uncollimated fields, while the dose-averaged LET (LETD) increased by a maximum of 7 keVµm-1. Despite the higher LET values produced by collimated fields, the predicted DNA damage yields remained lower, owing to the large dose reduction.Significance. This work demonstrated the dosimetric advantages of combining an aperture with PBS coupled with lower DNA damage induction. A methodology for calculating dose in water derived from measurements with a silicon-based detector was also presented. This work is the first to demonstrate experimentally the increase in LET caused by combining PBS with aperture, and to assess the potential DNA damage which is the initial step in the cascade of events leading to the majority of radiation-induced biological effects.

Complete patient exposure during paediatric brain cancer treatment for photon and proton therapy techniques including imaging procedures.

Background: In radiotherapy, especially when treating children, minimising exposure of healthy tissue can prevent the development of adverse outcomes, including second cancers. In this study we propose a validated Monte Carlo framework to evaluate the complete patient exposure during paediatric brain cancer treatment. Materials and methods: Organ doses were calculated for treatment of a diffuse midline glioma (50.4 Gy with 1.8 Gy per fraction) on a 5-year-old anthropomorphic phantom with 3D-conformal radiotherapy, intensity modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT) and intensity modulated pencil beam scanning (PBS) proton therapy. Doses from computed tomography (CT) for planning and on-board imaging for positioning (kV-cone beam CT and X-ray imaging) accounted for the estimate of the exposure of the patient including imaging therapeutic dose. For dose calculations we used validated Monte Carlo-based tools (PRIMO, TOPAS, PENELOPE), while lifetime attributable risk (LAR) was estimated from dose-response relationships for cancer induction, proposed by Schneider et al. Results: Out-of-field organ dose equivalent data of proton therapy are lower, with doses between 0.6 mSv (testes) and 120 mSv (thyroid), when compared to photon therapy revealing the highest out-of-field doses for IMRT ranging between 43 mSv (testes) and 575 mSv (thyroid). Dose delivered by CT ranged between 0.01 mSv (testes) and 72 mSv (scapula) while a single imaging positioning ranged between 2 µSv (testes) and 1.3 mSv (thyroid) for CBCT and 0.03 µSv (testes) and 48 µSv (scapula) for X-ray. Adding imaging dose from CT and daily CBCT to the therapeutic demonstrated an important contribution of imaging to the overall radiation burden in the course of treatment, which is subsequently used to predict the LAR, for selected organs. Conclusion: The complete patient exposure during paediatric brain cancer treatment was estimated by combining the results from different Monte Carlo-based dosimetry tools, showing that proton therapy allows significant reduction of the out-of-field doses and secondary cancer risk in selected organs.

Validation of a Monte Carlo Framework for Out-of-Field Dose Calculations in Proton Therapy.

Proton therapy enables to deliver highly conformed dose distributions owing to the characteristic Bragg peak and the finite range of protons. However, during proton therapy, secondary neutrons are created, which can travel long distances and deposit dose in out-of-field volumes. This out-of-field absorbed dose needs to be considered for radiation-induced secondary cancers, which are particularly relevant in the case of pediatric treatments. Unfortunately, no method exists in clinics for the computation of the out-of-field dose distributions in proton therapy. To help overcome this limitation, a computational tool has been developed based on the Monte Carlo code TOPAS. The purpose of this work is to evaluate the accuracy of this tool in comparison to experimental data obtained from an anthropomorphic phantom irradiation. An anthropomorphic phantom of a 5-year-old child (ATOM, CIRS) was irradiated for a brain tumor treatment in an IBA Proteus Plus facility using a pencil beam dedicated nozzle. The treatment consisted of three pencil beam scanning fields employing a lucite range shifter. Proton energies ranged from 100 to 165 MeV. A median dose of 50.4 Gy(RBE) with 1.8 Gy(RBE) per fraction was prescribed to the initial planning target volume (PTV), which was located in the cerebellum. Thermoluminescent detectors (TLDs), namely, Li-7-enriched LiF : Mg, Ti (MTS-7) type, were used to detect gamma radiation, which is produced by nuclear reactions, and secondary as well as recoil protons created out-of-field by secondary neutrons. Li-6-enriched LiF : Mg,Cu,P (MCP-6) was combined with Li-7-enriched MCP-7 to measure thermal neutrons. TLDs were calibrated in Co-60 and reported on absorbed dose in water per target dose (µGy/Gy) as well as thermal neutron dose equivalent per target dose (µSv/Gy). Additionally, bubble detectors for personal neutron dosimetry (BD-PND) were used for measuring neutrons (>50 keV), which were calibrated in a Cf-252 neutron beam to report on neutron dose equivalent dose data. The Monte Carlo code TOPAS (version 3.6) was run using a phase-space file containing 1010 histories reaching an average standard statistical uncertainty of less than 0.2% (coverage factor k = 1) on all voxels scoring more than 50% of the maximum dose. The primary beam was modeled following a Fermi-Eyges description of the spot envelope fitted to measurements. For the Monte Carlo simulation, the chemical composition of the tissues represented in ATOM was employed. The dose was tallied as dose-to-water, and data were normalized to the target dose (physical dose) to report on absorbed doses per target dose (mSv/Gy) or neutron dose equivalent per target dose (µSv/Gy), while also an estimate of the total organ dose was provided for a target dose of 50.4 Gy(RBE). Out-of-field doses showed absorbed doses that were 5 to 6 orders of magnitude lower than the target dose. The discrepancy between TLD data and the corresponding scored values in the Monte Carlo calculations involving proton and gamma contributions was on average 18%. The comparison between the neutron equivalent doses between the Monte Carlo simulation and the measured neutron doses was on average 8%. Organ dose calculations revealed the highest dose for the thyroid, which was 120 mSv, while other organ doses ranged from 18 mSv in the lungs to 0.6 mSv in the testes. The proposed computational method for routine calculation of the out-of-the-field dose in proton therapy produces results that are compatible with the experimental data and allow to calculate out-of-field organ doses during proton therapy.

Latanoprost stimulates secretion of matrix metalloproteinases in tenon fibroblasts both in vitro and in vivo.

PURPOSE: To investigate the presence and the possible role of different matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in Tenon capsule fibroblasts. These enzymes are essential for the control of tissue remodeling in the context of wound repair. This aspect is important to further the understanding of and possibly to influence the scarring process of filtering blebs after glaucoma surgery. METHODS: Untreated and latanoprost-treated human Tenon fibroblasts were examined for the presence of MMPs and TIMPs on the mRNA and protein levels. Assays performed included RT-PCR, real-time RT-PCR, immunocytochemistry, Western blot analysis, flow cytometry, and zymography. To investigate the changes in vivo, conjunctival specimens of rabbits treated with latanoprost eye drops were examined by immunohistochemistry. RESULTS: In all assays, both MMP-3 and TIMP-2 were detected. With the real-time RT-PCR technique, MMP-1, -2, -3, -7, -9, and -14 and TIMP-1 and -2 were detected. An upregulation of MMP-3 and TIMP-2 after latanoprost treatment of the fibroblasts was shown and found to occur on the mRNA and the protein levels. The upregulation of MMP-3 and TIMP-2 was confirmed in vivo. CONCLUSIONS: Tenon fibroblasts contain the ability on the mRNA level to synthesize all enzymes of the MMP and TIMP family that are related to remodeling of the extracellular matrix. The levels of MMP-3 and TIMP-2 increase after treatment with latanoprost. Tenon fibroblasts may be the target cells for attempts to influence the tissue levels of MMPs and TIMPs in the context of conjunctival wound healing after glaucoma surgery.

Mitomycin C induces multidrug resistance in glaucoma surgery.

BACKGROUND: Despite the adjuvant use of mitomycin C during trabeculectomy, failures still occur. We investigated whether cultured human Tenon fibroblasts exposed to low-dose mitomycin C developed a multidrug resistance phenotype in vitro, and whether mitomycin C treatment during previous filtration surgery induces P-glycoprotein expression in vivo. METHODS: Cultured human Tenon fibroblasts treated with low-dose 0.01 nM mitomycin C for 2 weeks were subsequently treated with 0.1 to 100 microM mitomycin C in the absence or presence of 4 microM verapamil, and allowed to recover for 24 hours. Low-dose mitomycin C-treated fibroblasts were analysed for P-glycoprotein expression using flow cytometry, immunoblotting, and RT-PCR for mdr-1 mRNA. In addition, fibroblasts were treated with low dose 0.1 nM 5-fluorouracil for 2 weeks and analysed for P-glycoprotein expression using flow cytometry. Expression of P-glycoprotein was analysed in surgically removed Tenon tissue (n = 30) using immunohistochemistry. Of the 30 patients, 20 had a previous trabeculectomy, of which nine had previous adjuvant therapy with mitomycin C during trabeculectomy. RESULTS: Partial resistance to mitomycin C after low-dose mitomycin C pre-treatment was significantly neutralised by the addition of verapamil. Low-dose mitomycin C up-regulated P-glycoprotein expression, but not mdr-1 mRNA expression. 5-Fluorouracil did not induce P-glycoprotein expression. P-glycoprotein expression was detected in all nine patients exposed to mitomycin C during previous trabeculectomies. Only six of 21 specimens from patients not previously exposed to mitomycin C showed faint P-glycoprotein expression. CONCLUSION: The induction of P-glycoprotein by mitomycin C could explain some failures that occur after repeated use of mitomycin C during trabeculectomy. The concomitant use of verapamil or the use of 5-fluorouracil alone could increase the success rate of repeat trabeculectomies.