Diamond based integrated detection system for dosimetric and microdosimetric characterization of radiotherapy ion beams.

BACKGROUND: Ion beam therapy allows for a substantial sparing of normal tissues and higher biological efficacy. Synthetic single crystal diamond is a very good material to produce high-spatial-resolution and highly radiation hard detectors for both dosimetry and microdosimetry in ion beam therapy. PURPOSE: The aim of this work is the design, fabrication and test of an integrated waterproof detector based on synthetic single crystal diamond able to simultaneously perform dosimetric and microdosimetric characterization of clinical ion beams. METHODS: The active elements of the integrated diamond device, that is, dosimeter and microdosimeter, were both realized in a Schottky diode configuration featured by different area, thickness, and shape by means of photolithography technologies for the selective growth of intrinsic and boron-doped CVD diamond. The cross-section of the sensitive volume of the dosimetric element is 4 mm2 and 1 µm-thick, while the microdosimetric one has an active cross-sectional area of 100 × 100 µm2 and a thickness of about 6.2 µm. The dosimetric and microdosimetric performance of the developed device was assessed at different depths in a water phantom at the MedAustron ion beam therapy facility using a monoenergetic uniformly scanned carbon ion beam of 284.7 MeV/u and proton beam of 148.7 MeV. The particle flux in the region of the microdosimeter was 6·107  cm2 /s for both irradiation fields. At each depth, dose and dose distributions in lineal energy were measured simultaneously and the dose mean lineal energy values were then calculated. Monte Carlo simulations were also carried out by using the GATE-Geant4 code to evaluate the relative dose, dose averaged linear energy transfer (LETd ), and microdosimetric spectra at various depths in water for the radiation fields used, by considering the contribution from the secondary particles generated in the ion interaction processes as well. RESULTS: Dosimetric and microdosimetric quantities were measured by the developed prototype with relatively low noise (∼2 keV/µm). A good agreement between the measured and simulated dose profiles was found, with discrepancies in the peak to plateau ratio of about 3% and 4% for proton and carbon ion beams respectively, showing a negligible LET dependence of the dosimetric element of the device. The microdosimetric spectra were validated with Monte Carlo simulations and a good agreement between the spectra shapes and positions was found. Dose mean lineal energy values were found to be in close agreement with those reported in the literature for clinical ion beams, showing a sharp increase along the Bragg curve, being also consistent with the calculated LETd for all depths within the experimental error of 10%. CONCLUSIONS: The experimental indicate that the proposed device can allow enhanced dosimetry in particle therapy centers, where the absorbed dose measurement is implemented by the microdosimetric characterization of the radiation field, thus providing complementary results. In addition, the proposed device allows for the reduction of the experimental uncertainties associated with detector positioning and could facilitate the partial overcoming of some drawbacks related to the low sensitivity of diamond microdosimeters to low LET radiation.

First microdosimetric measurements with a tissue-equivalent proportional counter at the MedAustron ion-beam therapy facility.

The aim of this work is to present the first microdosimetric spectra measured with a miniaturised tissue-equivalent proportional counter in the clinical environment of the MedAustron ion-beam therapy facility. These spectra were gathered with a 62.4-MeV proton beam and have been compared with microdosimetric spectra measured in the 62-MeV clinical proton beam of the CATANA beam line. Monte Carlo simulations were performed using the Geant4 toolkit GATE and a fully commissioned clinical beam line model. Finally, similarities and discrepancies of the measured data to simulations based on a simple and complex detector geometry are discussed.

3D printed 2D range modulators preserve radiation quality on a microdosimetric scale in proton and carbon ion beams.

INTRODUCTION: Particle therapy using pencil beam scanning (PBS) faces large uncertain- ties related to ranges and target motion. One possibility to improve existing mitigation strategies is a 2D range modulator (2DRM). A 2DRM offers faster irradiation times by reducing the number of layers and spots needed to create a spread-out Bragg peak. We have investigated the impact of 2DRM on microdosimetric spectra measured in proton and carbon ion beams. MATERIALS AND METHODS: Two 2DRMs were designed and 3D printed, one for. 124.7 MeV protons and one for 238.6 MeV/u carbon ions. Their dosimetric validation was performed using Roos and PinPoint ionization chamber and EBT3 films. Monte Carlo simulations were done using GATE. A silicon-based solid-state microdosimeter was used to collect pulse-height spectra along three depths for two irradiation modalities, PBS and a single central beam. RESULTS: For both particle types, the original pin design had to be optimized via GATE simulations. The difference between the R80 of the simulated and measured depth dose curve was 0.1 mm. The microdosimetric spectra collected with the two irradiation modalities overlap well. Their mean lineal energy values differ over all positions by 5.2 % for the proton 2DRM and 2.1 % for the carbon ion 2DRM. CONCLUSION: Radiation quality in terms of lineal energy was independent of the irradiation method. This supports the current approach in reference dosimetry, where the residual range is chosen as a beam quality index to select stopping power ratios.

Cellular and Molecular Biological Alterations after Photon, Proton, and Carbon Ions Irradiation in Human Chondrosarcoma Cells Linked with High-Quality Physics Data.

Chondrosarcomas are particularly difficult to treat due to their resistance to chemotherapy and radiotherapy. However, particle therapy can enhance local control and patient survival rates. To improve our understanding of the basic cellular radiation response, as a function of dose and linear energy transfer (LET), we developed a novel water phantom-based setup for cell culture experiments and characterized it dosimetrically. In a direct comparison, human chondrosarcoma cell lines were analyzed with regard to their viability, cell proliferation, cell cycle, and DNA repair behavior after irradiation with X-ray, proton, and carbon ions. Our results clearly showed that cell viability and proliferation were inhibited according to the increasing ionization density, i.e., LET, of the irradiation modes. Furthermore, a prominent G2/M arrest was shown. Gene expression profiling proved the upregulation of the senescence genes CDKN1A (p21), CDKN2A (p16NK4a), BMI1, and FOXO4 after particle irradiation. Both proton or C-ion irradiation caused a positive regulation of the repair genes ATM, NBN, ATXR, and XPC, and a highly significant increase in XRCC1/2/3, ERCC1, XPC, and PCNA expression, with C-ions appearing to activate DNA repair mechanisms more effectively. The link between the physical data and the cellular responses is an important contribution to the improvement of the treatment system.

On the measurement uncertainty of microdosimetric quantities using diamond and silicon microdosimeters in carbon-ion beams.

PURPOSE: The purpose of this paper is to compare the response of two different types of solid-state microdosimeters, that is, silicon and diamond, and their uncertainties. A study of the conversion of silicon microdosimetric spectra to the diamond equivalent for microdosimeters with different geometry of the sensitive volumes is performed, including the use of different stopping power databases. METHOD: Diamond and silicon microdosimeters were irradiated under the same conditions, aligned at the same depth in a carbon-ion beam at the MedAustron ion therapy center. In order to estimate the microdosimetric quantities, the readout electronic linearity was investigated with three different methods, that is, the first being a single linear regression, the second consisting of a double linear regression with a channel transition and last a multiple linear regression by splitting the data into odd and even groups. The uncertainty related to each of these methods was estimated as well. The edge calibration was performed using the intercept with the horizontal axis of the tangent through the inflection point of the Fermi function approximation multi-channel analyzer spectrum. It was assumed that this point corresponds to the maximum energy difference of particle traversing the sensitive volume (SV) for which the residual range difference in the continuous slowing down approximation is equal to the thickness of the SV of the microdosimeter. Four material conversion methods were explored, the edge method, the density method, the maximum-deposition energy method and the bin-by-bin transformation method. The uncertainties of the microdosimetric quantities resulting from the linearization, the edge calibration and the detectors thickness were also estimated. RESULTS: It was found that the double linear regression had the lowest uncertainty for both microdosimeters. The propagated standard (k = 1) uncertainties on the frequency-mean lineal energy y ¯ F ${\bar{y}}_{\rm{F}}$ and the dose-mean lineal energy y ¯ D ${\bar{y}}_{\rm{D}}$ values from the marker point, in the spectra, in the plateau were 0.1% and 0.2%, respectively, for the diamond microdosimeter, whilst for the silicon microdosimeter data converted to diamond, the uncertainty was estimated to be 0.1%. In the range corresponding to the 90% of the amplitude of the Bragg Peak at the distal part of the Bragg curve (R90 ) the uncertainty was found to be 0.1%. The uncertainty propagation from the stopping power tables was estimated to be between 5% and 7% depending on the method. The uncertainty on the y ¯ F ${\bar{y}}_{\rm{F}}$ and y ¯ D ${\bar{y}}_{\rm{D}}$ coming from the thickness of the detectors varied between 0.3% and 0.5%. CONCLUSION: This article demonstrate that the linearity of the readout electronics affects the microdosimetric spectra with a difference in y ¯ F ${\bar{y}}_{\rm{F}}$ values between the different linearization methods of up to 17.5%. The combined uncertainty was dominated by the uncertainty of stopping power on the edge.

Technical note: Experimental determination of the effective point of measurement of the PTW-31010 ionization chamber in proton and carbon ion beams.

PURPOSE: The accurate knowledge of the effective point of measurement (Peff ) is particularly important for measurements in proximity to high dose gradients such as in the distal fall-off of particle beams. For plane-parallel ionization chambers (ICs), Peff is well known and located at the center of the inner surface of the entrance window. For cylindrical ICs, Peff is shifted from the chamber's center toward the beam source. According to IAEA TRS-398, this shift can be calculated as 0.75·rcyl for light ions with rcyl being the radius of the cavity. For proton beams and in absence of a dose gradient, no shift is recommended. We have experimentally determined Peff for the 0.125 cc Semiflex IC in both proton and carbon ion beams. METHODS: The first method consisted of simultaneous irradiation of a plane-parallel IC and the Semiflex in a 4-cm wide spread-out Bragg peak. In the second method, a single-energy beam was used, and both ICs were positioned successively at the same measurement depths. For both approaches, the shift of the distal edge of the depth ionization distributions recorded by the two chambers at different reference points was used to calculate Peff of the Semiflex. Both methods were applied in carbon ion beams, and only the latter was applied in proton beams. RESULTS: Both methods yielded a similar Peff for carbon ions, 0.88·rcyl , and 0.84·rcyl , which results in a difference of only 0.1 mm. The difference to the recommended value of 0.75·rcyl is 0.4 and 0.3 mm, respectively, which is larger than the positioning uncertainty. In the proton beam, a Peff of 0.92·rcyl was obtained. CONCLUSIONS: The Peff for the 0.125 cc Semiflex IC is shifted further from the cavity center as recommended by IAEA TRS-398 for light ions, with the shift for proton beams being even larger than for carbon ion beams.

Human Biodistribution and Radiation Dosimetry of the P-Glycoprotein Radiotracer [11C]Metoclopramide.

PURPOSE: To assess in healthy volunteers the whole-body distribution and dosimetry of [11C]metoclopramide, a new positron emission tomography (PET) tracer to measure P-glycoprotein activity at the blood-brain barrier. PROCEDURES: Ten healthy volunteers (five women, five men) were intravenously injected with 387 ± 49 MBq of [11C]metoclopramide after low dose CT scans and were then imaged by whole-body PET scans from head to upper thigh over approximately 70 min. Ten source organs (brain, thyroid gland, right lung, myocardium, liver, gall bladder, left kidney, red bone marrow, muscle and the contents of the urinary bladder) were manually delineated on whole-body images. Absorbed doses were calculated with QDOSE (ABX-CRO) using the integrated IDAC-Dose 2.1 module. RESULTS: The majority of the administered dose of [11C]metoclopramide was taken up into the liver followed by urinary excretion and, to a smaller extent, biliary excretion of radioactivity. The mean effective dose of [11C]metoclopramide was 1.69 ± 0.26 µSv/MBq for female subjects and 1.55 ± 0.07 µSv/MBq for male subjects. The two organs receiving the highest radiation doses were the urinary bladder (10.81 ± 0.23 µGy/MBq and 8.78 ± 0.89 µGy/MBq) and the liver (6.80 ± 0.78 µGy/MBq and 4.91 ± 0.74 µGy/MBq) for female and male subjects, respectively. CONCLUSIONS: [11C]Metoclopramide showed predominantly renal excretion, and is safe and well tolerated in healthy adults. The effective dose of [11C]metoclopramide was comparable to other 11C-labeled PET tracers.

Dose Calculations and Dose-Effect Relationships in 177Lu-PSMA I&T Radionuclide Therapy for Metastatic Castration-Resistant Prostate Cancer.

Dose response of 22 patients experiencing mCRPC (metastatic castration-resistant prostate cancer) to Lu-PSMA I&T radionuclide therapy was investigated. Dosimetry calculations are used to assess correlations between dosimetric quantities and biomarker values. METHODS: The patients' age range was 74 ± 7 years at the time of the investigated treatment cycle, and the mean injected activity was 7416 ± 218 MBq. Planar images at several time points postinjection were used for evaluation of absorbed doses to organs and lesion. Ga-PSMA PET/CT follow-up imaging enabled the determination of individual tumor molecular volume (TMV) shrinkage. Changes in 7 different biomarkers after the first treatment cycle were correlated with the calculated absorbed organ and TMV doses, resulting in a total number of 259 investigated correlations. RESULTS: Sixty-three TMVs were identified in the bone, lymph node, and liver tissue with an average reduction of 32.3%, 84.7%, and 72.9%, respectively. Absorbed doses per unit of administered activity for organs and lesions show good agreement with previous works (0.77, 0.71, and 0.27 mGy/MBq for parotid gland, kidneys, and liver as well as 4.38, 5.47, and 4.95 mGy/MBq for bone, lymph node, and liver malignancies, respectively). Only 37 of 259 possible correlations turned out to be statistically significant, 26 of which are associated with the absorbed dose of an organ and the decrease of alkaline phosphatases. CONCLUSIONS: Although treatment with Lu-PSMA I&T leads to a big reduction of TMV in patients with mCRPC, the lack of correlations calls for studies using voxel-wise dosimetry based on SPECT/CTs.