Application of a new spectral deconvolution method for in vitro dosimetry in assessment of targeted alpha therapy.

BACKGROUND: The improvement of in vitro assessment of targeted alpha therapy (reproducibility, comparability of experiments…) requires precise evaluation of the dose delivered to the cells. To answer this need, a previous study proposed an innovative dosimetry method based on α-spectroscopy and a specific deconvolution process to recover the spatial distribution of 212 Pb isotopes inside in vitro culture wells. Nevertheless, although promising, the deconvolution method was time consuming and only tested for a simple isotope decay chain. PURPOSE: The purpose of this work is to propose a new matrix deconvolution method of α spectra based on a constrained-non-negative-maximum-likelihood decomposition, both faster and offering a greater modelling flexibility, allowing to study independently the kinetics of each of the daughter nuclides of complex decay chains (illustrated here with 223 Ra) in in vitro culture wells. METHODS: Firstly, the performance of the new method was fully evaluated through Monte Carlo simulations of in vitro irradiations. Different spatial distributions of 212 Pb and 223 Ra, the corresponding α spectra measured by a silicon detector and the doses delivered to the cells were simulated with Geant4. The deconvolution results were then compared to the simulation results. Secondly, measurements were carried out in culture wells without cells containing 15 kBq of 212 Pb or 9.3 kBq of 223 Ra, placed above silicon detectors recording α spectra in real time. The matrix deconvolution was then applied to determine the spatial and temporal distribution of all α-emitting daughters of studied isotopes. RESULTS: The matrix deconvolution was proved to recover the simulated distribution gradients, ensuring simulated doses within 3 % for both tested radionuclides, with errors on dose normally distributed around the reference value (consequently not exhibiting any bias), even in the case of complex decay chains as 223 Ra. The experimental study of 212 Pb and 223 Ra showed highly inhomogeneous distributions and time evolution of the concentration gradients, consistent with the previous study. Furthermore, it highlighted the complex kinetics of 223 Ra with different distributions of its α-emitting daughters (219 Rn, 215 Po, 215 At, 211 Bi, 211 Po). CONCLUSIONS: This study validates a new deconvolution method, fast and flexible, that proved to be accurate and reliable. This method allowed to reveal the complexity of isotopes kinetics in in vitro experiments, especially with complex decay chains. Experimental dosimetry, necessary to improve reliability of in vitro studies in targeted alpha therapy, is demonstrated to be feasible with the proposed method.

VCAM-1 targeted alpha-particle therapy for early brain metastases.

BACKGROUND: Brain metastases (BM) develop frequently in patients with breast cancer. Despite the use of external beam radiotherapy (EBRT), the average overall survival is short (6 months from diagnosis). The therapeutic challenge is to deliver molecularly targeted therapy at an early stage when relatively few metastatic tumor cells have invaded the brain. Vascular cell adhesion molecule 1 (VCAM-1), overexpressed by nearby endothelial cells during the early stages of BM development, is a promising target. The aim of this study was to investigate the therapeutic value of targeted alpha-particle radiotherapy, combining lead-212 (212Pb) with an anti-VCAM-1 antibody (212Pb-αVCAM-1). METHODS: Human breast carcinoma cells that metastasize to the brain, MDA-231-Br-GFP, were injected into the left cardiac ventricle of nude mice. Twenty-one days after injection, 212Pb-αVCAM-1 uptake in early BM was determined in a biodistribution study and systemic/brain toxicity was evaluated. Therapeutic efficacy was assessed using MR imaging and histology. Overall survival after 212Pb-αVCAM-1 treatment was compared with that observed after standard EBRT. RESULTS: 212Pb-αVCAM-1 was taken up into early BM with a tumor/healthy brain dose deposition ratio of 6 (5.52e108 and 0.92e108) disintegrations per gram of BM and healthy tissue, respectively. MRI analyses showed a statistically significant reduction in metastatic burden after 212Pb-αVCAM-1 treatment compared with EBRT (P < 0.001), translating to an increase in overall survival of 29% at 40 days post prescription (P < 0.01). No major toxicity was observed. CONCLUSIONS: The present investigation demonstrates that 212Pb-αVCAM-1 specifically accumulates at sites of early BM causing tumor growth inhibition.

In vivo surface dosimetry with a scintillating fiber dosimeter in preclinical image-guided radiotherapy.

PURPOSE: New preclinical image-guided irradiators and treatment planning systems represent a huge progress in radiobiology. Nevertheless, quality control of preclinical treatments is not as advanced as in clinical radiotherapy and in vivo dosimetry is less developed. In this study, we evaluate the use of a scintillating fiber dosimeter called DosiRat to verify the agreement between the doses planned with SmART-Plan and the measured doses during small animal irradiations. METHODS: In vivo dosimetry was first evaluated with DosiRat through dose measurements performed at the surface of a 3 × 9 × 3 cm3 phantom. Measured and planned doses were compared for different irradiation conditions (prescription point, anterior, and posterior beams, 5 mm and 10 mm irradiation fields). In a second phase, measured and planned doses were compared for rat brain irradiations performed with anterior beams, with DosiRat positioned at the beam entrance. Comparisons were performed for different tube currents (1.3 and 13 mA), collimations (5, 10 and 25 mm diameter), and planned doses (0.1, 0.5, 2, and 10 Gy). RESULTS: In the case of the phantom irradiations, planned and measured doses showed discrepancies smaller than the 5% accuracy of the TPS, except in cases in which the dosimeter was not centered in the irradiation field. The differences were larger for animal irradiations (from -3.3% to 8.8%) because of variations of the beam energy spectrum and the nonequivalence between materials at medium and low energy. CONCLUSIONS: This study highlighted the complexity to implement one-dimension in vivo dosimetry in orthovoltage millimetric beams. Nevertheless, DosiRat is well adapted to in vivo dosimetry because of its small volume and its direct reading and allowed in vivo control of planned doses for anterior beams down to 5 mm diameter.

Radionuclide spatial distribution and dose deposition for in vitro assessments of 212 Pb-αVCAM-1 targeted alpha therapy.

PURPOSE: Targeted alpha therapy (TAT) takes advantage of the short-range and high-linear energy transfer of α-particles and is increasingly used, especially for the treatment of metastatic lesions. Nevertheless, dosimetry of α-emitters is challenging for the very same reasons, even for in vitro experiments. Assumptions, such as the uniformity of the distribution of radionuclides in the culture medium, are commonly made, which could have a profound impact on dose calculations. In this study we measured the spatial distribution of α-emitting 212 Pb coupled to an anti-VCAM-1 antibody (212 Pb-αVCAM-1) and its evolution over time in the context of in vitro irradiations. METHODS: Two experimental setups were implemented without cells to measure α-particle count rates and energy spectra in culture medium containing 15 kBq of 212 Pb-α-VCAM-1. Silicon detectors were placed above and below cell culture dishes for 20 h. One of the dishes had a 2.5-µm-thick mylar-base allowing easy detection of the α-particles. Monte Carlo simulations were performed to analyze experimental spectra. Experimental setups were modeled and α-energy spectra were simulated in the silicon detectors for different decay positions in the culture medium. Simulated spectra were then used to deconvolute experimental spectra to determine the spatial distribution of 212 Pb-αVCAM-1 in the medium. This distribution was finally used to calculate the dose deposition in cell culture experiments. RESULTS: Experimental count rates and energy spectra showed differences in measurements taken at the top and the bottom of dishes and temporal variations that did not follow 212 Pb decay. The radionuclide spatial distribution was shown to be composed of a uniform distribution and concentration gradients at the top and the bottom, which were subjected to temporal variations that may be explained by gravity and electrostatic attraction. The absorbed dose in cells calculated from this distribution was compared with the dose expected for a uniform and static distribution and found to be 1.75 times higher, which is highly significant to interpret biological observations. CONCLUSIONS: This study demonstrated that accurate dosimetry of α-emitters requires the experimental determination of radionuclide spatial and temporal distribution and highlighted that in vitro assessment of dose for TAT cannot only rely on a uniform distribution of activity in the culture medium. The reliability and reproducibility of future experiments should benefit from specifically developed dosimetry tools and methods.

Characterization of a scintillating fibre detector for small animal imaging and irradiation dosimetry.

OBJECTIVE: Small animal image-guided irradiators have recently been developed to mimic the delivery techniques of clinical radiotherapy. A dosemeter adapted to millimetric beams of medium-energy X-rays is then required. This work presents the characterization of a dosemeter prototype for this particular application. METHODS: A scintillating optical fibre dosemeter (called DosiRat) has been implemented to perform real-time dose measurements with the dedicated small animal X-RAD® 225Cx (Precision X-Ray, Inc., North Branford, CT) irradiator. Its sensitivity, stem effect, stability, linearity and measurement precision were determined in large field conditions for three different beam qualities, consistent with small animal irradiation and imaging parameters. RESULTS: DosiRat demonstrates good sensitivity and stability; excellent air kerma and air kerma rate linearity; and a good repeatability for air kerma rates >1 mGy s-1. The stem effect was found to be negligible. DosiRat showed limited precision for low air kerma rate measurements (<1 mGy s-1), typically for imaging protocols. A positive energy dependence was found that can be accounted for by calibrating the dosemeter at the needed beam qualities. CONCLUSION: The dosimetric performances of DosiRat are very promising. Extensive studies of DosiRat energy dependence are still required. Further developments will allow to reduce the dosemeter size to ensure millimetric beams dosimetry and perform small animal in vivo dosimetry. Advances in knowledge: Among existing point dosemeters, very few are dedicated to both medium-energy X-rays and millimetric beams. Our work demonstrated that scintillating fibre dosemeters are suitable and promising tools for real-time dose measurements in the small animal field of interest.

Development of a dynamic phantom and investigation of mobile target imaging and irradiation in preclinical small animal research.

OBJECTIVE: Progress made in preclinical radiotherapy makes respiratory gating reachable. Nevertheless, technical means are still needed, as well as accurate investigations of the effect of motion on small animal treatment plans. METHODS: An animal-scaled dynamic phantom (0.3-11.1-mm motion peak-to-peak amplitude, 30-120 cycles per minute) was developed and characterized. It was used to evaluate respiratory monitoring and high resolution imaging (µPET/CT scans). The width and position variations of a fluorine-18 solution were measured for various motions and gating configurations. The phantom was finally used to measure the impact of motion on dose distribution for vertical irradiation using 2.5- and 5-mm collimations. RESULTS: Phantom motions accurately reproduced original waveforms with good rate and amplitude linearity (R2 = 1 and R2 = 0.9995, respectively). µPET/CT acquisitions showed an increase of 92% of the target size caused by a 4.9-mm sine motion and reduced to <12% by gating. Target motion measurements showed consistency better than 18% between modalities. Irradiations showed that motions >0.8 and 1.1 mm (for the 2.5- and 5-mm collimations, respectively) significantly impact dose homogeneity in the target. CONCLUSION: The phantom allowed studying motion in small animal imaging and irradiation. It showed the important impact of motions >2 mm and provided accurate data to improve the management of mobile tumour irradiation. The implementation of gated irradiation, associated with motion-compensated imaging, is currently under progress. Advances in knowledge: Small animal irradiation gating is not yet used in preclinical studies. As few solutions are under development, tools and accurate studies are highly needed.