Brachytherapy on-a-chip: a clinically-relevant approach for radiotherapy testing in 3d biology.

We describe the first microfluidic device for in vitro testing of brachytherapy (BT), with applications in translational cancer research. Our PDMS-made BT-on-chip system allows highly precise manual insertion of clinical BT seeds, reliable dose calculation using standard clinically-used TG-43 formalism and easy culture of naturally hypoxic spheroids in less than 3 days, thereby increasing the translational potential of the device. As the BT-on-chip platform is designed to be versatile, we showcase three different gold-standard post-irradiation bioassays and recapitulate, for the first time on-chip, key clinical observations such as dose rate effect and hypoxia-induced radioresistance. Our results suggest that BT-on-chip can be used to safely and efficiently integrate BT and radiotherapy to translational research and drug development pipelines, without expensive equipment or complex workflows.

Development of a stand-alone precalculated Monte Carlo code to calculate the dose by alpha and beta emitters from the Ra-224 decay chain.

BACKGROUND: Recent developments in alpha and beta emitting radionuclide therapy highlight the importance of developing efficient methods for patient-specific dosimetry. Traditional tabulated methods such as Medical Internal Radiation Dose (MIRD) estimate the dose at the organ level while more recent numerical methods based on Monte Carlo (MC) simulations are able to calculate dose at the voxel level. A precalculated MC (PMC) approach was developed in this work as an alternative to time-consuming fully simulated MC. Once the spatial distribution of alpha and beta emitters is determined using imaging and/or numerical methods, the PMC code can be used to achieve an accurate voxelized 3D distribution of the deposited energy without relying on full MC calculations. PURPOSE: To implement the PMC method to calculate energy deposited by alpha and beta particles emitted from the Ra-224 decay chain. METHODS: The GEANT4 (version 10.7) MC toolkit was used to generate databases of precalculated tracks to be integrated in the PMC code as well as to benchmark its output. In this regard, energy spectra of alpha and beta particles emitted by the Ra-224 decay chain were generated using GAMOS (version 6.2.0) and imported into GEANT4 macro files. Either alpha or beta emitting sources were defined at the center of a homogeneous phantom filled with various materials such as soft tissue, bone, and lung where particles were emitted either mono-directionally (for database generation) or isotropically (for benchmarking). Two heterogeneous phantoms were used to demonstrate PMC code compatibility with boundary crossing events. Each precalculated database was generated step-by-step by storing particle track information from GEANT4 simulations followed by its integration in a PMC code developed in MATLAB. For a user-defined number of histories, one of the tracks in a given database was selected randomly and rotated randomly to reflect an isotropic emission. Afterward, deposited energy was divided between voxels based on step length in each voxel using a ray-tracing approach. The radial distribution of deposited energy was benchmarked against fully simulated MC calculations using GEANT4. The effect of the GEANT4 parameter StepMax on the accuracy and speed of the code was also investigated. RESULTS: In the case of alpha decay, primary alpha particles show the highest contribution (>99%) in deposited energy compared to their secondary particles. In most cases, protons act as the main secondary particles in the deposition of energy. However, for a lung phantom, using a range cutoff parameter of 10 µm on primary alpha particles yields a higher contribution of secondary electrons than protons. Differences between deposited energy calculated by PMC and fully simulated MC are within 2% for all alpha and beta emitters in homogeneous and heterogeneous phantoms. Additionally, statistical uncertainties are less than 1% for voxels with doses higher than 5% of the maximum dose. Moreover, optimization of the parameter StepMax is necessary to achieve the best tradeoff between code accuracy and speed. CONCLUSIONS: The PMC code shows good performance for dose calculations deposited by alpha and beta emitters. As a stand-alone algorithm, it is suitable to be integrated into clinical treatment planning systems.

The Montreal split ring applicator: Towards highly adaptive gynecological brachytherapy using 3D-printed biocompatible patient-specific interstitial caps.

Purpose: The addition of interstitial (IS) needles to intra-cavitary (IC) brachytherapy applicators is associated with improved outcomes in locally advanced cervical cancers involving parametrial tumor extensions. The purpose of this work was to validate a clinical workflow involving 3D-printed caps for a commercial IC split ring applicator that enable using IS needle trajectories tailored to each treatment. Material and methods: A dedicated software module was developed in this work allowing users to design patient-specific IS caps without knowledge of computer-aided design (CAD) software. This software module was integrated to 3D Brachy, a commercial software developed by Adaptiiv Medical Technologies Inc. For validation of the workflow, CAD models of ground truth caps with five IS needle trajectories were designed with Fusion 360™, 3D-printed, assembled with a split ring applicator, and CT-scanned with radio-opaque markers. 3D Brachy was then applied to generate a replica based on trajectories reconstructed from the radio-opaque markers. A comparison between ground truth and replicated IS needle trajectories was done using intersection points with planes at the level of the cervix (z = 0 cm) and a representative needle depth (z = 3 cm). Results: Prototypes of interstitial caps 3D-printed in both BioMed Amber and BioMed Clear SLA resins were tested to be functional both pre- and post-sterilization for IS needles with obliquity angles ≤ 45°. Distance-to-agreement at z = 0 cm and 3 cm as well as deviations in pitch and yaw angles of the five IS needle trajectories were found to have mean values of 3.3 ±2.1 mm, 7.3 ±2.0 mm, 2.9° ±2.3°, and 7.0° ±7.0°, respectively. Conclusions: The clinical workflow for image-guided adaptive cervical cancer brachytherapy using the Montreal split ring applicator was validated.

Radiotherapy on-chip: microfluidics for translational radiation oncology.

The clinical importance of radiotherapy in the treatment of cancer patients justifies the development and use of research tools at the fundamental, pre-clinical, and ultimately clinical levels, to investigate their toxicities and synergies with systemic agents on relevant biological samples. Although microfluidics has prompted a paradigm shift in drug discovery in the past two decades, it appears to have yet to translate to radiotherapy research. However, the materials, dimensions, design versatility and multiplexing capabilities of microfluidic devices make them well-suited to a variety of studies involving radiation physics, radiobiology and radiotherapy. This review will present the state-of-the-art applications of microfluidics in these fields and specifically highlight the perspectives offered by radiotherapy on-a-chip in the field of translational radiobiology and precision medicine. This body of knowledge can serve both the microfluidics and radiotherapy communities by identifying potential collaboration avenues to improve patient care.

X-ray on chip: Quantifying therapeutic synergies between radiotherapy and anticancer drugs using soft tissue sarcoma tumor spheroids.

PURPOSE: Radioresistance, tumor microenvironment, and normal tissue toxicity from radiation limit the efficacy of radiotherapy in treating cancers. These challenges can be tackled by the discovery of new radiosensitizing and radioprotecting agents aimed at increasing the therapeutic efficacy of radiotherapy. The goal of this work was to develop a miniaturized microfluidic platform for the discovery of drugs that could be used in combination with radiotherapy. The microfluidic system will allow the toxicity testing of cancer spheroids to different combinations of radiotherapy and molecular agents. MATERIALS AND METHODS: An orthovoltage-based technique was used to expose the devices to multiple X-ray radiation doses simultaneously. Radiation dose-dependent DNA double-strand breaks in soft tissue sarcoma (STS) spheroids were quantified using comet assays. Analysis of proliferative death using clonogenic assays was also performed, and synergy between treatments with Talazoparib, Pazopanib, AZD7762, and radiotherapy was quantified using dedicated statistical tests. RESULTS: The developed microfluidic system with simple magnetic valves was capable of growing 336 homogeneous STS spheroids. The irradiation of the microfluidic system with an orthovoltage-based technique enabled the screening of sixteen drug-radiotherapy combinations with minimal reagent consumption. Using this framework, we predicted a therapeutic synergy between a novel anticancer drug Talazoparib and radiotherapy for STS. No synergy was found between RT and either Pazopanib or AZD7762, as the combinations were found to be additive. CONCLUSION: This methodology lays the basis for the systemic search for molecular agent/radiotherapy synergies among preexisting pharmaceutical compounds libraries, in the hope to identify failed drug candidates in monotherapy that, in the presence of radiotherapy, would make it through clinical trials.

Detector dose response in megavoltage small photon beams. I. Theoretical concepts.

PURPOSE: To explain the reasons for significant quality correction factors in megavoltage small photon fields and clarify the underlying concepts relevant to dosimetry under such conditions. METHODS: The validity of cavity theory and the requirement of charged particle equilibrium (CPE) are addressed from a theoretical point of view in the context of nonstandard beams. Perturbation effects are described into four main subeffects, explaining their nature and pointing out their relative importance in small photon fields. RESULTS: It is demonstrated that the failure to meet classical cavity theory requirements, such as CPE, is not the reason for significant quality correction factors. On the contrary, it is shown that the lack of CPE alone cannot explain these corrections and that what matters most, apart from volume averaging effects, is the relationship between the lack of CPE in the small field itself and the density of the detector cavity. The density perturbation effect is explained based on Fano's theorem, describing the compensating effect of two main contributions to cavity absorbed dose. Using the same approach, perturbation effects arising from the difference in atomic properties of the cavity medium and the presence of extracameral components are explained. Volume averaging effects are also discussed in detail. CONCLUSIONS: Quality correction factors of small megavoltage photon fields are mainly due to differences in electron density between water and the detector medium and to volume averaging over the detector cavity. Other effects, such as the presence of extracameral components and differences in atomic properties of the detection medium with respect to water, can also play an accentuated role in small photon fields compared to standard beams.

Detector dose response in megavoltage small photon beams. II. Pencil beam perturbation effects.

PURPOSE: To quantify detector perturbation effects in megavoltage small photon fields and support the theoretical explanation on the nature of quality correction factors in these conditions. METHODS: In this second paper, a modern approach to radiation dosimetry is defined for any detector and applied to small photon fields. Fano's theorem is adapted in the form of a cavity theory and applied in the context of nonstandard beams to express four main effects in the form of perturbation factors. The pencil-beam decomposition method is detailed and adapted to the calculation of perturbation factors and quality correction factors. The approach defines a perturbation function which, for a given field size or beam modulation, entirely determines these dosimetric factors. Monte Carlo calculations are performed in different cavity sizes for different detection materials, electron densities, and extracameral components. RESULTS: Perturbation effects are detailed with calculated perturbation functions, showing the relative magnitude of the effects as well as the geometrical extent to which collimating or modulating the beam impacts the dosimetric factors. The existence of a perturbation zone around the detector cavity is demonstrated and the approach is discussed and linked to previous approaches in the literature to determine critical field sizes. CONCLUSIONS: Monte Carlo simulations are valuable to describe pencil beam perturbation effects and detail the nature of dosimetric factors in megavoltage small photon fields. In practice, it is shown that dosimetric factors could be avoided if the field size remains larger than the detector perturbation zone. However, given a detector and beam quality, a full account for the detector geometry is necessary to determine critical field sizes.