Spatiotemporal Fractionation in Radiotherapy

In current clinical practice, radiotherapy treatments are often fractionated, i.e. the total radiation dose is equally divided into small fractions to be delivered daily over a period of few days or weeks. It has recently been shown in silico that spatiotemporal fractionation schemes, i.e. delivering distinct dose distributions in different fractions, can potentially improve the treatment. This is possible if these dose distributions are designed such that different fractions deliver similar doses to normal tissues (i.e. exploit the fractionation effect), but each fraction delivers high single-fraction doses to alternating parts of the tumor (i.e. achieve partial hypofractionation in the tumor). Thereby, the ratio of biological dose in the tumor versus the normal tissue can be improved. In this project, we further developed this innovative and novel concept. In particular, we focused on: 1. Developing new treatment planning algorithms for spatiotemporal fractionation 2. Identifying potential clinical applications of spatiotemporal fractionation with the aim of bringing spatiotemporal fractionation towards the design and implementation of a phase I clinical trial. Spatiotemporal fractionation is associated with higher complexity in treatment planning and delivery. Different plans with distinct dose distributions for different fractions must be designed such that all fractions together deliver the prescribed biological dose to the tumor. To that end, novel mathematical optimization methods for treatment planning have been developed, which are based on the cumulative biological dose rather than the physical dose. In particular, we developed robust treatment planning methods to account for geometric uncertainty in the patient setup and biological uncertainty in the fractionation sensitivity, which may lead to a degradation of the resulting treatment if not accounted for. It was shown that spatiotemporally fractionated treatments can be obtained which are robust against setup errors and uncertainty in the fractionation sensitivity. At the same time, these robust plans maintain most of their dosimetric benefit over uniformly fractionated plans. Besides liver cancer patients and patients with large arteriovenous malformations, patients with multiple brain metastases were identified to be especially well suited for spatiotemporal fractionation, because of the high accuracy in patient positioning. For theses patients, delivering high doses to different metastases in different fractions allows for fractionation of the normal brain dose in between the metastases while increasing the biological dose within the metastases. In addition, novel extensions of spatiotemporal fractionation were investigated. Spatiotemporal fractionation has been combined with other degrees of freedom that can be exploited in fractionated radiotherapy treatments, i.e. the combination of different particle types and treatment techniques, and the use of different beam orientations in different fractions. We showed that in the context of combined proton-photon therapy, spatiotemporal fractionation can be used to determine the optimal dose contribution of the proton and photon fractions to the tumor, thereby improving on simple proportional combination of intensity modulated radiotherapy and intensity modulated proton therapy plans. Also, we demonstrated that the quality of spatiotemporally fractionated treatments can be boosted by selecting fraction-specific beam orientations that are beneficial to treat specific regions of the tumor. To that end, a treatment planning algorithm was developed that allows for simultaneous optimization of multiple non-coplanar arc treatments. Finally, the simultaneous optimization of multiple dose distributions based on the cumulative biological dose is not supported by any commercial treatment planning system. To this end, we implemented a method which allows to import treatment plans optimized using our in-house research treatment planning system into a commercial treatment planning system. Thereby, it is possible to deliver spatiotemporally fractionated treatments in the clinics

Spatiotemporal fractionation schemes for stereotactic radiosurgery of multiple brain metastases

BACKGROUND Stereotactic radiosurgery (SRS) is an established treatment for patients with brain metastases (BMs). However, damage to the healthy brain may limit the tumor dose for patients with multiple lesions. PURPOSE In this study, we investigate the potential of spatiotemporal fractionation schemes to reduce the biological dose received by the healthy brain in SRS of multiple BMs, and also demonstrate a novel concept of spatiotemporal fractionation for polymetastatic cancer patients that faces less hurdles for clinical implementation. METHODS Spatiotemporal fractionation (STF) schemes aim at partial hypofractionation in the metastases along with more uniform fractionation in the healthy brain. This is achieved by delivering distinct dose distributions in different fractions, which are designed based on their cumulative biologically effective dose ( ) such that each fraction contributes with high doses to complementary parts of the target volume, while similar dose baths are delivered to the normal tissue. For patients with multiple brain metastases, a novel constrained approach to spatiotemporal fractionation (cSTF) is proposed, which is more robust against setup and biological uncertainties. The approach aims at irradiating entire metastases with possibly different doses, but spatially similar dose distributions in every fraction, where the optimal dose contribution of every fraction to each metastasis is determined using a new planning objective to be added to the BED-based treatment plan optimization problem. The benefits of spatiotemporal fractionation schemes are evaluated for three patients, each with >25 BMs. RESULTS For the same tumor BED$_{10}$ and the same brain volume exposed to high doses in all plans, the mean brain BED$_{2}$ can be reduced compared to uniformly fractionated plans by 9%-12% with the cSTF plans and by 13%-19% with the STF plans. In contrast to the STF plans, the cSTF plans avoid partial irradiation of the individual metastases and are less sensitive to misalignments of the fractional dose distributions when setup errors occur. CONCLUSION Spatiotemporal fractionation schemes represent an approach to lower the biological dose to the healthy brain in SRS-based treatments of multiple BMs. Although cSTF cannot achieve the full BED reduction of STF, it improves on uniform fractionation and is more robust against both setup errors and biological uncertainties related to partial tumor irradiation

A novel stochastic optimization method for handling misalignments of proton and photon doses in combined treatments

Objective.Combined proton-photon treatments, where most fractions are delivered with photons and only a few are delivered with protons, may represent a practical approach to optimally use limited proton resources. It has been shown that, when organs at risk (OARs) are located within or near the tumor, the optimal multi-modality treatment uses protons to hypofractionate parts of the target volume and photons to achieve near-uniform fractionation in dose-limiting healthy tissues, thus exploiting the fractionation effect. These plans may be sensitive to range and setup errors, especially misalignments between proton and photon doses. Thus, we developed a novel stochastic optimization method to directly incorporate these uncertainties into the biologically effective dose (BED)-based simultaneous optimization of proton and photon plans.Approach.The method considers the expected valueEband standard deviationσbof the cumulative BEDbin every voxel of a structure. For the target, a piecewise quadratic penalty function of the formbmin-Eb-2σb+2is minimized, aiming for plans in which the expected BED minus two times the standard deviation exceeds the prescribed BEDbmin.Analogously,Eb+2σb-bmax+2is considered for OARs.Main results.Using a spinal metastasis case and a liver cancer patient, it is demonstrated that the novel stochastic optimization method yields robust combined treatment plans. Tumor coverage and a good sparing of the main OARs are maintained despite range and setup errors, and especially misalignments between proton and photon doses. This is achieved without explicitly considering all combinations of proton and photon error scenarios.Significance.Concerns about range and setup errors for safe clinical implementation of optimized proton-photon radiotherapy can be addressed through an appropriate stochastic planning method

An in-silico planning study of stereotactic body radiation therapy for polymetastatic patients with more than ten extra-cranial lesions

BACKGROUND AND PURPOSE Limited data is available about the feasibility of stereotactic body radiation therapy (SBRT) for treating more than five extra-cranial metastases, and almost no data for treating more than ten. The aim of this study was to investigate the feasibility of SBRT in this polymetatstatic setting. MATERIALS AND METHODS Consecutive metastatic melanoma patients with more than ten extra-cranial metastases and a maximum lesion diameter below 11 cm were selected from a single-center prospective registry for this in-silico planning study. For each patient, SBRT plans were generated to treat all metastases with a prescribed dose of 5x7Gy, and dose-limiting organs (OARs) were analyzed. A cell-kill based inverse planning approach was used to automatically determine the maximum deliverable dose to each lesion individually, while respecting all OARs constraints. RESULTS A total of 23 polymetastatic patients with a medium of 17 metastases (range, 11-51) per patient were selected. SBRT plans with sufficient target coverage and respected OARs dose constraints were achieved in 16 out of 23 patients. In the remaining seven patients, the lungs V5Gy < 80 % and the liver D700 cm$^{3}$ < 15Gy were most frequently the dose-limiting constraints. The cell-kill based planning approach allowed optimizing the dose administration depending on metastases total volume and location. CONCLUSION This retrospective planning study shows the feasibility of definitive SBRT for 70% of polymetastatic patients with more than ten extra-cranial lesions and proposes the cell-killing planning approach as an approach to individualize treatment planning in polymetastatic patients'

Low Temperature Solution-Phase Deposition of SnS Thin Films

The solution-phase deposition of inorganic semiconductors is a promising, scalable method for the manufacture of thin film photovoltaics. Deposition of photovoltaic materials from molecular or colloidal inks offers the possibility of inexpensive, rapid, high-throughput thin film fabrication through processes such as spray coating. For example, CdTe, Cu(In,Ga)(S,Se)_2 (CIGS), and CH_3NH_3Pb(Cl,I)_3 perovskite-based thin film solar cells have been previously deposited using solution-based processes. Inks have also recently been developed for the solution deposition of Cu_2ZnSn(S,Se)_4 (CZTS) and FeS_2 (iron pyrite) absorber layers for thin film solar applications, in order to provide sustainable alternatives to materials that contain environmentally harmful heavy metals (e.g., Cd, Pb) and/or scarce elements (e.g., Te, In)

Efficiency enhancements of a Monte Carlo beamlet based treatment planning process: implementation and parameter study.

OBJECTIVE The computational effort to perform beamlet calculation, plan optimization and final dose calculation of a treatment planning process (TPP) generating intensity modulated treatment plans is enormous, especially if Monte Carlo (MC) simulations are used for dose calculation. The goal of this work is to improve the computational efficiency of a fully MC based TPP for static and dynamic photon, electron and mixed photon-electron treatment techniques by implementing multiple methods and studying the influence of their parameters. APPROACH A framework is implemented calculating MC beamlets efficiently in parallel on each available CPU core. The user can specify the desired statistical uncertainty of the beamlets, a fractional sparse dose threshold to save beamlets in a sparse format and minimal distances to the PTV surface from which 2x2x2=8 (medium) or even 4x4x4=64 (large) voxels are merged. The compromise between final plan quality and computational efficiency of beamlet calculation and optimization is studied for several parameter values to find a reasonable trade-off. For this purpose, four clinical and one academic case are considered with different treatment techniques. MAIN RESULTS Setting the statistical uncertainty to 5% (photon beamlets) and 15% (electron beamlets), the fractional sparse dose threshold relative to the maximal beamlet dose to 0.1% and minimal distances for medium and large voxels to the PTV to 1 cm and 2 cm, respectively, does not lead to substantial degradation in final plan quality. Only OAR sparing is slightly degraded. Furthermore, computation times are reduced by about 58% (photon beamlets), 88% (electron beamlets) and 96% (optimization) compared to using 2.5% (photon beamlets) and 5% (electron beamlets) statistical uncertainty and no sparse format nor voxel merging. SIGNIFICANCE Several methods are implemented improving computational efficiency of beamlet calculation and plan optimization of a fully MC based TPP without substantial degradation in final plan quality

Comparative Study in Acidic and Alkaline Media of the Effects of pH and Crystallinity on the Hydrogen-Evolution Reaction on MoS_2 and MoSe_2

Single crystals of n-type MoS_2 and n-MoSe_2 showed higher electrocatalytic activity for the evolution of H_2(g) in alkaline solutions than in acidic solutions. The overpotentials required to drive hydrogen evolution at −10 mA cm^(–2) of current density for MoS^2 samples were −0.76 ± 0.13 and −1.03 ± 0.21 V when in contact with 1.0 M NaOH(aq) and 1.0 M H_2SO_4(aq), respectively. For MoSe_2 samples, the overpotentials at −10 mA cm^(–2) were −0.652 ± 0.050 and −0.709 ± 0.073 V in contact with 1.0 M KOH(aq) and 1.0 M H_2SO_4(aq), respectively. Single crystals from two additional sources were also tested, and the absolute values of the measured overpotentials were consistently less (by 460 ± 250 mV) in alkaline solutions than in acidic solutions. When electrochemical etching was used to create edge sites on the single crystals, the kinetics improved in acid but changed little in alkaline media. The overpotentials measured for polycrystalline thin films (PTFs) and amorphous forms of MoS_2 showed less sensitivity to pH and edge density than was observed for single crystals and showed enhanced kinetics in acid when compared to alkaline solutions. These results suggest that the active sites for hydrogen evolution on MoS_2 and MoSe_2 are different in alkaline and acidic media. Thus, while edges are known to serve as active sites in acidic media, in alkaline media it is more likely that terraces function in this role

Nickel−Gallium-Catalyzed Electrochemical Reduction of CO_2 to Highly Reduced Products at Low Overpotentials

We report the electrocatalytic reduction of CO_2 to the highly reduced C_2 products, ethylene and ethane, as well as to the fully reduced C_1 product, methane, on three different phases of nickel–gallium (NiGa, Ni_3Ga, and Ni_5Ga_3) films prepared by drop-casting. In aqueous bicarbonate electrolytes at neutral pH, the onset potential for methane, ethylene, and ethane production on all three phases was found to be −0.48 V versus the reversible hydrogen electrode (RHE), among the lowest onset potentials reported to date for the production of C_2 products from CO_2. Similar product distributions and onset potentials were observed for all three nickel–gallium stoichiometries tested. The onset potential for the reduction of CO_2 to C_2 products at low current densities catalyzed by nickel–gallium was >250 mV more positive than that of polycrystalline copper, and approximately equal to that of single crystals of copper, which have some of the lowest overpotentials to date for the reduction of CO_2 to C_2 products and methane. The nickel–gallium films also reduced CO to ethylene, ethane, and methane, consistent with a CO_2 reduction mechanism that first involves the reduction of CO2 to CO. Isotopic labeling experiments with ^(13)CO_2 confirmed that the detected products were produced exclusively by the reduction of CO_2

Comparative Study in Acidic and Alkaline Media of the Effects of pH and Crystallinity on the Hydrogen-Evolution Reaction on MoS_2 and MoSe_2

Single crystals of n-type MoS_2 and n-MoSe_2 showed higher electrocatalytic activity for the evolution of H_2(g) in alkaline solutions than in acidic solutions. The overpotentials required to drive hydrogen evolution at −10 mA cm^(–2) of current density for MoS^2 samples were −0.76 ± 0.13 and −1.03 ± 0.21 V when in contact with 1.0 M NaOH(aq) and 1.0 M H_2SO_4(aq), respectively. For MoSe_2 samples, the overpotentials at −10 mA cm^(–2) were −0.652 ± 0.050 and −0.709 ± 0.073 V in contact with 1.0 M KOH(aq) and 1.0 M H_2SO_4(aq), respectively. Single crystals from two additional sources were also tested, and the absolute values of the measured overpotentials were consistently less (by 460 ± 250 mV) in alkaline solutions than in acidic solutions. When electrochemical etching was used to create edge sites on the single crystals, the kinetics improved in acid but changed little in alkaline media. The overpotentials measured for polycrystalline thin films (PTFs) and amorphous forms of MoS_2 showed less sensitivity to pH and edge density than was observed for single crystals and showed enhanced kinetics in acid when compared to alkaline solutions. These results suggest that the active sites for hydrogen evolution on MoS_2 and MoSe_2 are different in alkaline and acidic media. Thus, while edges are known to serve as active sites in acidic media, in alkaline media it is more likely that terraces function in this role