The low-LET radiation contribution to the tumor dose in diffusing alpha-emitters radiation therapy.

BACKGROUND: Diffusing alpha-emitters Radiation Therapy ("Alpha DaRT") is a new technique that enables the use of alpha particles for the treatment of solid tumors. Alpha DaRT employs interstitial sources carrying a few µ $\mu$ Ci of 224 $^{224}$ Ra below their surface, designed to release a chain of short-lived atoms (progeny of 224 $^{224}$ Ra) which emit alpha particles, along with beta, Auger, and conversion electrons, x- and gamma rays. These atoms diffuse around the source and create-primarily through their alpha decays-a lethal high-dose region measuring a few millimeters in diameter. PURPOSE: While previous studies focused on the dose from the alpha emissions alone, this work addresses the electron and photon dose contributed by the diffusing atoms and by the atoms remaining on the source surface, for both a single Alpha DaRT source and multi-source lattices. This allows to evaluate the low-LET contribution to the tumor dose and tumor cell survival, and demonstrate the sparing of surrounding healthy tissue. METHODS: The low-LET dose is calculated using the EGSnrc and FLUKA Monte Carlo (MC) codes. We compare the results of a simple line-source approximation with no diffusion to those of a full simulation, which implements a realistic source geometry and the spread of diffusing atoms. We consider two opposite scenarios: one with low diffusion and high 212 $^{212}$ Pb leakage, and the other with high diffusion and low leakage. The low-LET dose in source lattices is calculated by superposition of single-source contributions. Its effect on cell survival is estimated with the linear quadratic model in the limit of low dose rate. RESULTS: For sources carrying 3  µ $\umu$ Ci/cm 224 $^{224}$ Ra arranged in a hexagonal lattice with 4 mm spacing, the minimal low-LET dose between sources is ∼ 18 - 30 $\sim 18-30$  Gy for the two test cases and is dominated by the beta contribution. The low-LET dose drops below 5 Gy ∼ 3 $\sim 3$  mm away from the outermost source in the lattice with an effective maximal dose rate of < 0.04 $<0.04$  Gy/h. The accuracy of the line-source/no-diffusion approximation is ∼ 15 % $\sim 15\%$ for the total low-LET dose over clinically relevant distances (2-4 mm). The low-LET dose reduces tumor cell survival by a factor of ∼ 2 - 200 $\sim 2-200$ . CONCLUSIONS: The low-LET dose in Alpha DaRT can be modeled by conventional MC techniques with appropriate leakage corrections to the source activity. For 3  µ $\umu$ Ci/cm 224 $^{224}$ Ra sources, the contribution of the low-LET dose can reduce cell survival inside the tumor by up to two orders of magnitude. The low-LET dose to surrounding healthy tissue is negligible. Increasing source activities by a factor of 5 can bring the low-LET dose itself to therapeutic levels, in addition to the high-LET dose contributed by alpha particles, leading to a "self-boosted" Alpha DaRT configuration, and potentially allowing to increase the lattice spacing.

RADIATION DETECTOR FOR THE ISRAELI FIRST RESPONDERS-METHODOLOGY OF SELECTION.

This paper presents the rationale and development of a methodology of selection of a radiation detector that can be used by first responders arriving to a terror event scene, not knowing if the event involves any radioactive materials. This detector can be used to detect and quantify the presence of gamma radiation. The role of this detector in a radiological terror event is reviewed via the operational concept for handling radiological terror in Israel. The development of the methodology of selection included a literature survey of relevant radiation detector categories, followed by a user-side survey of requirements based on the first responders' experience along with the Israeli Ministry of Defense perspective on the management of radiological events, supplemented by the input from experts in aspects of radiation detection, radiation protection and dosimetry from the Israel Atomic Energy Commission's Soreq Nuclear Research Center. The general qualitative characterisation of requirements was then quantified using a scoring method, enabling the methodological evaluation and numerical ranking of available detectors. Plans to evaluate candidate detector models according to the developed methodology are outlined. The detectors evaluation will be conducted as part of the procurement procedure of future detectors for first responders.

Diffusing alpha-emitters radiation therapy in combination with temozolomide or bevacizumab in human glioblastoma multiforme xenografts.

Glioblastoma multiforme (GBM) is at present an incurable disease with a 5-year survival rate of 5.5%, despite improvements in treatment modalities such as surgery, radiation therapy, chemotherapy [e.g., temozolomide (TMZ)], and targeted therapy [e.g., the antiangiogenic agent bevacizumab (BEV)]. Diffusing alpha-emitters radiation therapy (DaRT) is a new modality that employs radium-224-loaded seeds that disperse alpha-emitting atoms inside the tumor. This treatment was shown to be effective in mice bearing human-derived GBM tumors. Here, the effect of DaRT in combination with standard-of-care therapies such as TMZ or BEV was investigated. In a viability assay, the combination of alpha radiation with TMZ doubled the cytotoxic effect of each of the treatments alone in U87 cultured cells. A colony formation assay demonstrated that the surviving fraction of U87 cells treated by TMZ in combination with alpha irradiation was lower than was achieved by alpha- or x-ray irradiation as monotherapies, or by x-ray combined with TMZ. The treatment of U87-bearing mice with DaRT and TMZ delayed tumor development more than the monotherapies. Unlike other radiation types, alpha radiation did not increase VEGF secretion from U87 cells in culture. BEV treatment introduced several days after DaRT implantation improved tumor control, compared to BEV or DaRT as monotherapies. The combination was also shown to be superior when starting BEV administration prior to DaRT implantation in large tumors relative to the seed size. BEV induced a decrease in CD31 staining under DaRT treatment, increased the diffusive spread of 224Ra progeny atoms in the tumor tissue, and decreased their clearance from the tumor through the blood. Taken together, the combinations of DaRT with standard-of-care chemotherapy or antiangiogenic therapy are promising approaches, which may improve the treatment of GBM patients.