Project summary / Abstract Radiation therapy machines deliver intrinsically divergent x-ray radiation that needs to be collimated to treat a diseased region. The penumbra and power efficiency limit the minimal size of a radiation field to about 5 millimeters for photon and charged particle beams. Therefore, a host of medical conditions that may be responsive to local radiation cannot be effectively treated because of their small size and intolerable collateral damages to surrounding critical organs. To overcome the fundamental issues of collimated radiation, this proposal aims to develop a focused kV x-ray system based on novel usage of polycapillary x-ray lens. The proposed technique can focus x-ray beams to less than 0.2 mm in diameter. The beam can scan to conformally delivery radiation dose to small, shallow targets while minimizing the radiation damage to surrounding healthy tissues. Our goal is to build and fully characterize a functional prototype focused kV x-ray platform for phantom and preclinical treatment planning research. Strong evidence has shown that radiation may be a viable treatment approach for neovascular age-related macular degeneration (AMD), which affects tens of millions of patients worldwide. It attacks a different AMD pathway than the mainstay vascular endothelial growth factor (VEGF) inhibitor for AMD treatment. Anti-VEGF therapy requires repeated injection every few weeks with a risk of surgical injury and costs over $30,000/year. Radiation treatment using one universal 4 mm diameter kV radiation for all patients is being trialed to synergistically combine with anti-VEGF drugs. The current results are promising in terms of reducing the number of required anti-VEGF injections, but indicate insufficient dosimetric coverage for lesions larger than 4 mm and occasional radiation toxicity. We hypothesize that using the proposed focused x-ray technique to personalize conformal radiation according to lesion morphology can improve outcomes by enhancing the target coverage and minimizing the toxicity to healthy retina/ macula at the same time. Besides, this technique offers a novel dose delivery strategy of highly spatially-modulated grid therapy, which has been shown to preferentially damage abnormal neovasculature vs normal blood vessels. The proposed technique can also treat ultrasmall targets in rodents (comparable to the relative size in humans) for preclinical research that cannot be performed using collimated divergent beams without inevitably irradiating a relatively large volume of uninvolved tissues. Specific aims: Design and build a prototype pre-clinical system, perform dosimetric commissioning of the system and develop a Monte Carlo (MC)-based treatment planning system for focused x- ray treatment. Study design: A unified MC code will be written to simulate the x-ray transport in polycapillary lens and in patient for dose calculation. Extensive phantom dosimetry measurements will be performed to tune the MC model. Treatment planning optimization and factors affecting the targeting and dosimetric uncertainties will be studied. Health relatedness: This proposal aims to address the unmet need of conformal radiotherapy delivery to small, mm-sized targets based on the lesion shape and critical structure sparing.

Project narrative / public health relevance statement The proposed focused kV x-ray technique by polycapillary lens can deliver personalized highly-conformal radiation treatment to small targets a few millimeters in size, which is not possible by current radiation devices, and has numerous potential applications in medicine. It can treat neovascular age-related macular degeneration of different sizes with conformal lesion coverage in contrast to the current way of using collimated divergent beams to deliver a universal treatment to all patients resulting in incomplete dosimetric coverage and/or toxic treatment. The ability of conformally treating ultrasmall targets also enables a new set of preclinical small animal researches with target sizes comparable to the relative sizes in humans, such as radiation-based neuromodulation, which can alter local neuronal function without ablative nerve destruction.