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abstract
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With >50% of cancer patients receiving radiation therapy (RT) for the management of their disease, RT is an essential part of a successful cancer treatment along with surgery and chemotherapy. The National Council on Radiation Protection and Measurements Report No.170 has indicated a steady gain in 5 year survival rate for all cancer patients (to a level of 66%). This increase is attributed, in part, to technological advancements, which allow better targeting of radiation dose to diseased tissue.1 Radiation oncology has undergone dramatic developments since its inception, many of which have been technology driven. These technologic advances have been the impetus for growing interest in personalized functional/molecular imaging guided therapy to improve treatment outcomes. While advanced imaging modalities capable of providing detailed biologic/physiologic information are rapidly developing, we lack preclinical methodologies to investigate how to approach this clinically by incorporating this information and leveraging modern clinical technologies to provide improved treatment outcomes.
Tumor hypoxia is the perfect example of a source of radiation resistance and treatment failure that has been known for over a century yet has not translated into guiding clinical radiation treatments. Means of imaging hypoxia exist and could be incorporated into treatment planning. The objective of the proposed work is to design, validate, and implement a novel approach to precision irradiation in the preclinical setting closely analogous to clinical intensity modulated radiation therapy (IMRT) in order to facilitate preclinical image guided radiation studies targeting radioresistant hypoxic tumor regions, which will be more readily translatable into the clinic.
The first specific aim will be to develop a computer optimization approach to IMRT treatment planning using the preclinical XRAD225 irradiator in the Department of Radiation and Cellular Oncology. The energy spectrum and geometry of the radiation beam will be modelled via comparison to experimental measurements. A treatment planning system capable of calculating dose and optimizing beam intensities based on dose objectives will be created. The calculated optimal beam intensities will be realized using 3D printed beam apertures and compensators and validated via comparison to film measurements. The results of these validation measurements will serve as the indicator of success for this first aim.
The second specific aim will apply this 3D printed aperture and collimator system of preclinical IMRT in a dosimetric study investigating the capability to selectively deliver radiation boosts to hypoxic tumor regions in a series of murine tumor models (breast, prostate and fibrosarcoma). Electron paramagnetic resonance imaging (EPRI) developed at the University of Chicago non-invasively provides spatial maps of absolute tissue oxygenation to guide the preclinical treatment planning. The success of this aim will be determined by assessing the capability of this novel approach to incorporate functional imaging data to design highly precise preclinical radiation plans specific to each tumor. Approaches in regular clinical use, including analysis of calculated radiation dose distributions (volumetric analysis of target coverage/conformality and healthy tissue sparing) as well as calculated versus measured dose distribution fidelity (in representative phantoms), will be used to determine the success of this aim.
The proposed work will have an important impact in the field of radiation oncology and how treatment of cancer patients is approached. Animal models have long been recognized as an important means of studying cancer biology, however this work often struggles to translate into clinical practice. For these preclinical approaches to be successful they should be closely analogous to modern clinical techniques in order to facilitate efficient translation into clinical benefits for cancer patients. The preclinical image guided treatment approach proposed is a crucial step in building a bridge between small animal studies and clinical practice; the relevance of this approach will be clearly demonstrated through application to a question that has plagued the field of radiation oncology for over a century: How can the known dictator of treatment outcome, tumor hypoxia, be incorporated into designing more effective treatments for cancer patients?
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label
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Precision small animal intensity modulated radiation therapy for functional image guided dose painting
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