Project Summary/Abstract Lung cancer is one of the most common and deadliest malignancies in the world. Radiation therapy (RT) is often used alone or in combination with surgery or chemotherapy, and thus is a critical component in the management of this disease. However, accurate delivery of RT in the lung is limited by respiratory motion, which can result in significant displacements of the tumor (up to 2 cm). Without compensation, this motion necessitates the irradiation of a larger volume of normal lung to account for displacement of the tumor. This larger volume of lung irradiated increases the incidence of symptomatic radiation pneumonitis. A number of methods have been used clinically to reduce the volume of lung irradiated including the use of breath hold and compression. However, both are uncomfortable and difficult for patients who often have multiple comorbidities. Alternatively, researchers are evaluating methods to track the tumor in real time and potentially adapt the treatment parameters to the position of the lung tumor. Methods to accomplish this goal require the implantation of fiducial markers or electromagnetic transponders. However, implantation of these devices carries a significant risk of pneumothorax, pulmonary hemorrhage and exacerbation of underlying chronic obstructive pulmonary disease (COPD). Another approach for tumor tracking – markerless tumor tracking (MTT) – relies on images of the tumor obtained at the time of treatment. The most common modality for the delivery of RT is the linear accelerator equipped with an on-board imager (OBI). X-ray-based MTT, using planar MV or kV imaging on a standard linear accelerator, is attractive as it uses a widely available technology and can be performed in near real time. In cases where the tumor is clearly visible, x-ray-based MTT can track tumors with a high degree of accuracy. However, a major difficulty with MTT is that tumor-overlapping bone may not be detectable on x-ray projections. Our group has explored dual energy (DE) fluoroscopic imaging to increase the likelihood of successful and accurate MTT, and have implemented DE imaging on the OBI of a commercial linear accelerator using fast-kV switching technology. DE imaging involves obtaining x-ray images at high (i.e., 120 kVp) and low (i.e., 60 kVp) energies. By performing a weighted-logarithmic subtraction (WLS), a third image is produced that suppresses bone and enhances soft tissue/tumor visibility. Our hypothesis is that implementing DE imaging on a linear accelerator will enable a practical and cost effective method for enhanced tumor visualization and image guidance in lung RT. Moreover, DE imaging will allow for MTT ensuring a high dose is delivered to the tumor while limiting the volume of normal tissue irradiated. To test this hypothesis and to accomplish the goals of this research, the following specific aims are proposed: A) Identify areas for improvement in fast-kV DE imaging and MTT with the goal toward cl...