ABSTRACT Radiation therapy (RT) is a curative treatment, used adjuvant to surgery and chemotherapy in over 60% of cancers. It is delivered to nearly 1 out of every 6 people at some point in their lifetime. External beam treatment is commonly fractionated (i.e., delivered in 25-40 daily fractions), although there is a trend towards hypofractionation (5-10 days) with higher doses per fraction. While RT is generally considered safe and effective, it is well known that minor deviations in treatment happen on a daily basis in a busy treatment facility, and these changes are prone to higher human error rates. Major potential side effects can occur if not administered with high daily accuracy, and the precision needed is at the millimeter level in patient and beam alignment, in order to keep normal tissue doses sufficiently low. However, there is a proven 1-5% incidence of secondary cancer from this treatment. This is particularly relevant in whole breast radiotherapy, where even 2% target dose delivery (1Gy) to part of the contralateral breast has been proven to lead to a high probability for a secondary cancer. In reality, no clinic actually knows their true incident rate, because no system exists to visualize every treatment as part of routine clinical practice. DoseOptics’ invention of Cherenkov imaging, branded as BeamSite™, provides time-gated single photon video rate imaging of the light coming off tissue during the radiation dose delivery as it happens. The parent Phase II grant for this proposal, funded development of Cherenkov imaging with the VisionRT surface guided radiotherapy system (SGRT) system. Together the combined system has been trademarked as DoseRTTM, where the Cherenkov video of dose delivery is displayed in the same window monitor as the SGRT metrics of patient position. This combined interface provides a complete intuitive package for the therapists, where daily assessment and corrections can be made as needed. VisionRT and DoseOptics have a signed a long-term partnership and license and finance agreement. In this Phase IIB application, key improvements are implemented from test use, to make DoseRT more commercially viable for widespread deployment across different vendor platforms, more easily used by various therapy teams, and with some customization approaches for each center. The project is based upon previous NIH supported hardware that is now FDA 510(k) cleared. Aims 1 & 2 advance strategic updates to hardware and software systems for which improve cost structure and robustness, improving commercial viability of the system. This updated system will also be 510(k) cleared in Aim 3 with beta deployment. The project will culminate in Aim 4 with broader deployment and testing validation with an image registry. This clinical registry data will be used to validate marketing claims around incident detection and improved radiotherapy delivery by visualization of the beam on the patient. The team involved encompasses the two compan...