Pancreatic ductal adenocarcinoma, the 12th most common malignancy in the USA, is the third leading cause of cancer-related death, with a very low 5-year overall survival (OS) rate of less than 10%. One-third of patients present with unresectable, locally advanced, pancreatic cancer (LAPC). For LAPC, improved local control may be achieved by advanced radiation therapy (RT) techniques, using dose-escalation with intensity modulated radiotherapy (IMRT) and stereotactic body radiation therapy (SBRT). Efficacy of dose escalation is limited in pancreatic cancer, primarily due to proximity of an organ at risk (OAR). In particular, the dose-limiting duodenum is directly adjacent to the head of the pancreas (HOP), where most adenocarcinomas occur. As a result, very tight planning treatment volume (PTV) margin expansion of the gross tumor volume (GTV) is prescribed. Even so, the PTV often protrudes into the duodenum, and is “shaved” at the discretion of the treating physician to avoid injuring the duodenum, but at the risk of missing the tumor. In addition, daily, inter- fraction variation of patient anatomy readily leads to violation of OAR constraints, thus frequent adaptations are inevitable. There is an urgent need for a new approach to allow safe dose escalation in the radiation therapy for pancreatic cancer. We propose to augment the current IGRT paradigm with systematic spacer implantation to increase the separation between the tumor and OAR. We name the procedure: Spacer Enabled Robust Radiation Therapy (SERRT) to emphasis a treatment that: (i) is robust against anatomic variations, (ii) relaxes the requirement of a tight PTV, and increases the OAR distances to the PTV, and thereby (iii) minimizes the frequency of plan adaptation. In our present focus on applying SERRT to LAPC, we direct our emphasis on the duodenum, the prevalent critical structure. We have demonstrated the feasibility of using EUS in a new application to guide the implantation of our newly developed absorbable and radiopaque spacer, achieving 1 cm separation between duodenum and HOP. The novel spacer is visible in cone beam CT (CBCT), and can be monitored following the RT treatment course. We expect the new spacer to revolutionize IGRT in most RT clinics which currently use onboard CBCT. With SERRT, we will innovate preoperative (before spacer implantation) intervention planning that incorporates a radiation treatment plan, as well as intraoperative (during spacer implantation) imaging feedback, to support optimal implantation of the spacer. SERRT is a new process that augments the current paradigm of IGRT by increasing robustness of RT against setup and organ variations in a systematic fashion. If successful, SERRT offers new transformative potential for dose escalation that is much needed for a devastating disease such as pancreatic cancer.