Abstract
Simple SummaryDespite intense research, the prognosis of patients with pancreatic cancer remains very poor without significant improvements over the past years. Novel therapeutic approaches may contribute to overcome therapeutic resistance and improve clinical outcome. Recently, small-animal imaging and high-precision irradiation devices for preclinical tumor models have been developed. The present preclinical study aimed to assess the accuracy of small-animal imaging and high-precision radiotherapy (RT) in an orthotopic xenograft pancreatic tumor mouse model by histopathological examination of the DNA damage marker γH2AX. Immunohistochemical staining of the pancreatic tumor and abdominal organs confirmed the accuracy of outlining based on CBCT imaging as well as the subsequent stereotactic RT. A clinical example from a patient with pancreatic cancer demonstrates the translational nature of this study. Longitudinal follow-up after high-precision RT showed a significant survival benefit in comparison to untreated tumor-bearing control mice. This preclinical RT platform provides the ability to mimic contemporary human RT closely and to evaluate novel RT concepts for pancreas cancer treatment.Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers. Innovative treatment concepts may enhance oncological outcome. Clinically relevant tumor models are essential in developing new therapeutic strategies. In the present study, we used two human PDAC cell lines for an orthotopic xenograft mouse model and compared treatment characteristics between this in vivo tumor model and PDAC patients. Tumor-bearing mice received stereotactic high-precision irradiation using arc technique after 3D-treatment planning. Induction of DNA damage in tumors and organs at risk (OARs) was histopathologically analyzed by the DNA damage marker γH2AX and compared with results after unprecise whole-abdomen irradiation. Our mouse model and preclinical setup reflect the characteristics of PDAC patients and clinical RT. It was feasible to perform stereotactic high-precision RT after defining tumor and OARs by CT imaging. After stereotactic RT, a high rate of DNA damage was mainly observed in the tumor but not in OARs. The calculated dose distributions and the extent of the irradiation field correlate with histopathological staining and the clinical example. We established and validated 3D-planned stereotactic RT in an orthotopic PDAC mouse model, which reflects the human RT. The efficacy of the whole workflow of imaging, treatment planning, and high-precision RT was proven by longitudinal analysis showing a significant improved survival. Importantly, this model can be used to analyze tumor regression and therapy-related toxicity in one model and will allow drawing clinically relevant conclusions.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers and is expected to be the second-leading cause of cancer-related deaths in the UnitedStates by 2030 [1,2]
The treatment of pancreatic cancer is still an unsolved health problem in industrialized countries and should be evaluated by multidisciplinary consensus at tumor boards to guarantee a therapy at the highest scientific standards [8,9]
We developed an orthotopic mouse model for CBCT imaging and the establishment of We developed an orthotopic mouse model and the establishment high-precision
Summary
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers and is expected to be the second-leading cause of cancer-related deaths in the UnitedStates by 2030 [1,2]. The overall 5-year survival rate among patients with PDAC is less than 10% and only modestly improved in recent years [3,4]. The poor survival can be attributed to aggressive tumor growth and high therapeutic resistance [5,6,7]. The treatment of pancreatic cancer is still an unsolved health problem in industrialized countries and should be evaluated by multidisciplinary consensus at tumor boards to guarantee a therapy at the highest scientific standards [8,9]. Previous clinical trials show that at least one-third of patients, predominantly with locally advanced but irresectable lesions, benefit from local radiotherapy (RT) [11]. The novel technique stereotactic body radiotherapy (SBRT) with high single doses achieves an excellent local control and a moderate toxicity rate [12,13].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
