Sep 30

QP 18 - Radiation and Cancer Biology 5: Cellular Radiation Effects & DNA Damage Response

1106 - First In Vitro and In Vivo Oxygen Ion FLASH Experiments with a Pancreatic Cancer Model

05:38pm - 05:44pm PT

Room 307/308

Presenter(s)

Celine Karle, MS - German Cancer Research Center (DKFZ), Heidelberg, Baden-Wurt

C. Karle¹, D. I. Filosa¹, N. Schuhmacher², M. Akbarpour², M. Mustafa¹, S. Brons³, R. Cee⁴, C. Schömers⁴, S. Scheloske⁴, K. Peterson⁵, T. Haberer⁶, A. Abdollahi⁷, J. Debus⁸, T. Tessonnier⁹, I. Dokic², and A. Mairani⁹; ¹Clinical Cooperation Unit Translational Radiation Oncology (E210), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany, Heidelberg, Germany, ²Clinical Cooperation Unit Translational Radiation Oncology, National Center for Tumor Diseases (NCT), Heidelberg University Hospital (UKHD) and German Cancer Research Center (DKFZ), Heidelberg, Germany, ³Radiation Oncology & Heidelberg Ion Therapy (HIT), University Hospital Heidelberg, Heidelberg, Germany, ⁴Heidelberg Ion-Beam Therapy Center (HIT), Im Neuenheimer Feld 450, 69120 Heidelberg, Germany, Heidelberg, Germany, ⁵Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK, Oxford, United Kingdom, ⁶Heidelberg Ion-Beam Therapy Center (HIT), Department of Radiation Oncology, Heidelberg University Hospital, Heidelberg, Germany, ⁷Heidelberg Ion-Beam Therapy Center, Heidelberg University Hospital (UKHD), Heidelberg, Germany, ⁸Molecular and Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany, ⁹Heidelberg Ion-Beam Therapy Center (HIT), Department of Radiation Oncology, Heidelberg University Hospital (UKHD), Heidelberg, Germany

Purpose/Objective(s):

Pancreatic cancer is the third most common cause of cancer-related death and has the lowest 5-year survival rate of all cancers. Due to the tendency for late diagnosis, these tumors are often unresectable, leaving chemotherapy and radiotherapy as the only treatment options. Nevertheless, in the context of radiotherapeutic intervention, pancreatic tumors exhibit characteristically hypoxic and radio resistant properties. The employment of high doses and high linear energy transfer (LET) irradiation has been demonstrated to address these treatment challenges and enhance local control. However, targeting such mobile tumors with surrounding radio-sensitive organs remains a challenging aspect. Ultra-high dose rate (UHDR) irradiation offers potential in this regard, as its rapid delivery could mitigate intra-fractional motion. The hypothesis of this study is that the combination of UHDR irradiation and high LET irradiation, with oxygen ions, may offer physical advantages for achieving conformally high doses and high LET in the target region.

Materials/Methods: For the first time, this study investigated the effects of oxygen ion UHDR irradiation provided by a synchrotron across three levels of biological complexity. Firstly, to investigate the radiochemical mechanisms at a molecular level, oxygen consumption rates were assessed in bovine serum albumin (BSA) 5% samples exposed to 15Gy at standard dose rate (SDR) and UHDR with a dose averaged LET (LETd) of 100.3keV/µm. Secondly, clonogenic survival assays were performed with KPC pancreatic cancer cells irradiated with 8Gy and the same LETd in hypoxic (~1% oxygen) and normoxic conditions. Thirdly, 6–8-week-old female C57BL/6 mice bearing subcutaneous pancreatic tumors in the hind limb were irradiated with a single fraction of 10Gy with an LETd of 134keV/µm.

Results:

At the molecular level, the difference in oxygen consumption between both dose rates was marginal with 0.003 %/Gy. Secondly, the in vitro results showed comparable cytotoxic efficacy of both dose rate applications in pancreatic cancer cell killing in hypoxia and normoxia. Importantly for in vivo, oxygen ion irradiation showed its benefits in effective tumor control through a substantial tumor volume reduction compared to the control and survival extension of approximately 4 days after both SDR and UHDR irradiation.

Conclusion: This study represents the first successful application of oxygen ion UHDR irradiation, demonstrating feasibility of in vitro and in vivo experiments. Both SDR and UHDR achieved comparable outcomes in cell survival in vitro and tumor response in vivo. These results highlight that oxygen ion FLASH therapy, with the oxygen ions established benefits of high LET and precise dose distributions, could mitigate an additional challenge in pancreas cancer treatment when applied at UHDR by minimizing motion-related uncertainties in tumor treatment.