The Therapeutic Potential of FLASH-RT for Pancreatic Cancer

Abstract

Recent preclinical evidence has shown that ionizing radiation given at an ultra-high dose rate (UHDR), also known as FLASH radiation therapy (FLASH-RT), can selectively reduce radiation injury to normal tissue while remaining isoeffective to conventional radiation therapy (CONV-RT) with respect to tumor killing. Unresectable pancreatic cancer is challenging to control without ablative doses of radiation, but this is difficult to achieve without significant gastrointestinal toxicity. In this review article, we explore the propsed mechanisms of FLASH-RT and its tissue-sparing effect, as well as its relevance and suitability for the treatment of pancreatic cancer. We also briefly discuss the challenges with regard to dosimetry, dose rate, and fractionation for using FLASH-RT to treat this disease.

Keywords: FLASH effect; FLASH radiation; conventional radiation; gastrointestinal toxicity; pancreatic cancer.

Figure 1

Oxygen depletion hypothesis of the FLASH effect. Tumors are extremely hypoxic relative to their surrounding normal tissue, with oxygen tensions ranging from 0.3% to 4.2%. The surrounding normal tissue is more highly oxygenated (i.e., physioxia), usually between 3% and 7.4% [36]. For this reason, a more pronounced decrease in oxygen level after FLASH treatment is observed in physioxic conditions compared with tumors. This correlates with a significant decrease in radiosensitivity (or increase in radiation resistance) in normal tissues, conferring the FLASH effect. Tumors, on the other hand, show little change in radiosensitivity, leading to the absence of the FLASH effect.

Figure 2

Immune hypothesis for the FLASH effect. Lymphocytes circulating within blood vessels are an important component of the immune response that influences tumor suppression. According to the immune hypothesis, the higher dose rates characteristic of FLASH-RT allow exposure of a much smaller volume of blood to radiation than CONV-RT. As a result, a higher number of circulating lymphocytes will survive and the immune response critical for tumor suppression is preserved to a greater degree. In contrast, the lower dose rates used in CONV-RT allow exposure of larger blood volumes circulating through the radiation field, leading to a significant loss of lymphocytes and a compromised immune response.

Figure 3

Gastrointestinal organs are susceptible to radiation damage from pancreatic cancer radiotherapy. (a) The duodenal portion of the small intestine, the stomach, and other nearby organs are prone to radiation-induced toxicity, especially the rapidly dividing intestinal cells; (b) Oxygen concentrations (blue wedge) vary between normal tissues and tumors. Pancreatic tumors near the duodenum are especially hypoxic relative to the physioxic environment of the healthy tissue at risk; (c) Nearby normal tissues that would be damaged by CONV-RT would be spared by FLASH-RT, and FLASH-RT would also kill the tumor through the FLASH effect.