Ultra high dose rate (35 Gy/sec) radiation does not spare the normal tissue in cardiac and splenic models of lymphopenia and gastrointestinal syndrome

Abstract

Recent reports have shown that very high dose rate radiation (35–100 Gy/second) referred to as FLASH tends to spare the normal tissues while retaining the therapeutic effect on tumor. We undertook a series of experiments to assess if ultra-high dose rate of 35 Gy/second can spare the immune system in models of radiation induced lymphopenia. We compared the tumoricidal potency of ultra-high dose rate and conventional dose rate radiation using a classical clonogenic assay in murine pancreatic cancer cell lines. We also assessed the lymphocyte sparing potential in cardiac and splenic irradiation models of lymphopenia and assessed the severity of radiation-induced gastrointestinal toxicity triggered by the two dose rate regimes in vivo. Ultra-high dose rate irradiation more potently induces clonogenic cell death than conventional dose rate irradiation with a dose enhancement factor at 10% survival (DEF10) of 1.310 and 1.365 for KPC and Panc02 cell lines, respectively. Ultra-high dose rate was equally potent in depleting CD3, CD4, CD8, and CD19 lymphocyte populations in both cardiac and splenic irradiation models of lymphopenia. Radiation-induced gastrointestinal toxicity was more pronounced and mouse survival (7 days vs. 15 days, p = 0.0001) was inferior in the ultra-high dose rate arm compared to conventional dose rate arm. These results suggest that, contrary to published data in other models of radiation-induced acute and chronic toxicity, dose rates of 35 Gy/s do not protect mice from the detrimental side effects of irradiation in our models of cardiac and splenic radiation-induced lymphopenia or gastrointestinal mucosal injury.

Ultra-High Dose Rate (FLASH) Radiotherapy: Silver Bullet or Fool's Gold?

“…This relationship is important to consider when examining studies such as those by Favaudon et al (10), and Vozenin et al (15,16), which used 40-60 and 300 Gy/s, respectively when administering FLASH-RT. In contrast to previously mentioned studies, a recent interesting study by Venkatesulu et al showed a higher toxicity for FLASH-RT delivered at 35 Gy/s than for CONV-RT delivered at 0.1 Gy/s (33). This dose rate is probably on the low side for a sparing effect to occur but that does not explain the highly unexpected increased toxicity they found for FLASH-RT in all of their experiments, especially the increased toxicity of a factor 1.3-1.4 for their in vitro data.…”

“…Many pre-clinical studies have reported a successful FLASH normal tissue sparing effect, but it cannot be overlooked that there have also been several studies reporting no significant sparing of normal tissues following irradiation at ultra-high dose rates (29)(30)(31)(32)(33). For example, Smyth et al delivered whole and partial body (abdominal or head) synchrotron irradiation to mice, at ultra-high dose rates of 37-41 Gy/s in the hope of characterizing the equivalent CONV-RT dose (32).…”

“…This dose rate is probably on the low side for a sparing effect to occur but that does not explain the highly unexpected increased toxicity they found for FLASH-RT in all of their experiments, especially the increased toxicity of a factor 1.3-1.4 for their in vitro data. There could be many reasons for these results, e.g., the dose-rate needed for a FLASH sparing effect might not be universal but rather tissue-specific, model and/or assay specific, or there could be dosimetric differences between the two delivery modes/setups, all of which highlights the challenge in performing studies at these dose rates, finding, and exploring a beneficial FLASH effect (33). Furthermore, there is a large degree of variation in the total dose of radiation used in pre-clinical FLASH-RT studies.…”

Immunomodulatory Effects of Radiotherapy

“…FLASH-RT may directly affect immune cells or indirectly influence the tumor microenvironment. Some evidence suggests that immune cells are not preferentially spared by ultra-high dose rates similar to FLASH [106]. TGF-β is a master regulator of immune homeostasis following RT, largely mediating immunosuppressive effects.…”

First demonstration of the FLASH effect with ultrahigh dose-rate high-energy X-rays

“…Electrons 10,13,15,[19][20][21][25][26][27][28] , kilo-voltage (keV) X-rays 18,29 and proton [30][31][32] have been utilized in FLASH preclinical research; however, those modalities are not ideal in clinical application. Electrons and keV X-rays are usually used to treat superficial tumor sites, but not suitable for tumors in the deep body, such as lung cancer, breast cancer, colorectal cancer, prostate cancer, due to their limited penetration powers.…”