Probability of Radiographic Radiation Pneumonitis (RP) and Fibrosis (RF) After Stereotactic Ablative Radiation Therapy (SABR) for Lung Cancer Using NTCP Model

Abstract

Materials/Methods: Male C57/Bl6 mice eight weeks of age were pretreated with saline or 8 mg of the prolyl hydroxylase inhibitor DMOG 16 hrs and 4 hrs prior to being irradiated with a single fraction of 20 Gy to the abdomen using a modified TLI jig that shields the upper body of the mouse to reduce hematopoietic toxicity. After XRT, the mice got daily doses of saline or DMOG for 5 days. Results: Mice treated with DMOG had a 1.5-fold enrichment of crypt regeneration in the colon as determined by the classical microcolony assay (13.3 3.4 vs. 21.2 1.7 crypts/section, saline vs. DMOG, nZ 10/group, p Z 0.005), which strongly suggests that prolyl hydroxylase inhibition radioprotects the colon. Death from GI radiotoxicity can result from compromised epithelial integrity. Death from GI radiotoxicity can result from compromised epithelial integrity through reduced barrier function and water absorption leading to sepsis, dehydration and electrolyte imbalance. We tested epithelial and barrier function by gavaging irradiated mice with FITC-dextran, which should be undetectable in the blood unless the GI epithelia are compromised. Treatment with DMOG decreased FITC-dextran uptake by 4-fold over controls (52.6 14.7 vs. 12.4 3.4 mcg/mL, n Z 6/group, p Z 0.02). Using metabolic cage analysis, we find that mice treated with DMOG had more formed stools, increased urine output and less weight loss than saline treated mice. Mice treated with only saline had higher sodium and Cr levels, further suggesting that GI function and water balance is improved with DMOG treatment. These physiologic improvements translated to improved overall survival with DMOG treatment after being exposed to 20 Gy of abdominal radiation (p Z 0.01). In addition, mice treated with DMOG within 4 hours after radiation also showed improved survival, although with more mortality than if dosed before receiving radiation. Conclusions: Maintaining epithelial integrity should be a therapeutic goal in treating GI radiotoxicity. Physiologic measurements are an important adjunct to cellular and histologic methods of assessing radioprotection in the gut. Author Disclosure: C.M. Taniguchi: None. T. Atwood: None. A.J. Giaccia: None.