18F-EF5 PET-based Imageable Hypoxia Predicts Local Recurrence in Tumors Treated with Highly Conformal Radiation Therapy

Abstract

Tumor hypoxia contributes to radiation resistance. A non-invasive assessment of tumor hypoxia would be valuable for prognostication and possibly selection for hypoxia targeted therapies. 18F-pentafluorinated etanidazole (18F-EF5) is a nitroimidazole derivative that has demonstrated promise as a positron emission tomography (PET) hypoxia imaging agent in preclinical and clinical studies. However, correlation of imageable hypoxia by EF5-PET with clinical outcomes after radiation therapy remains limited. We prospectively enrolled 28 patients undergoing radiation therapy for localized lung or other tumors to receive pretreatment EF5-PET imaging. Depending on the level of 18F-EF5 tumor uptake, patients underwent functional manipulation of tumor oxygenation with either carbogen breathing or oral dicholoracetate (DCA), followed by repeat EF5-PET. The hypoxic fraction (HF) of tumor was defined as the proportion of tumor voxels exhibiting higher 18F-EF5 uptake than the 95th percentile of 18F-EF5 uptake in the blood pool. Tumors with HF ≥ 10% on baseline 18F-EF5 PET imaging were classified as hypoxic by imaging. A Cox model was used to assess correlation between imageable hypoxia and clinical outcomes after treatment. At baseline, imageable hypoxia was demonstrated in 43% of all patients (12 of 28), including 6 of 16 patients with early-stage non-small cell lung cancer treated with SABR, and 6 of 12 patients with other cancers. Carbogen breathing was significantly associated with decreased imageable hypoxia, while DCA did not result in significant change under our protocol conditions. Tumors with imageable hypoxia had higher incidence of local recurrence at 12 months (30%) compared to those without (0%) (p < 0.01). Noninvasive hypoxia imaging by EF5-PET identified imageable hypoxia in a substantial proportion of tumors in our study population. Local tumor recurrence after highly conformal radiation therapy was higher in tumors with imageable hypoxia.