Enhanced delivery of iodine for synchrotron stereotactic radiotherapy by means of intracarotid injection and blood–brain barrier disruption: Quantitative iodine biodistribution studies and associated dosimetry

Abstract

Synchrotron stereotactic radiotherapy (SSR) is a binary cancer treatment modality that involves the selective accumulation of a high Z element, such as iodine, in tumors, followed by stereotactic irradiation with kilovoltage X-rays from a synchrotron source. The success of SSR is directly related to the absolute amount of iodine achievable in the tumor. The purposes of this preclinical study were to determine whether the delivery of iodine to brain tumor models in rats could be enhanced by the means of its intracarotid injection with or without a hyperosmotic solution and to evaluate corresponding absorbed X-ray doses. Experiments were performed on four groups of F98 glioma-bearing rats, which received either intracarotid (IC) or intravenous (IV) infusions of a mixture (6 mL in 12 min) of an iodinated contrast agent associated or not with a transient blood-brain barrier opener (mannitol). The mixture volumetric proportions were 8/13 of Iomeron (C = 350 mg/mL) for 5/13 of mannitol or saline, respectively. Absolute iodine concentration kinetic was measured in vivo in the tumor, blood, contralateral and ipsilateral brain, and muscle by monochromatic computed tomography. Associated dosimetry was performed by computing the iodine dose enhancement factor (DEF) in each region and building dose distribution maps by analytical simulations. Infusion of mannitol significantly enhanced iodine tumor uptake compared with the control values (p < 0.0001 and p = 0.0138, for IC and IV protocols, respectively). The mean iodine concentrations (C) reached 20.5 +/- 0.98 mg/mL (DEF = 4.1) after administration of iodine and mannitol vs. 4.1 +/- 1.2 mg/mL i.c. with serum (DEF = 1.6). The tumor iodine uptakes after jugular injection with mannitol (C = 4.4 +/- 2.1 mg/mL, DEF = 1.7) were not significantly different from IC injection of iodine without mannitol (p = 0.8142). The IV injection of iodine with saline led to an iodine concentration in the tumor of 1.2 +/- 0.98 mg/mL and a DEF of 1.2. This study established that optimizing the delivery of iodine by means of IC injection combined with a blood-brain barrier opener (mannitol) significantly increases the iodine uptake of F98 rat gliomas. This infusion protocol could potentially enhance the efficacy of SSR treatment, because the radiation dose is proportional to the iodine amount present in the irradiation bed.