Perfusion and diffusion MRI in the assessment of the antivascular effect of arsenic trioxide combined with radiotherapy for glioblastoma multiforme: NABTT phase I study

Abstract

1538 Background: Significant tumor control and prolongation of survival have been demonstrated by combined use of radiosurgery and antivascular agent, Arsenic Trioxide (ATO), in rodent gliosarcoma model in rats. This agent is now undergoing clinical evaluation in the NABTT Brain Tumor Consortium in a Phase I trial with ATO dose escalation in combination with fractionated radiation therapy. Since this agent showed rapid effect on the tumor vasculature in the animal studies, MRI perfusion and diffusion studies were performed shortly following ATO administration. Methods: The patients were treated with external beam radiotherapy 60 Gy in 6 weeks with ATO at a starting dose of 0.25 mg/kg once a week during the course radiotherapy. ATO dose was escalated by 0.05 mg. The perfusion images were acquired using a Echo Planar Image (EPI) sequence. Perfusion parameters were Mean Transit Time (MTT), relative Cerebral Blood Volume (rCBV), and relative Cerebral Blood Flow (rCBF). The perfusion parameter values under regions of interest (ROI) from the enhancing and non-enhancing portions of the lesion were then followed serially during treatment. Results: There was a delay on mean transit time (MTT) and relative cerebral flow (rCBF) by ATO and radiotherapy, compared to counterpart normal brain. This effect was apparent within 24 hours of ATO infusion. The extent and duration of these changes will be correlated with conventional measures of outcome, such as lesion volumes, response, and time to tumor progression (TTP). There were no dose limiting toxicities with doses of ATO as high as 0.35 mg/kg once a week. Conclusions: A total of 12 patients were treated with this phase I trial. At the doses studied thus far, ATO combined with radiotherapy appears safe in the treatment of glioblastoma multiforme. ATO induced a differential delay of blood flow in the tumor compared to the normal brain. ATO showed the immediate effects and serial evaluation highlights the dynamic nature of the intratumoral vasculature in response to ATO, antivascular agent. No significant financial relationships to disclose.