Imaging Chemotherapy-Induced Brain Damage in Pediatric Cancer Survivors

89 Purpose: Chemotherapy with methotrexate (MTX) is associated with chronic neurotoxicity. Many pediatric cancer survivors face chronic neurological problems after exposure to high dose MTX (>1000 mg/m2), ranging from mild symptoms to severe headaches, seizures, motor problems, and cognitive impairment. Currently, it is impossible to predict who will develop long-term neurocognitive effects after MTX. Our goal was to detect early imaging signs of chemotherapy-induced brain damage, that can be associated with chronic neurocognitive problems.Methods: In an IRB approved, retrospective study, we investigated 10 children (range: 2-24 years; mean±SD:17.5±5.2), with osteosarcoma (n=6) and lymphoma (n=4), who underwent 18F-FDG-PET/MR scans (range: 3-5 MBq/kg; mean±SD:3.5±1.6), before and after intravenous chemotherapy with high-dose-MTX (range: 3000-144.000 mg/m2; mean: 26.448). Follow up scans were compared to an atlas of normal pediatric brain images using the MIMvista 6.5 software, and any hyper- or hypometabolic brain areas (z-score±1.65, 95% statistical significance level) were collected. Single affected brain areas were grouped into larger macro-regions related to specific neurocognitive problems (Table 1). Max standardized uptake value (SUVmax) of these brain regions at baseline and follow-up scans were compared with a Wilcoxon signed-rank sum test (significance level p Results: Of 10 patients who received high dose MTX, 9 patients demonstrated abnormal brain metabolism on 18F-FDG-PET/MR scans after high-dose-MTX. Hyper or hypometabolic brain areas were noted in Brodmann areas 9,10 and 11 (region 1 and 2, related to executive functions and intelligence quotient) for 8 patients; in Brodmann areas 13 and 14 (region 3, related to attention ability) for 3 patients; in Brodmann areas 5,7,8,19,20,37 (region 4, related to academic function) for 6 patients and in Brodmann areas 11,22,37,39,40,47 (region 5, related to reading ability) for 9 patients. Average SUVmax values decreased from baseline to follow-up scans in all regions (10.4±2.6 vs 9.4±4.5 for region 1 and 2; 7.4±1.6 vs 4.9±1.2 for region 3; 7.8±1.7 vs 6.4±3.4 for region 4 as well as 10.1±2.5 vs 10±4.1 for region 5, respectively), but the difference was not significant (p>0.05). Ongoing prospective studies correlate these findings with neuropsychological testing of these patients.Conclusion: Our preliminary data show that PET/MRI can detect early signs of chemotherapy-induced brain damage. Since there is a window of time between drug exposure and morbidity, this early detection could enable non-invasive monitoring of interventions, which can improve clinical outcomes. Further evaluations are needed to confirm these data. Table 1: Brain regions, corresponding Brodmann areas, and related neurocognitive disorders. This work is funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NIH/NICHD), grant R21 HD101129.