1. Comparison of MRI Perfusion and PET-CT in Differentiating Brain Tumor Progression from Radiation Injury after Cranial Irradiation T. Jonathan Yang, M.D. 1, Robert Young, M.D. 2, Vaios Hatzoglou, M.D. 2, Taylor Schneider, B.S. 2, Kaitlin Woo, M.S. 3, Zhigang Zhang, Ph.D. 3, Antonio Omuro, M.D. 4, Timothy Chan, M.D., Ph.D. 1, Yoshiya Yamada, M.D. 1, Kathryn Beal, M.D. 1 Departments of Radiation Oncology 1, Radiology 2, Epidemiology and Biostatitics 3, and Neurology 4, Memorial Sloan Kettering Cancer Center, New York, NY, USA

2. Background/ Objective Radiation therapy (RT) has an essential role in the treatment of primary and metastatic brain tumors. It is not uncommon to observe post-RT enhancing changes at the treated intracranial sites. This frequently poses a diagnostic dilemma, as an enhancing lesion after RT could represent either tumor progression (PD) or radiation injury (RN) when applying standard response criteria 1, as these criteria usually rely on changes in size of the enhancing lesion on contrast magnetic resonance imaging (MRI). Advanced imaging, such as brain MRI perfusion imaging (MRP) and fluorine-18 flurodeoxyglucose positron emission tomography-computed tomography (PET-CT) have been incorporated for clinical use. However it is not clear what imaging metrics are more effective in distinguishing RN vs. RD. The objective of this study is to assess the efficacy of MRP and PET-CT in differentiating RN and PD. 1. Macdonald D. R., Cascino T. L., Schold S.C. et al. JCO 1990; 8 :1277-80

3. Patients and Lesions This is a prospective trial that included 53 patients with 55 lesions who received prior RT for primary gliomas or brain metastases and subsequently developed indeterminate enhancing lesions within prior RT volumes between 2012-2014. All patients were found to have nonspecific enhancing lesions on brain contrast MRI and subsequently underwent brain MRP and PET-CT as part of the protocol. Of the 53 patients, 29 received prior RT for 29 primary gliomas; all patients received standard fractionated partial brain RT (PBRT) to a median dose of 60Gy as part of definitive therapy, 1 patient received PBRT and whole brain RT. 24 patients received prior RT for 26 brain metastases, with the majority of the patients (69%) treated with single-fraction stereotactic radiosurgery (SRS) (median dose= 21Gy). Pathologic determination of RN vs. PD was obtained in 14 (25%) of the lesions. Clinical determination of RN vs. PD was performed using Response Assessment in Neuro-Oncology Working Group Criteria 2. Specifically, to be classified as RN, the lesion must spontaneously stabilize or decrease in size on subsequent scans over a minimum of 6 months without salvage therapeutic intervention. MRP and PET-CT metrics including V P (plasma volume), V E (extravascular extracellular distribution volume), K trans (volume transfer coefficient, K12= distribution in tissue, K21= distribution away from tissue), AUPC (area under perfusion curve), and PET-CT SUV max (standardized uptake value) were obtained. Statistical analysis was performed using Wilcoxon rank sum test and area under the curve (AUC) for receiver operating characteristic (ROC) analysis for correlation of imaging metrics and outcomes. 2. Wen PY, Macdonald DR, Reardon DA, et al. JCO 2010; 28:1963-72

4. Results The median time between RT and the protocol MRP and PET-CT scans was 11 months (range 2-101 months). PD was determined in 38 of the 55 lesions (69%) and RN in 17 lesions (31%). The great majority of prior treated gliomas (93%) that developed non-specific enhancements at RT sites were determined to be PD with clinical follow up or pathologic confirmation, while 42% of the brain metastases were PD and 58% were RN. Three imaging metrics were significant in determining PD vs. RN: V P ratio (V P lesion / V P normal brain, p< 0.001), K12 ratio (p=0.002), and PET-CT SUV max ratio (p=0.002). Lesions with PD exhibited increase in values of all 3 metrics compared to RN. V P ratio had the highest predictive value (AUC=0.87), with 92% sensitivity (rate of PD correctly classified as PD) and 77% specificity (rate of RN correctly classified as RN) with the optimal threshold of 2.1 (≥2.1 declares tumor). This was followed by K12 ratio (AUC=0.76), with 87% sensitivity and 71% specificity with threshold of 3.6; and SUV max ratio (AUC=0.75), with 68% sensitivity and 82% specificity with threshold of 1.2. When combing V P ratio and K 12ratio, the predictive power for RN was further improved. MetricsOutcomesSensitivitySpecificity V p ratio ≥2.1 and K12 ratio ≥3.6Tumor progression7994 V p ratio <2.1 and K12 ratio <3.6Radiation injury9553

5. ABCDE F A subgroup analysis including only the 26 metastatic lesions showed that V p ratio continued to have the strongest predictive value (AUC=0.87, sensitivity of 91% and specificity of 80% using a threshold of 2.6). This was followed by SUV max ratio (AUC= 0.82), with a sensitivity of 82% and specificity of 80% using an optimal threshold of 1.4. Below is a 39 year-old woman with metastatic breast cancer who underwent SRS to a right frontal lobe metastasis (A) and demonstrated complete response 3 months after RT (B). She subsequently developed an indeterminate enhancing lesion at RT site 1 year after SRS (C) and underwent MRP with no increase in plasma volume (D), and PET-CT with no increased SUV uptake (E). The lesion was concluded to be RN and remained stable 1 year after the protocol scans (F). Results

6. Conclusions This prospective evaluation of brain MRP and PET-CT metrics determined that MRP V P ratio is the most effective advanced imaging metric in distinguishing PD from RN in patients who developed indeterminate enhancing lesions within RT treatment volumes after RT for primary or metastatic brain lesions. An increase in accuracy in the diagnosis of RN was found when combing V P ratio and K 12ratio. While the great majority of patients who developed nonspecific enhancing lesions after RT for primary gliomas were determined to have tumor progression, we observed that <50% of lesions treated for brain metastases were found be PD. Further investigation with larger patient cohort is needed to determine the optimal combination of imaging metrics in distinguishing PD vs. RN after different types of RT treatments for brain metastases, including single vs. fractionated stereotactic radiosurgery.