Abstract 2355: Assessment of glioma recurrence following radiotherapy using the parametric response map: A preclinical study
Authors: Lemasson Benjamin , Galbán Stefanie , Li Fei , Heist Kevin A. , Sebolt-Leopold Judith , Rehemtulla Alnawez , Chenevert Thomas , Galbán Craig , Ross Brian D. 
Published: August 2012

Abstract
Heterogeneity of the glioblastoma multiforme (GBM) response to standard therapies can be due to spatially varying phenotypes within an individual tumor due to genomic instability. The goal of this study was to evaluate the parametric response map PRM, a voxel-based analytical approach, as a biomarker of tumor recurrence on an animal-by-animal basis in a radiation dose escalation protocol. Twenty-four genetically engineered murine GBM model [Ink4a/Arf-/- PtenloxP/loxp/ Ntv-a RCAS/PDGF(+)/Cre(+)] were imaged by MRI (contrast-enhanced (CE-T1w) and diffusion-weighted MRI) daily for a week and then every two days thereafter. Tumor bearing animals were introduced to the study (D0) when the tumors reached a volume of ∼20 mm3. Mice were randomized in 4 groups (n=6 per group): 0G and daily doses of 1G, 2G and 4G delivered daily for 5 days. Tumor volumes of interest (VOI) were manually contoured on the CE-T1w images and reported on the diffusion map. The relative ADC (rADC) maps were computed by normalized values using a VOI defined within the contralateral striatum. PRM was performed by calculating the difference in mid-treatment from pre-treatment rADC values for each voxel in the tumor. Voxels were classified, based on a user-defined threshold set at ±337 rADC units, as significantly increasing (PRMrADC+), significantly decreasing (PRMrADC-), and unchanged (PRMrADC0) rADC values following therapy. The volume fraction of each classification was calculated by summing the class specific voxels and normalizing by the tumor volume. Finally, for each animal the maximum PRMrADC+ value (maxPRMrADC+) was determined within the first 5 days following therapy initiation. The maxPRMrADC+ was correlated to time to recurrence using a linear regression (TTR; was defined as the time for the tumor to triple its initial volume at baseline (D0)). We observed a large inter- and intra-group variability of TTR (intra-group variability in day: [min-max] = [3-5], [3-9], [13-21] and [19-25] for the 0G, 1G, 2G and 4G groups; respectively). The day of the maxPRMrADC+ value measured animal by animal was somewhat variable over the week of treatment administration. We observed a linear increase of maxPRMrADC+ value which correlated with the dose of radiation received (from 4.5±2.7 % to 33.9±11.3 %; for control and 4G groups; respectively). We also found excellent correlation between TTR and the maxPRMrADC+ metric value of individual animals during the week of treatment (R2 = 0.85). This study demonstrates the efficacy of PRM as an imaging biomarker of tumor recurrence following radiotherapy. The maxPRMrADC+ values measured during radiation therapy were correlated strongly with TTR. PRMrADC technique may serve as a biomarker of tumor recurrence that is insensitive to the response heterogeneity typically observed in GBM.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2355. doi:1538-7445.AM2012-2355