Environmental PET Multimodality functional imaging of spontaneous canine tumors using 64 Cu-ATSM and 18 FDG PET/CT and dynamic contrast enhanced perfusion CT Anders E. Hansen a,⇑ , Annemarie T. Kristensen a , Ian Law b , Fintan J. McEvoy a , Andreas Kjær b,c , Svend A. Engelholm d a Department of Small Animal Clinical Sciences, University of Copenhagen; b Department of Clinical Physiology, nuclear medicine and PET, Copenhagen University Hospital; c Cluster of Molecular Imaging, University of Copenhagen; and d Department of Radiation Oncology, Copenhagen University Hospital, Denmark article info Article history: Received 29 July 2011 Received in revised form 13 October 2011 Accepted 24 October 2011 Available online 24 November 2011 Keywords: Cu-ATSM FDG Hypoxia Perfusion CT abstract Purpose: To compare the distribution and uptake of the hypoxia tracer 64 Cu-diacetyl-bis(N 4 -methylthi- osemicarbazone) ( 64 Cu-ATSM) PET/CT, FDG PET/CT and dynamic contrast enhanced perfusion CT (DCE- pCT) in spontaneous canine tumors. In addition 64 Cu-ATSM distribution over time was evaluated. Methods and materials: Nine spontaneous cancer-bearing dogs were prospectively enrolled. FDG (1 h pi.) and 64 Cu-ATSM (3 and 24 h pi.) PET/CT were performed over three consecutive days. DCE-pCT was per- formed on day 2. Tumor uptake of FDG and 64 Cu-ATSM was assessed semi-quantitatively and the distri- bution of FDG, 64 Cu-ATSM and CT perfusion parameters correlated. Results: 64 Cu-ATSM distribution on scans performed 24 h apart displayed moderate to strong correlation; however, temporal changes were observed. The spatial distribution pattern of 64 Cu-ATSM between scans was moderately to strongly positively correlated to FDG, whereas the correlation of CT perfusion param- eters to FDG and to 64 Cu-ATSM yielded more varying results. Conclusions: 64 Cu-ATSM uptake was positively correlated to FDG. 64 Cu-ATSM was found to be relatively stable between PET scans performed at different time points, important temporal changes were however observed in hypo-perfused regions. These findings potentially indicate that prolonged uptake periods for 64 Cu-ATSM imaging may be needed. Although a moderate to strong correlation between 64 Cu-ATSM and FDG PET/CT is observed, the two tracers provide different biological information with an overlapping spa- tial distribution. Ó 2011 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 102 (2012) 424–428 Tumor hypoxia is one of the key factors in the development of aggressive and treatment resistant tumors, and is generally divided into diffusion related chronic, perfusion related acute, and anemic hypoxia, although probably none of these can be seen as indepen- dent events [1]. Non-invasive functional imaging can potentially serve as the basis for biologically adapted therapy [2]. Cu-diacetyl- bis(N 4 -methylthiosemicarbazone) (Cu-ATSM) is among the most promising hypoxia PET tracers. The trapping mechanism of Cu- ATSM is currently incompletely understood and pre-clinical studies have yielded conflicting results, but hypoxic cell conditions are ex- pected to trap Cu-ATSM by a redox-dependent mechanism [3–5]. However, the redox inactive structural analog of Cu-ATSM, zinc- ATSM, has been found to accumulate in various cancer cells in vitro in a cell type dependent manner [6], suggesting that accumu- lation mechanisms unrelated to hypoxia could exist. Cu-ATSM has been evaluated in three clinical studies. In rectal cancer patients, accumulation of Cu-ATSM to levels above a tumor to muscle ratio of 2.6 was predictive of negative prognosis [7]. The distribution pattern of Cu-ATSM was found to correlate positively to 2-deoxy-2-( 18 F)fluoro-D-glucose (FDG) in five pulmonary adeno- carcinomas, but negatively in eight pulmonary squamous cell car- cinomas [8]. No correlation between FDG and Cu-ATSM uptake was found in cervical cancers, but a tumor to muscle Cu-ATSM uptake ratio above 3.5 was predictive for negative outcome [9], and a po- sitive correlation between Cu-ATSM and overexpression of hypox- ia-related molecular markers reported [10]. FDG uptake is correlated to expression levels of glucose trans- porter proteins and hexokinases in cancer cells and the functional- ity of regional microvasculature and proliferative activity [11]. Several glycolytic genes are induced under hypoxic conditions; however, studies have not identified a consistent correlation be- tween FDG and hypoxia markers [11,12]. Dynamic contrast en- hanced perfusion CT (DCE-pCT) provides non-invasive information on tumor blood perfusion parameters [13]. This study evaluates 64 Cu-ATSM in canine tumors, by measuring tumor uptake and distribution characteristics between consecutive 0167-8140/$ - see front matter Ó 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2011.10.021 ⇑ Corresponding author. Address: Department of Small Animal Clinical Sciences, Faculty of Life Sciences, University of Copenhagen, Dyrlaegevej 16, 1870 Frederi- ksberg, Denmark. E-mail address: aeha@life.ku.dk (A.E. Hansen). Radiotherapy and Oncology 102 (2012) 424–428 Contents lists available at SciVerse ScienceDirect Radiotherapy and Oncology journal homepage: www.thegreenjournal.com