Introduction: Tumor hypoxia is an important prognostic factor in overall survival for chemotherapy and radiotherapy. Quantifying and localizing hypoxia non-invasively is therefore important. At present, hypoxia PET tracers lack high tumor-to-background (TBR) ratios. The nitroimidazole [18F]HX4, has shown promise in pre-clinical (Dubois et al. PNAS 2011) and phase I human setting (van Loon et al. EJNMMI 2010). However, until now no comparative research has been conducted between the latest promising hypoxia tracers in order to define the best marker. In a pre-clinical study [18F]HX4 was compared to the hypoxia tracers [18F]FMISO and [18F]FAZA on 3 endpoints; optimal imaging time point, spatial reproducibility and oxygen dependency. Clinical studies investigated the optimal time point and spatial-temporal stability for [18F]HX4 imaging.

Methods: In pre-clinical experiments, WAG/Rij rats bearing rhabdomyosarcoma R1 tumors were injected with 20 ± 4 MBq of [18F]HX4, [18F]FMISO or [18F]FAZA, followed by PET/CT imaging up to 6h post-injection (h p.i.). For each tracer TBR was calculated and reproducibility was investigated by voxel-to-voxel analysis or a DICE similarity coefficient. Oxygen sensitivity was studied by altering the tumoral hypoxia status either by carbogen/nicotinamide treatment or 7% oxygen breathing. In clinical trials, NSCLC (N=15) [NCT01024829, NCT01210378] and HNSCC (N=10) [NCT01347281] patients were injected with 403 ± 53 MBq [18F]HX4 and PET/CT imaging was performed at several time points up to 4h p.i.. Tumor uptake (TBR>1.4), image contrast changes over time, hypoxic fraction (HF) and spatial-temporal stability were evaluated.

Results: In pre-clinical setting, [18F]HX4 uptake reached a stabilized and maximal TBR at 3h p.i. (TBR=7.2) which is significantly higher compared to the plateau phase of [18F]FAZA reached at 2h p.i. (TBR=3.9, P<0.05). [18F]FMISO did not reach a plateau. Voxel-to-voxel comparisons and DICE similarity coefficient calculations showed a high short- and long-term spatial reproducibility except for [18F]FAZA, which performed poor on a 48 hour interval. Increasing the hypoxic fraction by 7% oxygen breathing resulted in enhanced mean standardized uptake values for both [18F]HX4 (P<0.01) and [18F]FAZA (P<0.05). Only [18F]FMISO uptake was found to be reversible upon reoxygenation using nicotinamide and carbogen. In patients, a TBR>1.4 was observed in 72% of NSCLC and in 74% of HNSCC target lesions, with average HF of 14 ± 17% and 25 ± 22%, respectively. In the hypoxic lesions, TBR increased up to 4h p.i., providing a better contrast at the latest time-points. [18F]HX4 uptake was stable in time and space for the heterogeneous pattern in NSCLC lesions (2h vs. 4h p.i.: r = 0.77 ± 0.10).

Conclusions: Both pre-clinical and clinical studies support [18F]HX4 as a robust hypoxia tracer, with the highest image contrast from 3h p.i. onwards, sensitivity to hypoxia and high reproducibility.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B144.

Citation Format: Sarah Peeters, Catharina Zegers, Natasja Lieuwes, Wouter van Elmpt, Frank Hoebers, Hoda Sharifi, Bart Reymen, Michel Öllers, Felix Mottaghy, Jonas Eriksson, Albert Windhorst, Guus van Dongen, Dirk de Ruysscher, Ludwig Dubois, Philippe Lambin. Hypoxia imaging with [18F]HX4 PET compared with [18F]FMISO and [18F]FAZA: From preclinical to clinical studies. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B144.