Patient 1 demonstrated a large nodal mass in the left neck at the staging CT scan. This might have been expected to be hypoxic due to disorganised internal vasculature (as manifested by the heterogeneous contrast enhancement) but the mass was negative for hypoxia by [18F]HX4 PET, with a tumour to mediastinum SUVmax ratio of 1 (Fig. 1 and Table 1). This patient demonstrated a photopenic region in the anterior aspect of the mass which might have been due to necrosis. It should be noted that 2-nitroimidazole radiotracers are not retained in regions of necrosis as they require active reductase enzymes to activate the hypoxia trapping mechanism 13. While necrotic-hypoxic regions can therefore, give rise to false negative scans for hypoxia, the ability to differentiate viable-hypoxic from necrotic-hypoxic cells is considered an advantage for this class of radiotracer 13.
The authors thank the study participants for their generosity and willingness to take part in the project. They also acknowledge Dr S. Morgan, Dr C.P. Esler, Professor P.M. Patel, Dr J.D. Birchall, Dr R.H. Ganatra and K. Leach for helpful discussions and support of the trial. We acknowledge Nottingham University Hospitals National Health Service Trust Research and Innovation Department for acting as Sponsor, and in particular the contributions of Dr N. McGregor and H. Driver to study set up.
This study was funded by Nottingham Hospitals Charity. The authors acknowledge Threshold Pharmaceuticals for provision of precursor and reference material for HX4, PETNET Nottingham for manufacture of [18F]HX4 and Nottingham In Health for PET/CT scanning. Threshold Pharmaceuticals and Siemens Healthcare provided the Investigator Brochure.
There are no conflicts of interest.
1. Kelly JR, Park HS, An Y, Contessa JN, Yarbrough WG, Burtness BA, et al. Comparison of survival outcomes among human papillomavirus-negative cT1-2 N1-2b patients with oropharyngeal squamous cell cancer treated with upfront surgery vs
definitive chemoradiation therapy: an observational study. JAMA Oncol 2017; 3:1107–1111.
2. Nordsmark M, Bentzen SM, Rudat V, Brizel D, Lartigau E, Stadler P, et al. Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy. An international multi-center study. Radiother Oncol 2005; 77:18–24.
3. Gray LH, Conger AD, Ebert M, Hornsey S, Scott OC. The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br J Radiol 1953; 26:638–648.
4. Bredell MG, Ernst J, El-Kochairi I, Dahlem Y, Ikenberg K, Schumann DM. Current relevance of hypoxia
in head and neck cancer
. Oncotarget 2016; 7:50781–50804.
5. Mistry IN, Thomas M, Calder EDD, Conway SJ, Hammond EM. Clinical advances of hypoxia
-activated prodrugs in combination with radiation therapy. Int J Radiat Oncol Biol Phys 2017; 98:1183–1196.
6. Troost EGC, Koi L, Yaromina A, Krause M. Therapeutic options to overcome tumor hypoxia
in radiation oncology. Clin Transl Imaging 2017; 5:455–464.
7. Horsman MR, Saskø Mortensen L, Petersen JB, Busk M, Overgaard J. Imaging hypoxia
to improve radiotherapy outcome. Nat Rev Clin Oncol 2012; 9:674–687.
8. Evans CE, Mattock K, Humphries J, Saha P, Ahmad A, Waltham M, et al. Techniques of assessing hypoxia
at the bench and bedside. Angiogenesis 2011; 14:119–124.
9. Chen L, Zhang Z, Kolb HC, Walsh JC, Zhang J, Guan Y. 18F-HX4 hypoxia
imaging with PET/CT
in head and neck cancer
: a comparison with 18F-FMISO. Nucl Med Commun 2012; 33:1096–1102.
10. Dubois LJ, Lieuwes NG, Janssen MHN, Peeters WJ, Windhorst AD, Walsh JC, et al. Preclinical evaluation and validation of [18
F]HX4, a promising hypoxia
marker for PET imaging. Proc Natl Acad Sci USA 2011; 108:14620–14625.
11. Turton DR, Betts HM, Dutton D, Perkins AC. Automated radiosynthesis of GMP quality [18
F]HX4 for PET imaging of hypoxia
. Nucl Med Biol 2015; 42:494–498.
12. Doss M, Zhang JJ, Bélanger M-J, Stubbs JB, Hostetler ED, Alpaugh RK, et al. Biodistribution and radiation dosimetry of the hypoxia
marker 18F–HX4 in monkeys and humans determined from whole-body PET/CT
. Nucl Med Commun 2010; 31:1016–1024.
13. Fleming IN, Manavaki R, Blower PJ, West C, Williams KJ, Harris AL, et al. Imaging tumour hypoxia
with positron emission tomography. Br J Cancer 2015; 112:238–250.
14. Zegers CM, van Elmpt W, Wierts R, Reymen B, Sharifi H, Öllers MC, et al. Hypoxia
imaging with [18
F]HX4 PET in NSCLC: defining optimal imaging parameters. Radiother Oncol 2013; 109:58–64.
15. Zegers CM, van Elmpt W, Szardenings K, Kolb H, Waxman A, Subramaniam RM, et al. Repeatability of hypoxia
PET imaging using [18
F]HX4 in lung and head and neck cancer
patients: a prospective multicenter trial. Eur J Nucl Med Mol Imaging 2015; 42:1840–1849.
16. Zegers CM, van Elmpt W, Hoebers FJ, Troost EG, Öllers MC, Mottaghy FM, et al. Imaging of tumour hypoxia
and metabolism in patients with head and neck squamous cell carcinoma
. Acta Oncol 2015; 54:1378–1384.
17. Zegers CM, Hoebers FJ, van Elmpt W, Bons JA, Öllers MC, Troost EG, et al. Evaluation of tumour hypoxia
during radiotherapy using [18
F]HX4 PET imaging and blood biomarkers in patients with head and neck cancer
. Eur J Nucl Med Mol Imaging 2016; 43:2139–2146.
18. The Cancer Genome Atlas Network. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature 2015; 517:576–582.
19. Perakis S, Speicher MR. Emerging concepts in liquid biopsies. BMC Med 2017; 15:75.
20. Caudell JJ, Torres-Roca JF, Gillies RJ, Enderling H, Kim S, Rishi A, et al. The future of personalised radiotherapy for head and neck cancer
. Lancet Oncol 2017; 18:e266–e273.