Non invasive imaging of [18F]HX4 with Positron-Emission-Tomography (PET) in Head and Neck Cancer.

Tumor hypoxia is the situation where tumor cells have been deprived of oxygen.
Hypoxic tumor cells are usually more resistant to radiotherapy and chemotherapy
and more likely to develop metastasis3,4
Tumor oxygenation is frequently measured with an Eppendorf electrode. This is
an invasive procedure, limiting its application in clinical practice. Measuring
tumor hypoxia by non-invasive methods includes the use of bioreductive markers,
such as the 2-nitro-imidazole derivatives. These 2-nitroimidazoles are known to
be metabolically reduced and trapped within hypoxic cells. Based on this
mechanism of action they have been investigated extensively as a
radio-sensitizer5. The selective binding and retention of 2-nitroimidazoles in
hypoxic regions offers significant potential for one or more labelled
nitroimidazoles to emerge as a clinically useful non-invasive hypoxia markers.
The 2 nitroimidazole nucleoside analogue HX4 was developed as a potential
radio-sensitizer for hypoxic tumor cells6. In a recent phase 1 clinical study
from van Loon et al 1, PET-imaging with [18F]HX4 was feasible without any
toxicity. In head and neck cancer tumor hypoxia is known to be an important
prognostic factor for long term survival7. To define the added value of
anti-hypoxic therapies in this patient population, an estimation of the
proportion of tumors with hypoxia is essential. In previous research,
18F-fluoromisonidazole (18FMISO) was able to detect hypoxia in 71-87% of
patients with head and neck squamous cell carcinoma8-10. In this observational
imaging trial these results will be verified by hypoxia imaging with [18F]HX4.

Non invasive imaging of hypoxia with the aid of PET-scans could help to select
the patients having a hypoxic tumor who could be treated with specific
anti-hypoxic treatments. The added value of additional anti-hypoxic treatments
depends on the amount of patients who will benefit from them. Several
2-nitroimidazoles, labelled with Fluor-18 (18F) have already been used in
patients to identify hypoxia. However, suboptimal image quality and
unpredictable kinetics limit their use. In extensive pre-clinical models and a
clinical phase 1 study the combination of HX4 labelled with 18F showed to be a
promising and non-toxic new probe to determine hypoxia. With this tracer the
proportion of hypoxic tumors in head and neck cancer patients will be verified.

The aim of this study is to determine if tumor hypoxia can be accurately
visualised with [18F] HX4 PET imaging in head and neck tumors.

Phase II, single-centre imaging, non-randomized, open-label trial

Fluor-18 labelled HX-4 (444MBq, 27 *g HX-4)

All patients will be monitored carefully during and after administration of the
labelled [18F]HX4 by trained caregivers. The proposed [18F]HX4 dose is chosen
based on the phase 1 study with [18F]HX41. In view of previous experiences with
[18F]HX4, conventional PET-CT and other nitroimidazole drugs, we expect no
unforeseen side effects.