Evaluation of tumour hypoxia during radiotherapy using [18F]HX4 PET imaging and blood biomarkers in patients with head and neck cancer

Catharina M L Zegers, Frank J P Hoebers, Wouter van Elmpt, Judith A Bons, Michel C Öllers, Esther G C Troost, Daniëlle Eekers, Leo Balmaekers, Marlies Arts-Pechtold, Felix M Mottaghy, Philippe Lambin, Catharina M L Zegers, Frank J P Hoebers, Wouter van Elmpt, Judith A Bons, Michel C Öllers, Esther G C Troost, Daniëlle Eekers, Leo Balmaekers, Marlies Arts-Pechtold, Felix M Mottaghy, Philippe Lambin

Abstract

Background and purpose: Increased tumour hypoxia is associated with a worse overall survival in patients with head and neck squamous cell carcinoma (HNSCC). The aims of this study were to evaluate treatment-associated changes in [18F]HX4-PET, hypoxia-related blood biomarkers, and their interdependence.

Material and methods: [18F]HX4-PET/CT scans of 20 patients with HNSCC were acquired at baseline and after ±20Gy of radiotherapy. Within the gross-tumour-volumes (GTV; primary and lymph nodes), mean and maximum standardized uptake values, the hypoxic fraction (HF) and volume (HV) were calculated. Also, the changes in spatial uptake pattern were evaluated using [18F]HX4-PET/CT imaging. For all patients, the plasma concentration of CAIX, osteopontin and VEGF was assessed.

Results: At baseline, tumour hypoxia was detected in 69 % (22/32) of the GTVs. During therapy, we observed a significant decrease in all image parameters. The HF decreased from 21.7 ± 19.8 % (baseline) to 3.6 ± 10.0 % (during treatment; P < 0.001). Only two patients had a HV > 1 cm3 during treatment, which was located for >98 % within the baseline HV. During treatment, no significant changes in plasma CAIX or VEGF were observed, while osteopontin was increased.

Conclusions: [18F]HX4-PET/CT imaging allows monitoring changes in hypoxia during (chemo)radiotherapy whereas the blood biomarkers were not able to detect a treatment-associated decrease in hypoxia.

Keywords: CAIX; Hypoxia; Osteopontin; PET; VEGF.

Conflict of interest statement

Compliance with ethical standards Funding Authors acknowledge financial support from the QuIC-ConCePT project, which is partly funded by EFPI A companies and the Innovative Medicine Initiative Joint Undertaking (IMI JU) under Grant Agreement No. 115151. Authors also acknowledge financial support from EU 7th framework program (EURECA, ARTFORCE - n° 257144, REQUITE - n° 601826), Kankeronderzoekfonds Limburg from the Health Foundation Limburg and the Dutch Cancer Society (KWF MAC 2011–4970). Conflict of interest No actual or potential conflicts of interest exist. Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the Ethical Review Committee of Maastricht University Medical Centre. Informed consent Informed consent was obtained from all individual participants included in the study.

Figures

Fig. 1
Fig. 1
[18F]HX4 PET/CT scans of a patient with a T2N2bMx squamous cell carcinoma of the oropharynx, scanned at 1.5 h (a), 3 h (b), and 4 h p.i. (c). d: The tumour to muscle ratio (TMRmax) for all patients. Shown are the gross tumour volumes of the primary lesions (GTVprim) and the metastatic lymph nodes (GTVln), which increased significantly (1.5 h vs 3 h: p < 0.01, 3 h vs 4 h: p = 0.02)
Fig. 2
Fig. 2
[18F]HX4 PET/CT scan of a patient with a T3N2bMx squamous cell carcinoma of the hypopharynx treated with cisplatin chemo-radiation. a: Scan with hypoxic primary tumour at baseline, b: decreased level of hypoxia during treatment and c: Calculated hypoxic fraction (HF) of all primary tumours and lymph nodes before and during treatment, significant decrease (p < 0.001)
Fig. 3
Fig. 3
Spatial reproducibility of the [18F]HX4 PET uptake in two patients with persistent hypoxia during treatment (left: patient with cT2N2aM0 hypopharynx cancer, right: patient with cT2N2bM0 oropharynx cancer. The PET-CT scans during treatment were in both patients performed after 18 Gy. Visualised is the voxel-wise correlation of the [18F]HX4-uptake within the GTV

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