Session Item

Intratumoral hypoxia is known to deteriorate the oncological outcome of head-and-neck squamous cell carcinoma (HNSCC) patients receiving radiotherapy. Plasma hypoxia markers could potentially be used as biomarkers to monitor tumor-associated hypoxia; however, the exact correlation between plasma hypoxia markers and imaging-based intratumoral hypoxia is yet not fully understood. We therefore aimed to examine the value of established and novel hypoxia-associated plasma proteins as potential surrogate markers for tumor hypoxia.

Within a prospective imaging trial (DRKS00003830), serial blood samples of 27 HNSCC patients receiving definitive cisplatin-based chemoradiation were collected and analyzed for osteopontin, galectin-3, vascular endothelial growth factor (VEGF) and connective tissue growth factor (CTGF) plasma concentrations using enzyme-linked immunosorbent assays. The intratumoral hypoxic subvolume (HSV) was quantified in treatment weeks 0, 2 and 5 based on [¹⁸F]FMISO PET/CT. The association between plasma hypoxia markers and PET-defined hypoxia was assessed using Pearson’s correlations, and receiver-operating characteristic (ROC) analyses were performed to determine the prognostic power of the plasma hypoxia markers.

While osteopontin plasma concentrations increased during chemoradiation (p=0.07), there was a trend towards decreasing CTGF plasma over the course of chemoradiation (p=0.08). Baseline osteopontin (r=0.579, p=0.002) as well as galectin-3 (r=0.429, p=0.032) moderately correlated with the HSV prior to chemoradiation, whereas VEGF (r=0.196, p=0.357) and CTGF (r=0.314, p=0.118) did not. Patients with non-resolving tumor hypoxia in week 2 of treatment, as determined by [¹⁸F]FMISO PET, were found to exhibit significantly higher VEGF (451.1 versus 221.7 ng/mL, p<0.05) and CTGF (27.8 versus 17.3 ng/mL, p<0.05) plasma concentrations in treatment week 5. Baseline osteopontin plasma concentration was higher in patients with residual PET hypoxia at the end of treatment (38.4 versus 14.8 ng/mL, p<0.01) and predicted residual hypoxia with an AUC=0.821 (95% CI 0.612-1.000, p<0.05).

Baseline osteopontin and galectin-3 plasma levels moderately correlated with the pretherapeutic HSV and therefore indicated hypoxic tumors prior to radiotherapy. Pretherapeutic osteopontin was also associated with residual tumor hypoxia at the end of chemoradiation, providing a rationale to investigate hypoxic modification based on osteopontin plasma levels. However, as plasma hypoxia proteins do not convey any spatial distribution of tumor hypoxia, they rather add to than replace [¹⁸F]FMISO PET/CT-imaging for hypoxia-based radiotherapy dose escalation.