Interleukin-6 as surrogate marker for imaging-based hypoxia dynamics in patients with head-and-neck cancers undergoing definitive chemoradiation—results from a prospective pilot trial

Abstract

Purpose Intratumoral hypoxia increases resistance of head-and-neck squamous cell carcinoma (HNSCC) to radiotherapy. [18F]FMISO PET imaging enables noninvasive hypoxia monitoring, though requiring complex logistical efforts. We investigated the role of plasma interleukin-6 (IL-6) as potential surrogate parameter for intratumoral hypoxia in HNSCC using [18F]FMISO PET/CT as reference. Methods Within a prospective trial, serial blood samples of 27 HNSCC patients undergoing definitive chemoradiation were collected to analyze plasma IL-6 levels. Intratumoral hypoxia was assessed in treatment weeks 0, 2, and 5 using [18F]FMISO PET/CT imaging. The association between PET-based hypoxia and IL-6 was examined using Pearson’s correlation and multiple regression analyses, and the diagnostic power of IL-6 for tumor hypoxia response prediction was determined with receiver-operating characteristic analyses. Results Mean IL-6 concentrations were 15.1, 19.6, and 31.0 pg/mL at baseline, week 2 and week 5, respectively. Smoking (p=0.050) and reduced performance status (p=0.011) resulted in higher IL-6 levels, whereas tumor (p=0.427) and nodal stages (p=0.334), tumor localization (p=0.439), and HPV status (p=0.294) had no influence. IL-6 levels strongly correlated with the intratumoral hypoxic subvolume during treatment (baseline: r=0.775, p<0.001; week 2: r=0.553, p=0.007; week 5: r=0.734, p<0.001). IL-6 levels in week 2 were higher in patients with absent early tumor hypoxia response (p=0.016) and predicted early hypoxia response (AUC=0.822, p=0.031). Increased IL-6 levels at week 5 resulted in a trend towards reduced progression-free survival (p=0.078) and overall survival (p=0.013). Conclusion Plasma IL-6 is a promising surrogate marker for tumor hypoxia dynamics in HNSCC patients and may facilitate hypoxia-directed personalized radiotherapy concepts. Trial registration The prospective trial was registered in the German Clinical Trial Register (DRKS00003830). Registered 20 August 2015

Planning adaptive treatment by longitudinal response assessment implementing MR imaging, liquid biopsy and analysis of microenvironment during neoadjuvant treatment of rectal cancer (PRIMO)

“…Thus, an association to bad response is probable. Interleukin 6 may serve as surrogate for hypoxia dynamics [20] and will therefore be of interest in this trial.…”

Predictive value of SUA/SCr and IL-6 in patients with non-small cell lung cancer （ NSCLC ） undergoing concurrent chemoradiotherapy

“…Grosu and Nils H. Nicolay et al suggest that plasma IL-6 is a promising alternative marker for tumor hypoxia kinetics in patients with head-to-neck squamous cell carcinoma. And may promote the concept of hypoxia directed personalized radiotherapy [11].Bin Zhao, Hong Zhao and their team showed that cytotoxic T lymphocytes can improve the response of neoadjuvant chemoradiotherapy in tumor microenvironment, while tumor-associated macrophages has the opposite effect. These cells may be potential markers of clinical outcome for neoadjuvant chemoradiotherapy and may help locally advanced rectal cancer improve clinical decision making of clinical outcome [12].…”