Generation of biological hypotheses by functional imaging links tumor hypoxia to radiation induced tissue inflammation/glucose uptake in head and neck cancer

Abstract

Background and purpose: Positron emission tomography (PET) is a functional imaging modality which is able to deliver tracer specific biological information, e.g. about glucose uptake, inflammation or hypoxia of tumors. We performed a proof-of-principle study that used different tracers and expanded the analytical scope to non-tumor structures to evaluate tumor-host interactions. Materials and methods: Based on a previously reported prospective imaging study on 50 patients treated with curative intent chemoradiation (CRT) for head and neck squamous cell carcinoma, PET-based hypoxia and normal tissue inflammation measured by repeat 18F-fluoromisonidazole (FMISO) PET and 18F-fluorodesoxyglucose (FDG) PET, respectively, were correlated using the Spearman correlation coefficient R. PET parameters determined before and during CRT (week 1, 2 and 5), were associated with local tumor control and overall survival. Results: Tumor hypoxia at all measured times showed an inverse correlation with mid-treatment FDG-uptake of non-tumor affected oral (sub-)mucosa with R values between −0.35 and −0.6 (all p < 0.05). Mucosal FDG-uptake and mucosal hypoxia correlated positively but weaker (R values between 0.2 and 0.45). More tumor hypoxia in FMISO-PET (week 2) and less FDG-uptake of (sub-)mucosa in FDG-PET (week 4) were significantly associated with worse LC (FMISO TBRpeak: HR = 1.72, p = 0.030; FDG SUVmean: HR = 0.23, p = 0.025) and OS (FMISO TBRpeak: HR = 1.71, p = 0.007; FDG SUVmean: HR = 0.30, p = 0.003). Multivariable models including both parameters showed improved performance, suggesting that these modalities still bear distinct biological information despite their strong inter-correlation. Conclusion: We report first clinical evidence that tumor hypoxia is inversely correlated with increased FDG-uptake during radiation, potentially expressing inflammation. This observation merits further research and may have important implication for future research on tumor hypoxia and radio-immunology. Our study demonstrates that functional imaging can be utilized to assess complex tumor-host interactions and generate novel biological insights in vivo vero.