The prognostic value of the hypoxia markers CA IX and GLUT I and the cytokines VEGF and IL 6 in head and neck squamous cell carcinoma treated by radiotherapy chemotherapy

Background: Several parameters of the tumor microenvironment, such as hypoxia, inflammation and angiogenesis, play a critical role in tumor aggressiveness and treatment response. A major question remains if these markers can be used to stratify patients to certain treatment protocols. The purpose of this study was to investigate the inter- relationship and the prognostic significance of several biological and clinicopathological parameters in patients with head and neck squamous cell carcinoma ( HNSCC) treated by radiotherapy chemotherapy. Methods: We used two subgroups of a retrospective series for which CT- determined tumoral perfusion correlated with local control. In the first subgroup ( n = 67), immunohistochemistry for carbonic anhydrase IX ( CA IX) and glucose transporter- 1 ( GLUT- 1) was performed on the pretreatment tumor biopsy. In the second subgroup ( n = 34), enzyme linked immunosorbent assay ( ELISA) was used to determine pretreatment levels of the cytokines vascular endothelial growth factor ( VEGF) and interleukin- 6 ( IL- 6) in serum. Correlation was investigated between tumoral perfusion and each of these biological markers, as well as between the markers mutually. The prognostic value of these microenvironmental parameters was also evaluated. Results: For CA IX and GLUT- 1, the combined assessment of patients with both markers expressed above the median showed an independent correlation with local control ( p = 0.02) and disease- free survival ( p = 0.04) with a trend for regional control ( p = 0.06). In the second subgroup, IL- 6 pretreatment serum level above the median was the only independent predictor of local control ( p = 0.009), disease- free survival ( p = 0.02) and overall survival ( p = 0.005). Conclusion: To our knowledge, we are the first to report a link in HNSCC between IL- 6 pretreatment serum levels and radioresistance in vivo. This link is supported by the strong prognostic association of pretreatment IL- 6 with local control, known to be the most important parameter to judge radiotherapy responses. Furthermore, the combined assessment of CA IX and GLUT- 1 correlated independently with prognosis. This is a valuable indication that a combined approach is important in the investigation of prognostic markers.