Clinical implications of hypoxia biomarker expression in head and neck squamous cell carcinoma: a systematic review

Abstract

Awareness increases that the tumor biology influences treatment outcome and prognosis in cancer. Tumor hypoxia is thought to decrease sensitivity to radiotherapy and some forms of chemotherapy. Presence of hypoxia may be assessed by investigating expression of endogenous markers of hypoxia (EMH) using immunohistochemistry (IHC). In this systematic review we investigated the effect of EMH expression on local control and survival according to treatment modality in head and neck cancer (head and neck squamous cell carcinoma [HNSCC]). A search was performed in MEDLINE and EMBASE. Studies were eligible for inclusion that described EMH expression in relation to outcome in HNSCC patients. Quality was assessed using the Quality in Prognosis Studies (QUIPS) tool. Hazard ratios for locoregional control and survival were extracted. Forty studies of adequate quality were included. HIF-1a, HIF-2a, CA-IX, GLUT-1, and OPN were identified as the best described EMHs. With exception of HIF-2a, all EMHs were significantly related to adverse outcome in multiple studies, especially in studies where patients underwent single-modality treatment. Positive expression was often correlated with adverse clinical characteristics, including disease stage and differentiation grade. In summary, EMH expression was common in HNSCC patients and negatively influenced their prognosis. Future studies should investigate the effect of hypoxia-modified treatment schedules in patients with high In summary, EMH expression. These may include ARCON, treatment with nimorazole, or novel targeted therapies directed at hypoxic tissue. Also, the feasibility of surgical removal of the hypoxic tumor volume prior to radiotherapy should be investigated.

Keywords: head and neck neoplasms; hypoxia; hypoxia-inducible factor 1; personalized medicine; tumor microenvironment.

Figure 1

Study selection process. Study selection flowchart. Of the 66 suitable papers, 38 were found of adequate quality. A citation check yielded three additional results, of which two were of adequate quality. In total, 40 studies were included.

Figure 2

Forest plot: Overall survival and EMH Expression. Visual summary of studies that described overall survival. ARCON, accelerated radiotherapy, carbogen gas, and nicotinamide. HRs < 1 indicate beneficial prognosis for nonhypoxic tumors. Therapy not standardized: All treatment modalities were analyzed in a single cohort and results were not presented according to therapy. The studies of Pérez-Sayáns and Hong describe their entire cohort of patients, receiving any treatment. In the study of Wan, patients were randomized between neoadjuvant radiotherapy or chemoradiation, followed by concurrent chemoradiation. EMH, endogenous markers of hypoxia.