Prognostic markers in head and neck cancer

Purpose: The management of head and neck squamous cell carcinoma (HNSCC) is complex and often involves multimodality treatment. Currently, most management decisions are based on clinical parameters with little appreciation of patient differences in underlying tumour biology. The identification of biomarkers that predict response to radiotherapy would be clinically useful in determining optimal management. The purpose of the thesis was to investigate potential biomarkers that might predict radiotherapy outcome in patients with HNSCC. Aims: 1) To investigate the hypoxia-associated biomarkers carbonic anhydrase 9 (CA9) and hypoxia-inducible factor -1? (HIF-1? ) in patients with early glottis cancer who underwent radiotherapy as their primary mode of treatment, furthermore to investigate the role of accelerated hypofractionated radiotherapy in the management of T2 glottic cancer. 2) To investigate markers of hypoxia (CA9 and HIF-1? ) and viral infection in oropharyngeal cancer, and in particular to test for an association between hypoxia markers and viral infection. 3) To investigate HIF-1? and CA9 in a series of patients undergoing surgery as their primary mode of treatment to explore whether they are associated specifically with radioresponsiveness or a general poor prognosis.Results: 1) Adverse prognostic factors for locoregional control were low pre-treatment haemoglobin (Hb; p = 0.010), advancing T stage (p = 0.001) and high CA9 expression (p = 0.032). Low Hb and high CA9 expression were independent factors on multivariate analysis; and combined predicted locoregional recurrence with an odds ratio of 8.0 (95% CI: 2.7-23.9), or either/or with an odds ratio of 3.3 (95% CI 1.5-7.1). In the subset of T2 patients, five-year locoregional control following radiotherapy was 82% and cancer specific survival was 90%. Serious morbidity occurred in 1.8% of patients. T stage subdivided by vocal cord movement was significant for local control. 2) Features associated with a poor locoregional control were older age (p=0.002), tongue base subsite (p=0.002), heavy alcohol use (p=0.004), heavy smoker (p=0.0002), low Hb level (p=0.001), advancing T (p=<0.0001), N (p=0.001) and AJC (p=0.001) stage, high CA9 expression (p=0.020) and high HIF-1? expression (p<0.0001). In multivariate analysis T stage (p=0.003) and high HIF-1? expression (p=0.001) remained significant. 3) Extracapsular spread was significantly associated with poor cancer specific survival (p=0.022). No other patient variables were associated with outcome. HIF-1? expression was significantly associated with poorly differentiated tumour (p=0.019) and the tumour having a cohesive front (p=0.026). Conclusion: 1) Hb and CA9 have potential to be used together as a biomarker to identify glottis cancer patients with a high probability of a poor outcome following radiotherapy, furthermore, vocal cord movement should be taken into consideration when managing glottis cancer. 2) As it does not appear to be influenced by HPV status, HIF-1? warrants further investigation as a biomarker in oropharyngeal patients treated with primary radiotherapy. 3) As HIF-1? and CA9 had no prognostic significance in patients undergoing surgery, they should be explored further as markers to help guide management decisions in patients with HNSCC.