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 -1α (HIF-1α) 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-1α) 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-1α expression (p<0.0001). In multivariate analysis T stage (p=0.003) and high HIF-1α 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-1α 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-1α warrants further investigation as a biomarker in oropharyngeal patients treated with primary radiotherapy. 3) As HIF-1α 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.

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The purpose of this study was to determine the efficacy and toxicity of amonafide in unresectable or recurrent head and neck cancer and to determine if the degree of toxicity with amonafide correlated with the acetylator phenotype of the patient. Thirty patients were registered on the study and received amonafide, 300 mg/m2, over two hours each day for five consecutive days every 21 days. There was one partial response (3%) which lasted four months. The dose-limiting toxicity was myelosuppression. Acetylator phenotype was determined prior to treatment using HPLC to quantitate caffeine metabolites in urine samples after administration of caffeine. This pharmacokinetic evaluation was performed in 21 patients and revealed that (17/21) 81% of the patients were slow acetylators and 19% of the patients were rapid acetylators. No association was found between acetylator phenotype and toxicity in our patient population. Based on this study, it appears that amonafide given at 300 mg/m2 for 5 consecutive days every 21 days is not active in squamous cell carcinoma of the head and neck, and that acetylator status does not correlate with toxicity.

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