Mawdsley, S.K.V.; (2005) The prognostic and therapeutic significance of biological molecular markers in human anorectal carcinomas treated with 5'fluorouracil chemoradiation. Doctoral thesis , University of London.

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Abstract

Advances in tumour biology have led to studies of new biological markers, which may predict treatment response and clinical outcome independently of standard clinicopathological variables. An immunohistochemical analysis of a panel of molecular markers was studied, in a series of anorectal tumours, treated with 5'fluorouaracil (5FU) chemoradiation. 240 tumour samples from the ACT I anal cancer trial were analysed. Patients were randomised to radiation alone (RT) or concurrent mitomycin/5FU/RT (CMT). On multivariate analyses tumour stage, treatment response, CD34 (vascularity), thymidine phosphorylase (TP) and p53 expression were independent predictors of clinical outcome. Tumour stage and p53 expression were associated with a poorer response to treatment in both randomisation arms. Increasing cyclin A and decreasing bcl-2 predicted for an improved response to radiation alone whilst CD34, tumour stage and TP expression predicted for an improved survival in the CMT arm. Archived tumour samples from 60 patients with locally advanced rectal carcinoma were also studied. On multivariate analyses resection margin, nodal stage, treatment response, EGFR and p53 expression were independent predictors of clinical outcome. Increasing TP and cyclin A expression were associated with an improved response to chemoradiation. The response of TP and thymidylate synthase (TS) to radiation was investigated in two colon carcinoma cell lines. TP activity significantly increased in response to a single and fractionated RT dose and TS significantly decreased. This may explain the lack of prognostic significance of TS and confirms that capecitabine, which is activated by TP in tumour cells, is a rational agent to combine with radiation. In conclusion survival and treatment response in anorectal carcinomas can be predicted independently of standard clinicopathological characteristics. They can also predict survival between different therapeutic modalities, which may lead to improved chemoradiation strategies. Tailoring the treatment to the individual may become a future possibility.

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