The key to understanding the heterogeneous behaviour of similar stage locally advance rectal cancer lies in the understanding of tumour biology. The aim of this project was to investigate the biological behaviour of rectal cancers and its alterations in response to neoadjuvant chemoradiotherapy, by studying the intrinsic radiosensitivity, pathophysiology and angiogenesis of rectal cancers. It was intended to provide information that may help risk-stratify patients for individualised treatments including optimal timing of surgery after chemoradiotherapy. Consecutive patients with locally advanced, non-metastatic rectal cancer, who were considered suitable for long-course neoadjuvant chemoradiotherapy, were prospectively recruited. Radiosensitivity was studied by investigating the timing of DNA repair analysis with single cell gel electrophoresis (comet assay). The tumour pathophysiology and angiogenesis was investigated in vivo by novel functional imaging techniques (multiparametric magnetic resonance imaging and dynamic contrast enhanced computed tomography). It is demonstrated that rectal cancer tissue consists of cells with heterogeneous radiosensitivities and functional microvascularity. Until six weeks after NCRT, the DNA repair remains inhibited with progressive devascularisation and increasing hypoxic blood volume resulting in loss of tumour cells. Thereafter, variable fractions of cancer cell may continue to perish or survive with corresponding changes in vascularity. Therefore, the period between the sixth and eleventh weeks after neoadjuvant therapy is a critical time when surviving cells from rectal cancers may develop aggressive traits with long-term consequences. Hence, biological assessment of locally advance rectal cancers after six weeks post-NCRT may help risk-stratify patients for individualised therapy
