An investigation of the determinants of the local and systemic inflammatory responses in patients with colorectal cancer

Colorectal cancer is the second most common cause of cancer death in the Western world but the factors that determine disease progression remain poorly understood. At the outset of this thesis it was recognised that tumour growth and metastases were determined by complex interactions between tumour and host. It was evident that a systemic inflammatory response was associated with poor prognosis in colorectal cancer while a strong local immune cell response conferred a favourable outcome. This thesis investigated this topic by examining the factors responsible for activating, maintaining and regulating these inflammatory responses and drew the following conclusions: Chapter 3 concluded that abnormal patient physiology, in particular the presence of anaemia and cardiac disease, was strongly associated with a systemic inflammatory response in patients with colorectal cancer. Targeting specific physiological parameters may therefore be a novel way to improve a patients’ inflammatory status. Chapter 5 used CT image analysis to confirm a strong relationship between systemic inflammation and reduced skeletal muscle mass in patients with colorectal cancer. This offered insight into the underlying basis of cancer-related weight loss and suggested attenuation of the host inflammatory response may be a therapeutic target in cancer cachexia. Chapter 6 built on these results with a detailed examination of the relative importance of pre-, intra- and post-operative factors in patients undergoing surgery for colorectal cancer. Rather than being the cause of disease recurrence, surgical complications appeared to be a consequence of pre-existing physiological disturbance and systemic inflammation, supporting a concept whereby pre-operative status is of paramount importance to long-term cancer outcomes. Chapter 7 investigated possible links between the local and systemic inflammatory responses. The pathological feature of tumour necrosis was confirmed as both an independent prognostic indicator in colorectal cancer and the first documented link between local and systemic inflammation. A model was proposed whereby failure of local anti-tumour control leads to rapid growth, tissue hypoxia and cellular necrosis, triggering the host to initiate a systemic inflammatory response. The local inflammatory response in colorectal cancer was then considered. Chapter 8 confirmed that, while a strong local response was primarily the result of lymphocyte infiltration, the examination of individual cell types did not add prognostic value compared to an overall grade of peritumoural inflammation. Chapter 9 built on this knowledge to examine the clinical utility of the local inflammatory response in colorectal cancer. It was clear that the density of cellular infiltrate was more important than the type or location of individual immune cells. After comparing a number of methodologies, an overall grade of peritumoural inflammation, using the Klintrup-Makinen (K-M) criteria, was established as the preferred technique for assessing the local inflammatory response in colorectal cancer