Abstract
Colorectal cancer is an important global health problem as the second most common cause of cancer deaths worldwide. The ability to risk-stratify patients according to predicted outcome is fundamental to patient management and historically the TNM staging system has formed the basis for this. As more is becoming understood about the role of the host’s immune response on cancer progression and its influence on outcome, there is a growing need to evaluate the potential role of circulating inflammatory cytokines as prognostic markers in colorectal cancer.
In chapter Two, the patterns of disease recurrence were evaluated in a cohort of 237 patients. Recurrences were observed most frequently within two years of surgery and at distant sites. The prognostic value of pre-treatment carcinoembryonic antigen (CEA), as the most widely used circulating prognostic biomarker, was also evaluated in a subset of this cohort. We found it to be predictive of overall and disease free survival, independent of TNM stage and through these findings, we established CEA as a benchmark against which novel approaches could then be compared.
Chapter Three comprises a systematic review whereby seven studies were found to evaluate the prognostic value of multiple cytokine analysis. A combined cytokine score was utilised in four studies although the individual cytokines used and the methods by which they were combined varied between studies. Some promise was shown by applying a multi-marker approach to circulating cytokines.
Chapters Four and Five were prospective studies. In Chapter Four, IL-6, IL-8, IL-1β and TNFα plasma levels were compared between subjects who were recruited into three groups: healthy controls, stage II disease and stage IV disease. Plasma IL-6 and IL-8 were found to differ significantly between patients with stage IV disease and those without. Furthermore, when a combined IL8-CEA score was developed, the ability to distinguish between the three groups was enhanced, compared to any individual marker. In Chapter Five, we went on to evaluate the prognostic value of circulating cytokine markers in a longitudinal study. A panel of eight cytokines was selected, each with a foundation in experimental data linking their actions to colorectal cancer progression. These cytokines were measured in a cohort of 73 patients with non-metastatic colorectal cancer, including the combination of IL8 and CEA, developed in Chapter Four. Following a median duration of 18 months, combined scores composed of IL-8 and IL-10, when combined with CEA, were shown to improve marginally upon CEA alone in risk-stratifying the cohort by disease free survival. A number of limitations to the study were acknowledged including a relatively small sample size and short follow-up duration, preventing the feasibility of a multi-variate survival analysis.
Whilst we found a multi-marker approach, combining circulating inflammatory cytokines with CEA, to offer some promise in colorectal cancer prognostication, further study is necessary to evaluate the IL10-CEA score in a larger study sample over a five year follow-up duration.