An investigation into the role of adenoma and host-specific factors on the incidence and recurrence of colorectal neoplasia

Colorectal cancer (CRC) is the fourth most common cancer in the United Kingdom. For males and females combined, it is the second most common cause of cancer death in the UK. The majority of CRC develops as a result of malignant transformation of adenomas via the adenoma-carcinoma sequence. Firm evidence exists that bowel screening, colonoscopy, and polypectomy results in a reduction of CRC incidence and death. An understanding of the association between both adenoma-specific and host characteristics, on the incidence and recurrence of colorectal neoplasia, is necessary to target finite colonoscopy resources, enhance post-polypectomy surveillance guidelines and reduce CRC incidence. An improved understanding of the host mechanisms underpinning the early and pre-malignant stage of CRC could encourage the development of targeted intervention strategies aimed at reducing the primary incidence, post-polypectomy recurrence, and progression of colorectal adenomas to cancer. Notably, bowel screening is now understandably an integral part of the strategy to reduce CRC incidence and mortality, mainly by intervention at the pre-malignant stage. However, it must be ensured that several inherent risks of screening are considered, especially in the era of CT colonography (CTC), where the entire abdomen is imaged, resulting in the identification of extracolonic findings. Chapter 1 presents an overview of CRC, including the risk factors, treatment, and determinants of prognosis and outcome. This is followed by an outline of the process, evidence for, risks, benefits, and outcomes of CRC screening in Scotland. Finally, a detailed summary of the potential risk factors, natural history, management, and surveillance strategies relating to colorectal adenomatous polyps is presented. Chapter 2 presents findings from a systematic review and meta-analysis using pooled, raw data with regards to post-polypectomy colorectal adenoma recurrence. The work found that age ≥60 years, OR 1.56 [95% CI; 1.13-2.14, p<0.01], male sex, OR 1.58 [95% CI; 1.42-1.76, p<0.001] and BMI ≥25, OR 1.35 [95% CI; 1.14-1.58, p<0.001] were associated with post-polypectomy adenoma recurrence. The work concluded that these host factors could be considered for inclusion in post-polypectomy surveillance guidelines. Chapter 3 presents original data from the Scottish Bowel Screening Programme (SBoSP). An examination was undertaken of the association between adenoma-specific and host characteristics, on subsequent adenoma recurrence post-polypectomy in intermediate and high-risk bowel screening patients. The work reported that in high-risk groups, 50% of patients were found to have adenoma recurrence at follow-up, and a third of these patients harbour advanced adenomas. The work also demonstrates that although host characteristics, other than male sex, were not associated with adenoma recurrence, a higher baseline adenoma number was associated with the finding of subsequent adenomas at follow-up (OR 2.23 [95% CI; 1.53-3.25, p<0.001] and 4.19 [9% CI; 2.53-6.97, p<0.001], for 3–4 and ≥5 vs. 1–2 adenomas at baseline respectively). While elevated adenoma number at baseline did not increase the risk of subsequent advanced adenomas at follow-up, the presence of advanced adenomas at baseline was itself a risk for subsequent advanced adenomas, OR 2.34 [95% CI; 1.18-4.61, p<0.05]. This chapter concluded that adenoma-specific factors are superior to host characteristics in predicting future risk for bowel screening patients. On that basis, additional work is required to explore the adenoma further at a genetic level, while additional adenoma-specific factors, other than solely size, should be considered for inclusion in post-polypectomy surveillance guidelines. Chapter 4 presents original, prospectively collected data, from patients attending for colonoscopy as part of the SBoSP. In contrast to Chapter 2 and Chapter 3, which focussed on secondary prevention (post-polypectomy) of colorectal adenomas, Chapter 4 focussed on primary prevention. The association between host characteristics, systemic inflammation, and colorectal neoplasia incidence at bowel screening was examined. The work reported that obesity, adjusted OR 2.72 [95% CI; 1.35–5.49, p<0.01], smoking, OR 2.26 [95% CI; 1.33-3.84, p<0.01] and aspirin use, OR 2.59 [95% CI; 1.15-5.86, p<0.05] were associated with a systemic inflammatory response. Despite this, none of the host factors were associated with an increased risk of incident colorectal neoplasia, while aspirin was associated with reduced risk, OR 0.51 [95% CI; 0.29–0.89, p<0.05] when adjusting for age, sex and smoking. The work concluded that while several host factors are associated with systemic inflammation, a direct link between these host factors, systemic inflammation and incident colorectal neoplasia remains unclear. It also concluded that BMI might be an inferior measure with which to study the effects of adiposity on colorectal neoplasia incidence, and suggested more precise measures of body composition could be used to explore the relationship further. Chapter 5 presents original data collected from patients undergoing CTC as part of the SBoSP. The association between CT derived body composition and colorectal neoplasia incidence was examined. The work concludes that; similar to Chapter 4, BMI was not useful in predicting the risk of colorectal neoplasia, but the presence of visceral obesity was strongly associated with neoplasia incidence, adjusted OR 2.79 [95% CI; 1.48-5.25, p