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Title: Determinants of sphincter preservation in low rectal surgery for cancer
Author: Lynes, Kathryn V.
ISNI:       0000 0004 9355 4802
Awarding Body: Queen Mary University of London
Current Institution: Queen Mary, University of London
Date of Award: 2020
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Introduction The assessment and management of rectal cancer is complex, involving clinicians from several specialities, with a broad and expanding range of therapeutic options. As oncological outcomes have improved, the preservation of functioning sphincters with avoidance of long-term functional problems, and the negative impact that these have on quality of life, is a priority in the management of rectal cancer. Aims and objectives This thesis aimed to discover what determines the ability to preserve functioning sphincters during the management of low rectal cancer. Objectives were (1) to systematically review the evidence base for treatment of rectal cancer (2) to determine the proportion of patients following anterior resection in the UK with low anterior resection syndrome (LARS) and identify risk factors (3) to determine ability of measures derived from diffusion-weighted MRI (DWI) to predict and assess response to neoadjuvant chemoradiotherapy (CRT) in rectal cancer (4) to identify microRNA targets with potential as predictive biomarkers of response to CRT and (5) to define altered sphincter function following anterior resection and CRT using high-resolution anorectal manometry (HRAM). Methods Objective 1: A systematic review of the current literature. Objective 2: A prospective epidemiological cohort study using LARS and QLQ-C30 quality of life questionnaires. Objective 3: A retrospective cohort study of patients undergoing DWI for rectal cancer. Objective 4: A retrospective MicroRNA profiling using pretreatment rectal cancer biopsies. Objective 5: A prospective cohort study of rectal cancer patients undergoing HRAM. Results A review of the literature showed that there is data on oncological outcomes following sphincter preserving rectal cancer surgery, but data on functional 4 outcomes is limited. 1093 participants completed the LARS questionnaire, 22% had minor LARS and 41% major LARS. The risk factors for LARS identified by the study were neoadjuvant radiotherapy, defunctioning stoma, female gender and younger age. The DWI study included 39 patients and found that use of DWI was feasible and that measures derived from DWI show potential as non-invasive biomarkers for predicting and assessing response to CRT in rectal cancer. The laboratory study confirmed that analysis of microRNA expression from rectal biopsy tissue from 28 patients was feasible and that, with further study, microRNAs could possibly act as predictive biomarkers for response to neoadjuvant therapy. 51 patients underwent HRAM, which showed potential for being a tool to help improve assessment and understanding of pre and post treatment sphincter function in patients with rectal cancer. Conclusions Patients undergoing sphincter-preserving surgery for rectal cancer are at risk of developing LARS. This has a long-term impact on quality of life. Neoadjuvant therapy significantly increases risk of LARS. Imaging and laboratory studies confirmed that DWI and microRNA analysis are feasible approaches to the identification of potential biomarkers; with further study these could meet the aim of individualised therapy and limit use of neoadjuvant therapy to preserve anorectal function where possible. The exact pathophysiology behind LARS remains unexplained; HRAM can be used as an investigative tool to improve this understanding with the aim to preserve function. Multicentre prospective studies incorporating all of these methods are required.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available