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Title: Recurrence and the relevance of circumferential resection margins in oesophageal adenocarcinoma : working towards a patient specific treatment strategy
Author: Knight, William Robert Charles
ISNI:       0000 0004 8505 5237
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2020
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Background: Oesophageal cancer survival has improved with the introduction of neoadjuvant treatment. Compared to surgery alone, neoadjuvant chemotherapy and chemoradiotherapy reduce rates of positive resection margins and overall tumour recurrence. Despite this, positive resection margin rates and recurrence remain disappointingly high following surgery. There is ongoing debate as to the optimum neoadjuvant treatment strategy and more emphasis is now being placed on tailoring neoadjuvant treatments to individual patients. Understanding risk factors associated with margin positivity and recurrence is essential in creating individualised neoadjuvant treatment pathways. Methods: A large prospectively collected database of consecutive resections was used. Included in the study cohort were patients who underwent oesophagectomy between 2000 and 2014 for oesophageal adenocarcinoma (AC) or squamous cell carcinoma (SCC). This data was rigorously updated and cross checked and was then analysed by a team of affiliated bio-statisticians. The aim of this thesis was to analyse risk factors associated with recurrence patterns in adenocarcinoma (study 1), assess the validity of current definitions of a positive circumferential resection margin and analyse the association between incremental oesophageal resection margin distance with recurrence and survival (study 2) and determine if clinicopathological and radiological variables can be used to predict circumferential resection margin positivity (study 3). Results: Pathological nodal disease in both pT1-2 (pN1 OR 2.72; 95%CI 1.35-5.48, pN2,3 OR 5.00; 95%CI 2.35-10.66) and pT3-4 patients (pN1 OR 3.03, 95%CI 1.51-6.07; pN2-3 OR 5.75, 95%CI 3.15-10.49) predisposed to systemic recurrence. Lymphovascular invasion (OR 2.09, 95%CI 1.18-3.71) and preoperative stenting (OR 3.70, 95%CI 1.34-10.23) were independent risk factors for isolated locoregional recurrence in oesophageal adenocarcinoma. Poor or no response to chemotherapy was also an independent risk factor for isolated systemic recurrence (OR 1.85, 95%CI 1.05-3.26). An involved circumferential resection margin (CRM) was not associated with significantly increased risk of isolated locoregional recurrence (OR 1.37, 95%CI 0.81-2.33). Kaplan-Meier and unadjusted analyses found a significant incremental improvement in overall survival (p<0.0001) and recurrence rates (p trend < 0.0001) with increasing distance from the CRM. Tumour distance of >2mm remained a significant predictor of survival on multivariable analysis (risk of death HR 0.66; 95%CI 0.44-1.00). Multivariable analysis of overall survival demonstrated a significant difference between a positive and negative CRM with the Royal College of Pathologists definition (HR 1.37 95%CI 1.01-1.85) and not with the College of American Pathologists' definition (HR 1.22 95%CI 0.90-1.65). Poor tumour differentiation (OR 2.84, 95%CI 1.39-6.01) and advanced clinical T-stage (T3-4) (OR 2.93 95%CI 1.03-9.48) were independently associated with an increased risk of a positive CRM. CT non-response (stable or progressive disease) following chemotherapy independently corresponded with an increased risk of CRM positivity (OR 3.38 95% CI 1.43-8.50). Additional CT evidence of local invasion/pleural thickening and higher CT tumour volume (14cm3) improved the performance of a prediction model, including all above parameters; with AUC (c-index) of 0.76 (0.68-0.83). Conclusion: Analysis of clinicopathological risk factors associated with positive circumferential resection margins and recurrence patterns demonstrate the complexity of adenocarcinoma of the oesophagus. Adenocarcinoma of the oesophagus has a propensity to recur systemically and neoadjuvant treatment strategies should take account of this. Understanding the mechanisms behind the aggressive nature of some cell lines to disseminate early will be vital in the next step in developing a patient centred neoadjuvant and adjuvant treatment strategy.
Supervisor: Lagergren, Jesper ; Davies, Andrew Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available