An investigation into the clinicopathological characteristics of radiotherapy response in locally advanced rectal cancer

McMahon, Ross Keir (2026) An investigation into the clinicopathological characteristics of radiotherapy response in locally advanced rectal cancer. PhD thesis, University of Glasgow.

Abstract

The standard management of Locally advanced rectal cancer (LARC) is neoadjuvant therapy (NAT) by administering radiotherapy (RT), with or without chemotherapy, prior to resectional surgery. Response to NAT is an important prognosticator but is heterogenous, even in patients of the same disease stage. Pathological (pCR), with no specimen evidence of tumour or positive lymph nodes, or Clinical complete response (cCR), with no endoscopic or radiological evidence of residual tumour, are the epitomes of good response.

Understanding the mechanisms that govern NAT response, as well as the means by which to assess and predict it, is key to overcoming radio-resistance and increase the number of patients achieving a complete response. Using in-depth analysis of tumours through medical imaging and endoscopy, in addition to analysis of the patient as a host through systemic inflammation and body composition studies, the present thesis examines the clinicopathological factors that characterise response. The present thesis aims to explore the relationships between the tumour and host, validate past studies on NAT response in a large western cohort, and advance the understanding of how to categorise response by developing novel assessments.

Chapter 1 provides a broad overview of LARC, including the diagnosis, staging, multimodal and surgical management, and predictors of NAT response. In Chapter 2, the aims of this thesis are outlined.

Retrospective analysis

Chapters 3 – 10 retrospectively analyse a dataset of patients from NHS Greater Glasgow and Clyde who have undergone curative intent NAT at The Beatson West of Scotland Cancer Centre. These patients have either progressed to organ preservation if a cCR has been achieved or surgical resection. In Chapter 3, the role of MRI for staging and re-staging of LARC is explored. In this chapter, several MRI features are examined and reported to be predictors of recurrence and survival outcomes in LARC. A combination score of these features better stratifies patient prognosis after NAT over more established MRI assessments of response / regression.

Chapter 4 reviews the Neoadjuvant Rectal (NAR) Score – a validated surrogate endpoint score of long-term outcomes used to assess response in LARC. The NAR score is validated within the current cohort and is then adapted to produce a novel surrogate score that utilises MRI staging and re-staging. This novel MRI NAR score (mrNAR) has stage independent prognostic value and, unlike the NAR score, can be used to stratify patients who do not progress to resection.
Chapter 5 begins to explore the role of the host in NAT response through haematological markers of systemic inflammation. An elevated systemic inflammatory response (SIR) is known to consistently associate with worse prognosis in colorectal cancers. In this chapter I demonstrate that patients who have an elevated SIR at a time point after NAT are more likely to have an incomplete response to NAT. I hypothesise that this elevated SIR, represented by the validated modified Glasgow Prognostic Score (mGPS), results in a degree of radio-resistance.

Chapter 6 begins to explore dimensional tumour measurements that are not a part of standard staging criteria. The role of dimensional tumour measurements in NAT response and recurrence remains unclear. In this chapter I explore this and also work to establish the relationship of tumour size to the SIR. Dimensional tumour size measurements provide additional predictive information for NAT response beyond clinical staging criteria and larger tumours are associated with elevated SIR markers.

Chapter 7 builds on the study of imaging modalities of the tumour beyond that of standard features or dimensional measurements from diagnostic CT and MRI. This chapter utilises radiomics, which is an emerging field that involves the extraction of numerous quantitative features from medical images using advanced data algorithms. In this chapter, an exploratory radiomics study of the tumour is conducted with expert input from Cardiff University School of Engineering and The San Raffaele Scientific Institute in Milan. The lack of standardisation across centres is a limitation of radiomics, and so we develop combined models of standardised radiomic features on CT imaging and clinical features. Our models were able to differentiate between measurements of response to NAT and predict cancer death and local recurrence at 5 years with relatively good accuracy.

Chapters 8 & 9 explore the roles that body composition parameters (BCp), specifically fat, can play in NAT response. Systemically, defined BCp parameters of patients’ visceral fat, subcutaneous fat, and musculature, are analysed in Chapter 8. Chapter 9 analyses fat more local to the tumour by establishing the role of mesorectal fat in LARC over and above that of an important anatomical landmark for surgery. Systemically, I conclude that the visceral fat to subcutaneous fat ratio could influences NAT response. I also report that patients with high VFA/SFA ratios are more likely to exhibit systemic inflammation. At a local level, mesorectal fat correlates most strongly with visceral fat. Again, a higher volume of mesorectal fat associate with systemic inflammation as well as incomplete response to NAT.

The final analysis of this retrospective cohort was to determine if there are gross endoscopic tumour features that associate with NAT response. Chapter 10 establishes endoscopic features following a focus group meeting of consultant endoscopists to define criteria. In addition to establishing endoscopic features that associate with NAT response, I analyse interrater accuracy between endoscopists to agree on the interpretation of these measurements. A fair agreement is reached for the majority of features, which could be the foundation of a standardised assessment criteria for describing rectal cancers at time of endoscopic diagnosis.

Prospective analysis

Chapters 11 – 13 explore a prospectively maintained dataset of LARC patients receiving NAT who are involved in a serial tumour tissue biopsy study at The Glasgow Royal Infirmary. This study has been ongoing within the department since 2018 following a successful pilot study that demonstrated feasibility. The majority of patients were recruited to the study during the period of the thesis (2021 – 2024). Patients were approached at a time point prior to their RT planning imaging and, if they agreed to participate, would voluntarily attend for 4 additional proctosigmoidoscopy biopsies at a time-point prior to, and at 2-, 6-, and 12 or 16-weeks after commencing RT. At each of these 4 serial time points a blood sample, as well as proctosigmoidoscopy tissue biopsies and an image capture of the tumour was performed.

Chapter 11 recognises that additional proctosigmoidoscopies are indeed invasive tests and so reflects on patient feedback relating to their involvement in the project. Through use of a validated Patient Reported Outcome Measure, The Decision Regret Scale, it is established that patients have extremely low levels of regret regarding their involvement with the project. In addition, patients provide encouraging free text feedback that highlights many benefits relating to serial proctosigmoidoscopy assessment during their cancer journey.

Chapter 12 utilises serial blood sampling at timepoints during this serial biopsy projects. Building upon the retrospective work from Chapter 5, relating to the SIR, haematological markers of SIR and percentage changes are analysed prospectively during NAT. Although no biomarkers of NAT response are identified, significant changes are witnessed when comparing long to short course RT regimens, with the former causing more marked and prolonged lymphopenia in patients. This is hypothesised to be relevant when exploring new and expanding regimens that combine NAT with immunotherapy.

Chapter 13 examines the endoscopic changes witnessed during the 4 timepoints of serial tissue sampling. It is a unique resource, unlike anything previously described in the current literature. I analyse how the percentage reduction in endoscopic tumour size between these timepoints may give earlier insight into the final response outcome of a patient. At only week 6 from commencing RT there are significant differences in the tumour size reduction when comparing eventual complete to incomplete responders. This could provide more immediate insight into tumour response which is clinically applicable as it may allow for discontinuation of ineffective treatment or allow for dynamic dose escalation in those who are responding.

Finally, chapter 14 summarises the main findings of the thesis and lays out potential future work.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
• Colleges/Schools: College of Medical Veterinary and Life Sciences
• Supervisor's Name: Roxburgh, Professor Campbell and Steele, Dr. Colin
• Date of Award: 2026
• Depositing User: Theses Team
• Unique ID: glathesis:2026-86200
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 26 Aug 2026 12:42
• Last Modified: 26 Aug 2026 12:48
• Thesis DOI: 10.5525/gla.thesis.86200
• URI: https://theses.gla.ac.uk/id/eprint/86200

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