An investigation into the role of the innate immune system in patients undergoing surgery for colorectal cancer

Watt, David G. (2018) An investigation into the role of the innate immune system in patients undergoing surgery for colorectal cancer. MD thesis, University of Glasgow.

Abstract

Colorectal cancer is the 4th most common cancer in the UK and the second commonest cause of cancer death. Whilst mortality rates from colorectal cancer haven fallen over the last 2 decades, around 40% of those diagnosed with colorectal cancer will die from their disease. Surgery currently remains the only chance of cure. Around 10% of patients present as an emergency with perforation, obstruction or bleeding. Outcomes from these emergency operations are substantially worse than from elective procedures.
The presence of a systemic inflammatory response pre-operatively is now widely recognised as a predictor of disease progression and poor outcomes, both long and short term, regardless of tumour stage in those with colorectal cancer. Numerous scoring systems that measure various components of the systemic inflammatory response have been documented, the most commonly used are the modified Glasgow Prognostic Score (mGPS) and the Neutrophil-Lymphocyte Ratio (NLR). The NLR has the advantage of using 2 components of the differential white cell count, which is routinely measured in surgical and oncological practice, whereas CRP is less commonly routinely measured. However, studies utilising the NLR have used a variety of thresholds, making comparison of the results from study to study difficult. Whether one of the components of the NLR is more important than the other remains to be seen and indeed whether there is a more optimal score that utilises the white cell count is not clear. To date no work has examined similar scoring systems in the post-operative period.
The present thesis aims to examine the impact of the innate immune response, through such systemic inflammation based scoring systems, on patients undergoing surgery for colorectal cancer. Furthermore, it analyses the nature of the inflammatory response in the post-operative period in order to ascertain whether similar scoring systems may be of clinical utility.
Chapter 1 provides an overview of colorectal cancer, its presentation and treatment and its known determinants of outcomes. Furthermore, the immune response to injury and post-operative inflammatory response are discussed. Chapter 2 documents a survey of clinicians who have an interest in systemic inflammation. The survey asks the participants whether they routinely measure systemic inflammation, to what purpose and which scoring system they prefer. Unsurprisingly, the majority of participants use these scoring systems for research purposes only with an even split in terms of which scoring system they prefer to use. Their use in clinical practice remains small but their use in some oncological studies may signify a step towards their incorporation into clinical practice in the future.
Chapter 3 presents data from a cohort of patients whom have undergone surgery for colorectal cancer with pre-operative differential white cell counts in order to determine whether any of the white cell count components are important in determining long term outcomes. Only the neutrophil count was independently associated with poor long term survival in patients undergoing surgery for colorectal cancer. These results highlight the importance of both the neutrophil count and the innate immune system in outcomes in patients with colorectal cancer.
In chapter 4, a cohort of colorectal cancer patients and a cohort of patients with cancer were utilised in order to determine whether a pre-operative systemic inflammation based score using the neutrophil and platelet count was capable of predicting survival in these patients. This was based on the fact that recent in-vitro work had suggested that a critical checkpoint early in the inflammatory process involved the interaction between neutrophils and activated platelets. The subsequent score – the neutrophil platelet score (NPS)- was shown to be capable of predicting survival, independent of TNM stage, in patients with colorectal cancer and had prognostic value in patients with a variety of other tumours.
Chapter 5 describes a systematic review of studies analysing the effect of various surgical procedures on markers of the systemic inflammatory response. Only CRP and IL-6 were found to represent the degree of surgical trauma and invasiveness of the procedure. This work provides a framework for analysing the post-operative SIR and how it is affected by surgery and peri-operative programmes such as ERAS that are reported to improve length of stay and sort term outcomes following surgery for colorectal cancer.
It was of interest in the previous chapter that white cell count did not reflect the degree of surgical trauma. Whether individual white cell components act differently and represent the degree of surgical trauma was unclear. Chapter 6 sought to clarify this by analysing, in a cohort of patients undergoing surgery for colorectal cancer, the differential white cell count and whether it reflected the magnitude of injury and short term outcomes. Only the neutrophil count reflected the magnitude of trauma and development of infective complications. However, it remains inferior to other well established markers such as CRP.
Whilst the pre-operative systemic inflammatory response is a well-recognised determinant of both long term outcomes and short term outcomes such as infective complications, little work has focussed on the post-operative systemic inflammatory response. In chapter 7, the possibility of the post-operative systemic inflammatory response also being capable of predicting both short and long term outcomes was explored in a cohort of patients whom had undergone surgery for colorectal cancer. A score using the combination of post-operative CRP and albumin was created and called the post-operative Glasgow Prognostic Score (poGPS). In this cohort of patients, this score predicted the development of infective complications and also long term survival. Given that these results would indicate that a reduction in the post-operative systemic inflammatory response would improve outcomes, the clinicopathological factors that may alter this post-operative systemic inflammatory response should be investigated as some of these may be modifiable and may therefore improve outcomes following surgery for colorectal cancer.
ERAS programmes have changed perioperative management and are reported to be beneficial in reducing length of hospital stay and post-operative complications. It is purposed that this is due to the reduction on the surgical stress response. However it is unclear which of the components of an ERAS programme are responsible for this reduction in the systemic inflammatory response. Chapter 8 describes a systematic review analysing studies of the various ERAS components and whether there is objective evidence of a reduction in the SIR, evidenced by a reduction in either CRP or IL-6. Only laparoscopic surgery was reported to reduce the SIR in these studies, all the remaining components had either little or no evidence of a reduction in the SIR. Further work is required to ascertain whether any of the other components also reduce the SIR. This will hopefully allow streamlining of the ERAS process in order to improve outcomes.
Specific clinicopathological factors that may alter the post-operative systemic inflammatory response are examined in chapter 9. Common clinicopathological factors were examined using the poGPS to ascertain which factors resulted in increased poGPS scores. In those patients undergoing elective surgery, year of operation, ASA grade, pre-operative systemic inflammation, and tumour site were associated with increased poGPS scores. These findings may have important clinical consequences as whilst factors such as ASA grade and BMI are not readily modifiable in the short time frame between diagnosis and surgery, pre-operative inflammation could potentially be targeted with anti-inflammatory medication. However, more work is required to identify the specific agent and the timing of its delivery.
In chapter 10, a cohort of patients undergoing surgery for colorectal cancer in whom there was prescription information available. Patients prescribed aspirin or statin were identified and their post-operative inflammatory response and short term outcomes were compared to those not prescribed aspirin or statins. In 446 patients, neither aspirin nor statin prescription was associated with a reduction in the post-operative systemic inflammatory response. Therefore, it would appear that these medications will not be useful in moderating the systemic inflammatory response following surgery. However, further work is required to identify which medications will be of benefit and should take the format of a randomised controlled trial.
Chapter 11 provides a summary of the main findings of this thesis, discussed their implications and provides some discussion surrounding future work in this field.

• Item Type: Thesis (MD)
• Qualification Level: Doctoral
• Additional Information: Chapters 2, 3, 4, 5, 7, 8 and 9 have all been published in peer reviewed journals.
• Keywords: Colorectal cancer, systemic inflammation, innate immune system, CRP.
• Subjects: R Medicine > R Medicine (General); R Medicine > RD Surgery
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• Supervisor's Name: McMillan, Professor Donald and Horgan, Professor Paul
• Date of Award: 2018
• Depositing User: Mr David G Watt
• Unique ID: glathesis:2018-8915
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 04 Apr 2018 14:03
• Last Modified: 25 Apr 2018 09:13
• URI: https://theses.gla.ac.uk/id/eprint/8915

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