An investigation into the relationship between the postoperative systemic inflammatory response, complications, and oncologic outcomes following surgery for colorectal cancer

Colorectal cancer is the second most common cause of cancer death in the United Kingdom (UK). At present, surgery remains the cornerstone of its management and is the mainstay of curative treatment. However, surgery for colorectal cancer is associated with significant postoperative morbidity and mortality. These postoperative complications, whether classified by their type or severity, are associated with poorer quality of life, increased socioeconomic and direct healthcare costs, and poorer oncologic outcomes. The stress response to surgery is a neurohormonal and immune response to trauma which seeks to stop haemorrhage, prevent infection, and promote healing. However, an inappropriately exaggerated postoperative systemic inflammatory response is now understood to be associated with infective complications following surgery for colorectal cancer. It is thought that this may occur through the suppression of the adaptive immune system by this overwhelming innate response. However, it’s effect on the longer term and oncologic outcomes is less clear. In addition, the factors which influence this postoperative systemic inflammatory response are unclear. Furthermore, it remains to be determined whether attenuation of the postoperative systemic inflammatory response will improve short and long term outcomes following surgery for colorectal cancer. The work presented in this thesis further examines the relationship between the postoperative systemic inflammatory response, postoperative complications, and long term oncologic outcomes following surgery for colorectal cancer. Several perioperative factors which might influence the postoperative systemic inflammatory response are examined. Finally, the question as to whether attenuation of the postoperative systemic inflammatory response might result in improved outcomes following surgery for colorectal cancer is examined. The magnitude of the postoperative systemic inflammatory response, in particular, exceeding C-reactive protein (CRP) concentrations of 150mg/L on postoperative days 3 or 4, has been reported to be associated with the development of infective type postoperative complications. Chapter 3 examined the relationship between the postoperative systemic inflammatory response and complication severity, reporting that exceeding these CRP thresholds was associated with major complications as defined by Clavien Dindo grades 3 to 5. Although postoperative complications are recognised to have a negative prognostic impact, the relationship between the postoperative systemic inflammatory response and long term oncologic outcome is less clear. The results of Chapter 4 suggest that an exaggerated postoperative systemic inflammatory response has a negative prognostic impact independent of complications following surgery for colorectal cancer. There is already some evidence to suggest that patient and operative factors such as the use of laparoscopic surgery, body mass index (BMI), comorbid disease, and the presence of preoperative systemic inflammation influence the postoperative systemic inflammatory response. Chapters 5 to 11 examined some other important patient and perioperative factors which might have an influence on the postoperative systemic inflammatory response. Chapter 5 reported that BMI and visceral obesity measured by preoperative CT scans are associated with the magnitude of the postoperative systemic inflammatory response and complications in female patients only. Chapter 6 reported no significant association between poorer exercise tolerance, a lower anaerobic threshold as measured by cardiopulmonary exercise testing (CPEX), and the magnitude of the postoperative systemic inflammatory response in a small number of patients. Chapter 7 reported no association between the formation of a temporary defunctioning stoma (at the time of anterior resection for rectal cancer), and the magnitude of the postoperative systemic inflammatory response. Chapter 8 reported that operation duration is not directly associated with the postoperative systemic inflammatory response, instead suggesting that the surgical approach is more important. Chapter 9 reported no association between perioperative blood transfusion and the magnitude of the postoperative systemic inflammatory response, but did find a significant association between preoperative inflammation and anaemia. Chapter 10 reported no association between preoperative neoadjuvant chemoradiotherapy (nCRT) and the magnitude of the postoperative systemic inflammatory response in patients undergoing surgery for rectal cancer. Chapter 11 compared the postoperative systemic inflammatory response of patients undergoing surgery for colorectal cancer in the UK and Japan, using propensity scoring to match patients from each country by various demographic, pathological, and perioperative variables. The results suggest a significant difference in the magnitude of the postoperative systemic inflammatory response, possibly dependent on ethnicity, which appears to be confirmed on further examination of the literature. Chapter 12 examined the possibility of a new paradigm of postoperative care following surgery for colorectal cancer. At present the investigation of potential complications following surgery is primarily reactive in nature and based on markers of patient physiology such as heart rate, core body temperature, blood pressure etc. Chapter 12 proposed the use of CRP on day 4 to prompt early investigation of such potential complications by computed tomography (CT) in the presence of an exaggerated postoperative systemic inflammatory response. The results suggest that such a postoperative care protocol could result in the earlier and more accurate diagnosis of postoperative complications. Chapters 13 to 15 examined the use of single dose preoperative corticosteroids for the attenuation of the postoperative systemic inflammatory response and whether it might improve short term complications following surgery for colorectal cancer. Meta-analysis of the existing randomised controlled trials in gastrointestinal cancer surgery in Chapter 13 reported that corticosteroids result in lower postoperative CRP concentrations and fewer postoperative complications, but only in patients undergoing oesophageal and hepatic surgery and not in patients having a colorectal resection. In Chapter 14, a propensity score matched analysis of the GRI cohort of patients given dexamethasone at the induction of anaesthesia, for the prevention of postoperative nausea and vomiting (PONV), reported a significant reduction in postoperative CRP concentrations and complications. Finally, Chapter 15 set out a protocol for a randomised controlled trial of preoperative dexamethasone to assess dose response with relation to the magnitude of the postoperative systemic inflammatory response. In summary, the postoperative systemic inflammatory response may impact on the short and long term outcomes of patients undergoing surgery for colorectal cancer. Attenuation of this postoperative systemic inflammatory response might reduce the rate of postoperative complications, although the impact of such strategies on long term outcomes is as yet unknown. Future research in this area might examine various methods of attenuating the postoperative systemic inflammatory response; including anaesthetic techniques, the use of minimally invasive surgery, and pharmacological techniques such perioperative steroids and other anti-inflammatory drugs, and their impact on short and long term outcomes after surgery for colorectal cancer