Reducing Inflammatory Syndrome in Surgery - Colorectal (RISIS-CR) Trial

Overview

The study proposes to identify inflammatory responsiveness of patients prior to CRC surgery and administer prophylactic anti-inflammatory treatment targeted only to those with an excessive pro-inflammatory response. The study team believe this to be a creative approach as the principles of personalized medicine will be used to treat the appropriate patients, and equally as importantly, to not further suppress the inflammatory response of those who have poor immune function already. Geroprotectors reduce inflammation, and may reduce postoperative SIR and complications after CRC surgery. In this proposal, we intend to use alpha ketoglutarate (AKG), a geroprotector supplement that enjoys a GRAS (generally regarded as safe) status with the FDA. \[12\] Apart from reducing inflammation and inhibiting the mTOR pathway, AKG also prevents loss of muscle mass, improves brain oxygenation, has cardioprotective effects, and improves renal function. It also has anti-cancer effects beyond mTOR pathway inhibition, including regulating HIF-1 activity, suppressing secretion of angiogenic factors, and regulating epigenetic processes.

The incidence of colorectal cancer (CRC) increases exponentially with age, with \>50% of CRC first diagnosed at 50 years or older. Surgery is the mainstay of treatment. However, older patients are more likely to develop postoperative ileus and anastomotic leak, longer hospital stays and higher mortality. In the long-term, they are more likely to experience fatigue and slow recovery. Surgery triggers an inflammatory response. In some cases, the immune system is unable to distinguish between the stimuli of major surgery (ideally a modest response) and trauma or infection. This overshoot manifests as a postoperative systemic inflammatory response (SIR) and may lead to tissue destruction and organ dysfunction. In CRC surgery, SIR as defined by C-reactive protein (CRP) elevation is associated with postoperative Clavien-Dindo grades III and IV complications where intervention is needed. These complications include infection and anastomotic leak, and are linked to reduced overall survival independent of both surgery-related complications and tumour stage. In addition, preoperative systemic inflammation is a marker of poor prognosis. As ageing is often accompanied by a chronic low-grade inflammation, it was not surprising that preoperative systemic inflammation is more common in older patients. The use of anti-inflammatory drugs to reduce SIR has had mixed successes. Chronic steroid use is a recognized risk factor for anastomotic leak, but in a recent meta-analysis, the use of preoperative corticosteroids lowered markers of SIR and reduced postoperative infective complications. Similarly, although NSAIDs have been shown to reduce hospital stay and hasten recovery in bowel function, a recent meta-analysis indicated that it increases the risk of anastomotic leaks. Older patients may have impaired immune response to surgical stress from immunosenescence but conversely, some may develop a more intense and prolonged response. In a population study of elderly people, this heterogeneity conferred a survival benefit to those who could mount a pro-inflammatory response, whereas those with poor pro-inflammatory response were more prone to infections. Therefore, suppressing the postoperative SIR in pro-inflammatory patients is likely beneficial but not in patients with low pro-inflammatory potential.