The prevalence and prognostic value of abnormal body composition phenotypes in Irish oncology patients

Advancements in image-based technologies and body composition research over the past decade has led to increased understanding of the importance of muscle abnormalities, such as low muscle mass (sarcopenia), and more recently low muscle attenuation (MA), as important prognostic indicators of unfavourable outcomes in patients with cancer. The aim of this thesis was to identify the prevalence of cancer-associated malnutrition, particularly sarcopenia and low MA in Irish oncology patients using gold standard methods and assess their impact on clinical outcomes such as tolerance to anticancer treatment, quality of life (QoL) and survival. This thesis reports the findings from a prospective cohort study of 1,015 cancer patients undergoing chemotherapy, evaluating for the first time the prevalence of cancer-associated malnutrition in Irish oncology patients (chapter 3). Alarmingly high levels of malnutrition were observed, despite 57% of patients being overweight/obese. Overall, 42%, 39% and 45% of the cohort were found to have cancer cachexia, sarcopenia and low MA, respectively. Using random forest algorithms, percentage weight loss was identified as the biggest predictor of global QoL, with weight stable patients having the highest QoL scores after adjustment for all other variables. Important predictors of overall survival were cancer site, and stage, followed by systemic inflammation, anorexia, weight loss and mean MA, collectively considered components of the cancer cachexia syndrome. Importantly, these nutritional parameters were more reliable prognostic indicators than many clinical variables. Compounding the high levels of malnutrition is the high rate of nutritional decline observed in patients receiving systemic treatment. Chapter 4, a prospective examination of the longitudinal changes in body composition in foregut cancer patients revealed systemic chemotherapy exacerbates muscle loss. On average patients lost muscle at a rate of of 3.9% per 100 days, a rate 14-fold more rapid compared with healthy aging adults (1% per year). These findings were corroborated in chapter 5, whereby patients with metastatic melanoma receiving ipilimumab lost muscle at a rate of 3.3% per 100 days, and the prevalence of sarcopenia almost doubled (from 17% to 32%) during 12 weeks of treatment. Importantly in both studies, a high rate of muscle loss was an independent predictor of overall survival and patients with the highest rates of muscle loss were at more than double the risk of mortality. The impact of body composition parameters on tolerance to systemic anti-cancer treatment in patients with cancer was assessed in chapter 5. In a retrospective study of 84 patients with metastatic melanoma treated with ipilimumab, patients with sarcopenia and low MA were five times more likely to experience a severe treatment related adverse events. Importantly, patients with low MA experienced more dose limiting toxicities, completing fewer cycles of treatment. Chapter 6 explored the relationship between muscle mass (skeletal muscle index, SMI) and mortality risk in 561 patients with lung and gastrointestinal cancer receiving chemotherapy. The aim was to determine gender specific cut points for low muscle mass that best separate patients into two groups with respect to survival, allowing distinct risk categorization of patients. SMI was prognostic of reduced survival in men, but no clear pattern of its relationship to mortality was observed in women. On multivariate analysis, men with a SMI below the identified threshold were at a 47% increased risk of death. The routine availability of CT scans in oncology represents a unique and exploitable opportunity to assess body composition and its change within this patient group, identifying those at nutritional risk, and allowing earlier nutritional intervention when it is proven to be most effective. Prevention and treatment of cancer cachexia and its associated muscle loss has huge potential to improve patient-focused clinical outcomes, however, better treatment options are sorely needed