Prevalence, early detection and classification of cancer cachexia

Cancer cachexia is characterized by loss of muscle mass accompanied by a variable loss of fat mass. It leads to a decline in physical function and quality of life, and an increase in psychological distress and mortality. The pathophysiology is complex and characterized by a negative protein and energy balance mediated by inflammation and neuroendocrine changes. Anorexia and lack of exercise contributes to the decay. Estimates of cancer cachexia prevalence vary between 30-85% depending on how it is defined, and the population examined. There is no established treatment of cancer cachexia, and nutrition therapy alone will not fully reverse the condition. Several different pharmacological agents have been tested, but so far, no drug has been licensed. An important barrier against progress in cachexia management has been the absence of a consensus definition, and thus, a common perception of what cachexia is. In the clinical setting, cachexia has most often been recognized by its historical phenotype of severe weight loss and poor physical function and as such not recognized until late in its development. This may have compounded the lack of awareness among health care professionals to the development of cachexia. Criteria for the diagnosis of cachexia in studies have varied; often based on weight loss in varying degrees, but other characteristics of cachexia such as markers of appetite loss and the systemic inflammatory response have also been used. This heterogeneity has made comparison of research results challenging, and the differing estimates of prevalence have led to uncertainty as to the impact and extent of cachexia in the cancer population. Progress was made in 2011 when an international consensus definition incorporating diagnostic criteria for cancer cachexia was published. Fundamental to this was a framework for the classification of the trajectory of cancer cachexia through the stages of ‘pre-cachexia’, ‘cachexia’ and ‘refractory cachexia’. Cachexia is present if 6 months’ weight loss is >5%, or if the patient either has a body mass index 2%. Pre-cachexia is a stage of early metabolic change and appetite loss, and refractory cachexia a stage of variable degree of cachexia, but where the cancer disease is pro-catabolic and no longer responsive to anti-cancer therapy. The ability to classify patients according to where they are in the trajectory may help stratify treatment. To illustrate, where a patient with pre-cachexia or cachexia might be susceptible to treatment aiming to delay or reverse cachexia, such treatment would seem futile in a patient with refractory cachexia. Instead, treatment aiming to provide optimal symptom relief would be more appropriate. Although the consensus definition and classification framework was an important starting point, it was acknowledged that further research was necessary to find objective and reliable criteria for the cachexia stages. Moreover, it was necessary to establish an accurate estimate of cancer cachexia prevalence based on the new definition to better understand the extent of the condition. To this end, the overall aim of the thesis was to gain new knowledge of the prevalence of cancer cachexia and contribute to a better classification system to allow for optimal selection of anti-cachexia treatment for each individual patient in the future. The aims pertaining to paper I were to estimate prevalence of cancer cachexia in an unselected population as well as in cohorts based on demographical and clinical characteristics, and to evaluate patient-perceived importance of clinical attention to cachexia. A cross-sectional study was conducted in patients with cancer at three centers in the Regional Health Authority of Central-Norway. Fifty-one percent (95%CI40-63) of inpatients and 22% (95%CI 17-27) of outpatients had cachexia. Prevalence varied significantly with cancer type and was higher in patients with gastrointestinal (OR 4.4 [95%CI 2.0-9.6]) and lung cancer (OR 5.5 [95%CI 2.0-15.1]) compared to patients with hematologic cancer. Twenty percent of inpatients and 15% of outpatients wanted more clinical attention to cachexia. Having cachexia (p=0.02), symptoms of a mood disorder (p=0.05) or being male (p<0.01) were factors significantly associated with a need for more attention. The aims pertaining to paper II were to confirm the survival prognostic validity of the Weight loss grading system (WLGS), a potential classification system of cancer cachexia; evaluate its relationship with established cachexia characteristics and to explore its ability to predict cachexia progression. An analysis of an international cohort of patients with incurable cancer (European Palliative Care Cancer Symptom study, EPCCS) was conducted. The WLGS significantly predicted survival (p<0.001), and the addition of measurements of performance status (p<0.001), appetite (p=0.005), physical (p<0.001) and emotional functioning (p=0.004) to this model significantly improved the prognostic accuracy. The WLGS was associated with increased severity of all evaluated cachexia characteristics (p<0.001), and patients with weight loss grade 2 were more likely to have cachexia progression than patients with weight loss grade 0 and 1 (descriptive analysis only). The aims pertaining to paper III were to identify predictors of cachexia development and to create and evaluate a predictive model of cancer cachexia based on these predictors. Patients included in the EPCCS cohort that had not developed cachexia at baseline were included in this analysis. Early weight loss (p<0.001), cancer type (p