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About Cancer Cachexia

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What is Cancer Anorexia Cachexia

Cancer Anorexia Cachexia is a multifactorial syndrome that negatively impacts the functional performance, quality of life and prognosis of cancer patients.1,2,3,4,5 It is characterized by muscle loss (with or without lipolysis) that cannot be fully reversed by conventional nutritional support, and a cluster of symptoms that include anorexia, early satiety, and weakness.6 The prevalence of Cancer Anorexia Cachexia is high, especially in patients with advanced cancer, nonetheless Cancer Anorexia Cachexia is often underdiagnosed and remains an unmet medical need.7

The differentiation between cachexia and other causes of weight or muscle loss (such as malnutrition related to anorexia or malabsorption related to impaired gastro intestinal function) can be difficult.8 As mentioned above, the most prominent feature of Cancer Anorexia Cachexia is its non-responsiveness to traditional treatment approaches9; moreover, loss of skeletal muscle and fat distinguish it from starvation.4

Although the understanding of cachexia has progressed over the last decade, lack of consensus on a definition, diagnostic criteria and classification has impeded, until recently, a meaningful advancement in both clinical trials and clinical practice. Newer definitions try to integrate the concept of cachexia as a complex metabolic disorder, which is distinctly different to malnutrition.8 In 2011 an international consensus on the definition of Cancer Anorexia Cachexia (originally indicated as Cancer Cachexia) was reached. The agreed definition is the following:1

“Cancer cachexia is a multifactorial syndrome defined by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment”. [Fearon, Lancet Oncol 2011]1

Cancer Anorexia Cachexia is a multifactorial syndrome defined by

  • an ongoing loss of skeletal muscle mass (± loss of fat mass)
  • inability to be fully reversed by conventional nutritional support
  • progressive functional impairment

Fearon K et al. Lancet Oncol 2011

The panel of experts involved in the consensus process has also defined the criteria for diagnosing cachexia in cancer patients:1

  1. Weight loss >5% over the past 6 months (in absence of simple starvation); or.
  2. BMI <20 and any degree of weight loss >2%; or
  3. Appendicular skeletal muscle index consistent with sarcopenia (males <7.26 kg/m2; females <5.45 kg/m2) and any degree of weight loss >2%.

Both this definition and the diagnostic criteria focus on the complex interplay between reduced food intake and abnormal metabolism, and identifies loss of skeletal muscle as key in patients’ functional impairment.1

Causes and pathophysiology

Cancer Anorexia Cachexia is seen as having both primary and secondary causes. The primary cause is related to metabolic changes that take place in response to the host–tumor interaction. Secondary causes are factors that contribute to primary cachexia through reduced food intake. These factors can include difficulty in swallowing, depression, change in taste, nausea, and food aversion.10

The pathophysiology of Cancer Anorexia Cachexia is characterized by a negative protein and energy balance driven by a variable combination of reduced food intake and abnormal metabolism (Figure 1).2

In particular, Cancer Anorexia Cachexia is often associated with an elevated basal metabolic rate, despite a decrease in physical activity and total energy expenditure. Muscle atrophy results from a decrease in protein synthesis, and increase in protein degradation, or a combination of both.6

There has been great progress in understanding the underlying mechanisms of cachexia. Recent literature reports that many of the primary events driving cachexia are likely mediated via the central nervous system and several proinflammatory cytokines, including interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α, play a role in the pathogenesis of Cancer Anorexia Cachexia and associated metabolic changes.2,11,12

Stages of Cancer Anorexia Cachexia: the clinical continuum

Fearon et al. suggested that Cancer Anorexia Cachexia represents a continuum, with three stages of clinical relevance: precachexia, cachexia, and refractory cachexia (Figure 2). Not all patients pass through the entire spectrum.11

In patients with pre-cachexia, early clinical and metabolic signs (e.g., anorexia and impaired glucose tolerance) can precede substantial involuntary weight loss (i.e., ≤5%). The risk of progression varies depending on several factors such as cancer type and stage, presence of systemic inflammation and lack of response to anticancer therapy.

Patients who have more than 5% loss of stable body weight over the past 6 months, or a body mass index (BMI) of less than 20 kg/m² and an ongoing weight loss of more than 2%, or sarcopenia and an ongoing weight loss of more than 2%, but that have not entered the refractory stage, are classified as having cachexia.

Finally, refractory cachexia is associated with active catabolism, or the presence of factors that render active management of weight-loss no longer possible or appropriate. Patients at the refractory stage are characterized by poor performance status and a life expectancy of less than 3 months.1,6 At present there are no robust biomarkers to identify pre-cachectic patients who are likely to progress further or the rate at which they will progress.1

New studies are exploring the clinical relevance of these Cancer Anorexia Cachexia stages and how to apply these stages in the clinical management of Cancer Anorexia Cachexia. Preliminary data published by Vigano et al. have shown a significant correlation between the stages of Cancer Anorexia Cachexia and patient-centered indicators, such as overall symptom burden, quality of life, and tolerability to chemotherapy, body composition, and survival. But while pre-cachectic and cachectic patients behaved similarly in all these outcomes, these two groups of patients were significantly different from both non-cachectic and refractory cachectic patients. Authors of the study conclude that the data produced supports the clinical relevance and applicability of the stages of Cancer Anorexia Cachexia. However, the results seem to indicate that pre-cachexia may represent an early stage of cachexia rather than a disease state highly predisposed to cachexia.13

The clinical continuum of Cancer Anorexia Cachexia is an important concept that will require further research and validation.6 Particularly, the recognition that cachexia can move through different phases, and that the latter phases are less amenable to reversal, brings the focus of therapy forwards to the time of cancer diagnosis.2

Impact

About half of all patients with cancer experience cachexia. This prevalence rises to as high as 86% in the last 1–2 weeks of life, and with 45 % of patients losing more than 10% of their original body weight over disease progression.5

Cachexia is a very serious complication, as weight loss during cancer treatment is associated with more chemotherapy-related side effects, fewer completed cycles of chemotherapy, a reduction in response to therapy and decreased survival rates.11,14,15 It is estimated that more than 30% of cancer patients die due to cachexia, and more than 50% of patients die with cachexia being present.7

In addition to its physical impact, Cancer Anorexia Cachexia has a marked psychological impact that contributes to decreased quality of life for both patients and their families.5 The psychological impact of Cancer Anorexia Cachexia includes distress, anxiety, depression and concerns about body image.16

Moreover, the inability to eat and the associated weight loss often causes conflicts within relationships.16 In fact, nutrition and nutritional status have a central position in the concept of health and wellbeing for many patients and care givers, and weight loss and inadequate nutritional intake can lead to anxiety and a feeling of hopelessness.8 Available data suggest that patients and their families view poor appetite as the most distressing symptom they encounter during cancer treatment.6

References

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