Cancer Cachexia: A Multifactoral Disease That Needs a Multimodal Approach

Renee Stubbins; Eric H. Bernicker; Eamonn M.M. Quigley

Disclosures

Curr Opin Gastroenterol. 2020;36(2):141-146. 

In This Article

Abstract and Introduction

Abstract

Purpose of review: Cancer cachexia is a complex condition that occurs in approximately 50% of cancer patients and in 80% of those with advanced cancer. It is characterized by lean body mass loss, adipose tissue loss, altered metabolism, increased inflammation, and a decrease in quality of life. Cancer cachexia is a frustrating condition to manage and treatment requires an innovative approach. The purpose of this article is to review the current treatments for cancer cachexia and how they could be used in a multimodal approach.

Recent findings: Cancer cachexia has many causes, but is primarily a result of reduced energy-protein intake and altered metabolism augmented by a proinflammatory state. There is not a formal consensus on diagnosing cancer cachexia, but proactive screening and assessments for malnutrition are an effective first step toward identifying high-risk patients. Treatment of cancer cachexia includes optimizing nutrition care, using appropriate pharmacological agents, preserving lean body mass, and the cooperation of the healthcare team.

Summary: Cancer cachexia is a complex multifactorial condition that can only be successfully managed and treated with a multimodal approach that involves a multidisciplinary team that includes an oncology registered dietitian nutritionist and exercise physiologist that target early detection and management of cancer cachexia.

Introduction

The Cancer Cachexia Population

Cancer cachexia is a complex condition that occurs in approximately 50% of cancer patients, in 80% of advanced cancer patients and, is especially common among those afflicted by gastrointestinal and pancreatic cancers.[1,2] However, cachexia is also present in other chronic conditions such as congestive heart failure, chronic obstructive pulmonary disease, chronic kidney disease, and the AIDS.[3,4] Cancer cachexia is ultimately a wasting syndrome that is characterized by lean body mass loss, adipose tissue loss, altered metabolism, increased inflammation, and a decrease in quality of life (QoL).[5–7] It is a condition that has frustrated clinicians for many years because it is often irreversible and a sure sign of increased morbidity and mortality.[8,9] Researchers have explored several modalities in treating this condition. Current practices include optimizing the patient's nutrition by improving energy-protein intake and maintaining weight stability; however, even with proper nutrition cancer cachexia persists. This resistance of reversal exhibited by cancer cachexia is multifactoral and to better understand how to manage this condition we need to decipher the major causes. Thus, the purpose of this article is to review the current treatments for cancer cachexia and how they could be used in a potential multimodal approach.

The Causes of Cancer Cachexia

The causes of cancer cachexia are multifactoral, but most of the literature concludes that it is primarily a result of reduced energy-protein intake and altered metabolism.[10–12] Reduced energy-protein intake can be due to many factors such as depression, stress, pain, chemotherapy, radiation, surgery, food insecurity, performance status, and the underlying cancer itself.[13,14] However, reduced oral intake alone does not lead to cancer cachexia. Several studies have confirmed that the tumor and the tumor microenvironment produce proinflammatory cytokines that alter the patient's metabolism, specifically their energy expenditure, as well as adipose tissue and skeletal muscle metabolism.[1,15,16]

Reduced energy-protein intake can also be the result of tumor burden in the abdominal cavity; causing early satiety, impeding digestion or by causing difficult or painful swallowing.

During the state of cachexia, the increase in proinflammatory cytokines and alterations in nutrient metabolism contribute to a hypermetabolic state. Proinflammatory cytokines, such as TNFα and IL6 have been correlated with cancer cachexia due to their association with chronic inflammation in carcinogenesis.[17–20] In-vitro studies have shown that elevated levels of TNFα hinder adipocyte and myocyte differentiation and increase insulin resistance.[21–23] In addition, it has been shown that IL1 and IL6 are elevated in the state of cancer cachexia; specifically, it has been suggested that elevated levels of IL1 could affect food intake and elevated levels of IL6 hinder adipocyte biology and contribute to muscle wasting via the JAK/STAT3 pathway.[24–27]

Chronic inflammation causes alterations in nutrient metabolism, specifically glucose, fat, and protein metabolism. The previously mentioned inflammatory markers have been strongly correlated with insulin resistance, which causes hyperglycemia. Insulin resistance refers to that state in which both insulin and glucose levels are elevated due to malfunction of insulin receptors, thus altering metabolism and ultimately resulting in muscle and adipose tissue wasting. Thus, the elevated glucose and insulin levels contribute to the proinflammatory carcinogenic environment. In addition, proinflammatory markers increase lipolysis and proteolysis.[28] The breakdown of protein in the skeletal muscle is thought to be partly due to the alterations at the level of mitochondria.[29] Mitochondrial dysfunction has been related to alterations in thermogenesis via changes in uncoupling proteins and ATP production through both oxidative phosphorylation and beta oxidation.[30–32]

Our understanding of the causes of cancer cachexia continue to expand and will, hopefully, lead to improvements in treatment. However, several studies have highlighted that effective treatment depends on the timing of the treatment, which relies on determining when a patient develops and is diagnosed with cancer cachexia.

Diagnosing Cancer Cachexia

Traditionally, cancer cachexia was diagnosed on the basis of BMI alone; specifically a BMI less than 18.5 kg/m2.[33] However, in our current society where an overweight BMI (BMI ≥ 25 kg/m2) and obesity (≥30 kg/m2) account for a significant proportion of the population, BMI is not the best indicator of cancer cachexia. Obese patients may have a sufficient BMI but insufficient lean body mass; this state is referred to as sarcopenia and is, unfortunately, very common in cancer.[34] Thus, in more recent years the criteria for cancer cachexia have expanded to include, not only weight loss, but also measurements of loss of lean body mass.

In 2011, an international consensus was published and classified cancer cachexia into three categories (precachexia, cachexia, and refractory cachexia); severity was determined by the significance of weight loss, primarily lean body mass loss. The same group agreed that management of this condition is multifactoral and practice guidelines should be developed.[5] An essential first step to determining if a patient is showing signs of cancer cachexia is to screen for malnutrition.

In 2012, the Academy of Dietetics and Nutrition along with American Society for Parenteral and Enteral Nutrition published a consensus statement regarding malnutrition; specifically standardizing the characteristics and assessment of malnutrition.[35] To determine if a cancer patient is malnourished, a clinician would use the following characteristics:

Moderately (nonsevere) malnourished

Energy intake: less than 75% of estimated needs for at least 1 month

Weight loss: more than 5% in 1 month

more than 7.5% in 3 months

more than 10% in 6 months

Severely malnourished

Energy intake: less than 75% of estimated needs for at least 1 month

Weight loss: at least 5% in 1 month

at least 7.5% in 3 months

at least 10% in 6 months

In addition, a registered dietitian nutritionist (RDN) could physically assess the patient using the Nutrition Focused Physical Exam; this assessment allows the RDN to determine if there is significant loss in fat or muscle stores. The RDN can determine if edema is present potentially skewing the bodyweight and if there are potential micronutrient deficiencies. If a patient is diagnosed with severe malnutrition, this could be used as a strong risk for factor for cancer cachexia and the patient should be monitored closely.

More recently, the European Society of Clinical Nutrition and Metabolism published nutrition care guidelines that recommend: screening all patients with cancer for nutritional risk early in the course of their care, regardless of BMI, and weight history; expanding nutrition-related assessment practices to include measures of anorexia, body composition, inflammatory biomarkers, resting energy expenditure, and physical function; using multimodal nutritional interventions with individualized plans, including care focused on increasing nutritional intake, lessening inflammation and hypermetabolic stress, and increasing physical activity.[36]

Although there is not a formal consensus on diagnosing cancer cachexia, proactive screening, and assessments for malnutrition are an effective first step toward identifying patients that are at an increased risk. Once identified, a potential treatment plan should focus on optimizing energy intake and maintaining bodyweight and lean body mass. However, managing and treating cancer cachexia is still an on-going challenge for clinicians and active field of research.

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