Cancer cachexia: Diagnosis, assessment, and treatment

Highlights

• A global consensus on the diagnosis and treatment of cancer cachexia is needed.

• This review thoroughly examines the latest updates in cancer cachexia management.

• Different cancer cachexia definitions and diagnostic criteria are compared.

• Nutritional, muscularity, psychosocial, and biomarker assessments are investigated.

• Pharmacologic, nutritional, exercise, and psychosocial treatments are discussed.

Abstract

Cancer cachexia is a multi-factorial syndrome, which negatively affects quality of life, responsiveness to chemotherapy, and survival in advanced cancer patients. Our understanding of cachexia has grown greatly in recent years and the roles of many tumor-derived and host-derived compounds have been elucidated as mediators of cancer cachexia. However, cancer cachexia remains an unmet medical need and attempts towards a standard treatment guideline have been unsuccessful. This review covers the diagnosis, assessment, and treatment of cancer cachexia; the elements impeding the formulation of a standard management guideline; and future directions of research for the improvement and standardization of current treatment procedures.

Introduction

Cachexia is a multifactorial and multi-organ syndrome that is one of the main causes of morbidity and mortality in late stages of chronic conditions such as AIDS, chronic obstructive pulmonary disease (COPD), congestive heart failure, multiple sclerosis, tuberculosis, and cancer. More than 50 percent of cancer patients suffer from cachexia at death, with the distribution varying by tumor type; the incidence is highest in patients with gastric and pancreatic cancer (∼80%) while patients with breast cancer and leukemia demonstrate the lowest frequency (∼40%) of affliction with cachexia (Argiles et al., 2005; Muscaritoli et al., 2006; Tisdale, 2005). Furthermore, one estimate of the role of cachexia as a major contributor to cancer deaths stands at almost 20 percent (Warren, 1932). Other studies, however, have found this proportion to be lower (Sesterhenn et al., 2012; Ambrus et al., 1975; Inagaki et al., 1974), whereas some have considered this estimate conservative (Langer et al., 2001)(Sesterhenn et al., 2012) achieved this estimate even though they had studied head and neck cancer patients who are known to be at an especially high risk for malnutrition (Gorenc et al., 2015). Nevertheless, cachexia can contribute directly or indirectly to the death of a significant proportion of cancer patients. Moreover, cachexia negatively affects quality of life, responsiveness to chemotherapy, and survival (Bachmann et al., 2008; Dewys et al., 1980; Penet and Bhujwalla, 2015). In 2011, an international consensus statement defined cancer cachexia as:” a multifactorial syndrome characterized by 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 et al., 2011).” The main clinical presentation of cachexia in cancer patients is involuntary weight loss. Anorexia, systemic inflammation, insulin resistance, and increased resting energy expenditure (REE) are also usually associated with the condition.

The wide variety of symptoms observed in cachexia is mediated through a spectrum of both tumor-derived and host-derived factors. Zinc alpha 2-glycoprotein (ZAG) is a well-recognized procachectic factor secreted by tumor cells (Wyke and Tisdale, 2005; Felix et al., 2011; Hirai et al., 1998). Moreover, cytokines secreted by tumor cells may complement the host inflammatory response to the tumor (Tan et al., 2014; Argiles et al., 2009). Pro-inflammatory cytokines (IL-1, IL-6, TNF-α, IFN-γ) act through both centrally-mediated and peripheral pathways. These factors, either independently (Faggioni et al., 1997) or through dysregulation of the leptin response pathway (Janik et al., 1997; Grunfeld et al., 1996), cause the persistent stimulation of anorexigenic pathways (Grossberg et al., 2010). These cytokines also lead to the many metabolic changes observed in cachexia. These changes characterize the state of hypercatabolism (lipolysis (Petruzzelli et al., 2014; Kir et al., 2014), muscle degradation (Fearon et al., 2013), and acute phase response (Fearon et al., 1999)) observed in cachectic patients. In addition to the numerous molecular mediators of cachexia, mechanical or digestive factors have been identified (Fearon et al., 2013; Tuca et al., 2013). Tumor burden or chemotherapy may lead to nausea, dysphagia, mucositis, pancreatic insufficiency, and malabsorption (Deutsch and Kolhouse, 2004), resulting in reduced food intake and subsequently weight loss (Wigmore et al., 1997).

Although the aforementioned consensus-definition for cachexia has been validated (Blum et al., 2014), diagnosis remains a challenge due to several confounding factors such as cachexia-like complications of cancer therapy and sarcopenic obesity (Fearon et al., 2013). Even though our knowledge of cancer cachexia has increased considerably during the last decade, cachexia remains an unmet medical need. The condition is rarely recognized in clinical settings as weight loss is not routinely assessed (Churm et al., 2009) and treatment is usually inadequate (Sun et al., 2015; Spiro et al., 2006). Furthermore, heterogeneity in the clinical presentation of cachexia (Fearon et al., 2012), difficulties in consistent diagnosis of the disease at early stages (pre-cachexia) (Blum et al., 2014; Argiles et al., 2014), the advanced age of many patients (Dodson et al., 2011), and the complexity of the multimodal approach needed to manage cachexia (Fearon, 2008) have hampered efforts towards a standardized and effective treatment. In this review, we focus on the clinical management of cancer cachexia (diagnosis, assessment, and treatment) and the latest advances in this field. We will also propose future directions towards the development of an effective and standard guideline for the treatment of cachexia.