Cancer-associated malnutrition

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Summary

Malnutrition is a common problem among patients with cancer, affecting up to 85% of patients with certain cancers (e.g. pancreas). In severe cases, malnutrition can progress to cachexia, a specific form of malnutrition characterised by loss of lean body mass, muscle wasting, and impaired immune, physical and mental function. Cancer cachexia is also associated with poor response to therapy, increased susceptibility to treatment-related adverse events, as well as poor outcome and quality of life. Cancer cachexia is a complex, multifactorial syndrome, which is thought to result from the actions of both host- and tumour-derived factors, including cytokines involved in a systemic inflammatory response to the tumour. Early intervention with nutritional supplementation has been shown to halt malnutrition, and may improve outcome in some patients. However, increasing nutritional intake is insufficient to prevent the development of cachexia, reflecting the complex pathogenesis of this condition. Nutritional supplements containing anti-inflammatory agents, for example the polyunsaturated fatty acid (PUFA) eicosapentanoic acid (EPA), have been shown to be more beneficial to malnourished patients than nutritional supplementation alone. EPA has been shown to interfere with multiple mechanisms implicated in the pathogenesis of cancer cachexia, and in clinical studies, has been associated with reversal of cachexia and improved survival.

Zusammenfassung

Mangelernährung ist eine bei Krebspatienten häufig auftretende Komplikation. Bei manchen Krebsarten (z. B. bei Pankreaskarzinom) sind bis zu 85 % der Patienten von einer Mangelernährung betroffen. In schweren Fällen kann aus einer Mangelernährung eine Kachexie entstehen: Kachexie ist eine Sonderform der Mangelernährung, bei der es zum Verlust von fettfreier Körpermasse, Muskel-Wasting, Immunschwäche sowie zu einer Verschlechterung des körperlichen und geistigen Zustandes kommt. Darüber hinaus ist eine Tumorkachexie mit einem schlechten Ansprechen auf die verabreichte Therapie, einer größeren Häufigkeit von therapieassoziierten unerwünschten Wirkungen, einem ungünstigen Einfluss auf die Prognose und einer Verschlechterung der Lebensqualität assoziiert. Eine Tumorkachexie stellt ein komplexes multifaktorielles Syndrom dar, das wahrscheinlich auf den Wirkungen von Faktoren beruht, die sowohl aus Patientengeweben als auch aus Tumorgewebe stammen (host- and tumor-derived factors), einschließlich von Zytokinen, die an einer systemischen Entzündungsantwort auf den Tumor beteiligt sind. Die frühzeitige Verabreichung einer Nahrungsergänzung kann eine Mangelernährung korrigieren und bei manchen Patienten die Prognose verbessern. Die alleinige Erhöhung der Nährstoffzufuhr reicht jedoch nicht aus, um die Entstehung einer Kachexie zu verhindern: Diese Beobachtung spiegelt die Komplexität der Pathogenese der Kachexie wider. Nahrungsergänzungsmittel, die entzündungshemmende Wirkstoffe wie beispielsweise mehrfach ungesättigte Fettsäuren (PUFA) oder Eicosapentaensäure (EPA) enthalten, haben sich bei mangelernährten Patienten als vorteilhafter erwiesen als eine reine Supplementierung von Nährstoffen. Es konnte gezeigt werden, dass EPA mit zahlreichen Mechanismen interferiert, die an der Pathogenese der Tumorkachexie beteiligt sind. In klinischen Studien war die Zufuhr von EPA mit einer Korrektur der Kachexie und einer Verlängerung der Lebensdauer assoziiert.

Introduction

Cancer is a major global public health problem with over 2.9 million new cases being reported annually in the European Union (EU) (Boyle and Ferlay, 2005). Each year, there are 1.7 million deaths from cancer, making it the second most common cause of death in the EU. Breast, lung, prostate and colorectal cancer are the most common cancers; breast and prostate cancer are the most common forms in females and males, respectively.

Nutritional status greatly affects outcome in cancer patients. Progressive weight loss is a common feature of many cancers: the global incidence of malnutrition in cancer ranges from 30% to 85%, being most prevalent in patients with gastric, pancreatic, lung, prostate and colon cancer (Laviano and Meguid, 1996; Bozzetti, 2001a). In addition to the type, location, grade and stage of cancer, the incidence of malnutrition is also affected by anticancer treatments and patient characteristics, including age, gender and individual susceptibilities. Cancer-associated malnutrition occurs as a consequence of an imbalance between the nutritional needs of the patient, the demands of the tumour and the availability of nutrients in the body. Prolonged undernutrition can result in cachexia, a specific form of malnutrition characterised by progressive, involuntary weight loss with depletion of lean body mass, muscle wasting and weakness, oedema, impaired immune responses, and declines in motor and mental function. Cancer-associated malnutrition can also be associated with taste changes and food aversion (Fearon, 1992). This pattern of weight loss differs from simple starvation seen in otherwise healthy patients, in which loss of body fat with sparing of skeletal muscle occurs.

Nutritional decline leading to cancer cachexia may start before clinical signs are apparent, and the majority of patients present with weight loss prior to diagnosis (DeWys et al., 1980). Furthermore, loss of greater than 10% of pre-diagnosis weight is seen in approximately 45% of patients (Bosaeus et al., 2001; Bozzetti, 2001a). Cancer-associated malnutrition and cachexia cause considerable morbidity and mortality. Decreased quality of life (Ovesen et al., 1993; Andreyev et al., 1998), impaired response to chemotherapy (DeWys et al., 1980; Andreyev et al., 1998), increased susceptibility to chemotherapy-induced toxicity (Rickard et al., 1983; Andreyev et al., 1998), impaired muscle function (Zeiderman and McMahon, 1989) and higher incidence of post-operative complications (Meguid et al., 1986; van Bokhorst-de van der Schueren et al., 1997; Jagoe et al., 2001) have all been reported in malnourished patients compared with those maintaining normal body weight. Further effects of progressive weight loss include impaired immune function, decreased mobility and increased susceptibility to infections and pressure ulcers (Ek et al., 1991). All of these factors can lead to prolonged periods of hospitalisation and rehabilitation and, hence, higher healthcare costs (Braunschweig et al., 2000). Pre-treatment malnutrition has also been associated with shorter survival and higher mortality rates in patients with gastrointestinal (GI) cancers (Meguid et al., 1986; Rey-Ferro et al., 1997; Andreyev et al., 1998), head and neck cancers (van Bokhorst-de van der Schueren et al., 1999) and those undergoing bone marrow transplantation (Deeg et al., 1995; Dickson et al., 1999).

Effective treatment and prevention of cancer cachexia is difficult owing to the complex pathophysiology of the disease. Providing nutritional support can be beneficial to affected patients. Nutritional support aims to ensure the patient obtains sufficient energy and nutrients to maintain or improve nutritional status and immune function, minimise GI symptoms and improve quality of life. Early provision of nutritional supplementation to adequately nourished patients, or those with early signs of nutritional decline, can delay the progression of malnutrition (MacDonald, 2003). A ‘vicious circle’ of cancer cachexia can develop, in which the effects of cancer lead to nutritional decline, predisposing to increased complications and more severe disease, which promote further nutritional decline. Early nutritional intervention, which can prevent or break the vicious circle (Green, 1999), is essential to achieve maximum clinical benefit (Ottery, 1994), demonstrating the importance of assessing nutritional status in all patients with cancer. Nutritional support strategies are discussed in detail later in this issue (van Bokhorst-de van der Schueren, 2005).

The pathophysiology of cancer-associated malnutrition is complex and cannot be explained on the basis of poor nutrient intake alone, suggesting that increasing nutrient intake alone is insufficient to prevent or reverse malnutrition. In patients with cancer, the tumour itself is thought to contribute to development of malnutrition, and several factors have been implicated in the pathophysiology of cancer cachexia (Argilés et al., 2003a). Both tumour-derived factors and systemic factors, such as hormones and inflammatory cytokines produced by the host in response to the tumour, have been proposed, and there is increasing evidence to support a role for these factors in cancer-associated malnutrition (Argilés et al., 2003a, Argilés et al., 2003b, Argilés et al., 2003c). Eicosopentanoic acid (EPA), a polyunsaturated fatty acid (PUFA) found in fish oil, has been shown to inhibit inflammation in vivo and has been associated with weight gain, better response to therapy, fewer complications and even improved survival in some patients (Jho et al., 2004; Elia et al., 2005).

Section snippets

Development of malnutrition

Malnutrition occurs when nutrient availability fails to meet the body's nutritional needs. This imbalance can result from inadequate food intake, a poor or unbalanced diet or excess needs despite good nutritional intake. Digestion chemically breaks down nutrients from food into compounds that can be absorbed through the gut wall into the bloodstream for transport around the body. Nutrients can be classified as macronutrients or micronutrients. Macronutrients are consumed in large amounts and

Biological changes due to simple starvation and malnutrition

During prolonged periods of reduced food intake and starvation, some structural proteins, particularly those making up skeletal muscle and internal organs, are used to provide energy. In the absence of concurrent disease (simple starvation), the body preferentially metabolises fat stores so that many structural proteins are conserved. Under certain situations, for example during disease or after stress or trauma, such protective mechanisms may be affected and reduced food intake is associated

Cancer-associated malnutrition and cachexia

Cancer-associated malnutrition occurs when the nutritional needs of the patient are not met due to poor food intake, absorption and/or assimilation, and increased nutrient losses to tumour metabolism. There is no universally accepted definition for cancer-associated malnutrition, however, a recent suggestion is ‘a state of nutrition in which a deficiency or excess (or imbalance) of energy, protein and other nutrients causes measurable adverse effects on tissue/body form, function and clinical

Prevalence of cancer-associated malnutrition and cancer cachexia

A large series of studies performed in patients enrolled in Eastern Cooperative Oncology Group (ECOG) chemotherapy protocols for a variety of cancers revealed that over half of patients with cancer present with weight loss at diagnosis (DeWys et al., 1980). It was reported that 54% of patients had experienced weight loss prior to treatment: <5% had been lost in 22% of patients, 5–10% in 17% and 15% of patients had lost over 10% of their normal body weight, suggesting cancer-associated

Metabolic changes in cancer-associated malnutrition and cachexia

Inadequate food intake alone does not account for the clinical ‘picture’ seen in cancer-associated malnutrition. Both the tumour and anticancer treatments are thought to give rise to reduced nutritional intake and metabolic abnormalities, which contribute to the pathogenesis of malnutrition (Argilés et al., 2003c; Tisdale, 2003). Some patients are unable to consume sufficient nutrients due to the disease, either from physical obstruction of the GI tract by a tumour, reduced appetite or nutrient

Pathophysiology of cancer-associated malnutrition and cachexia

Several factors have been implicated in the pathogenesis of cancer cachexia, including those derived from the tumour and those produced as a result of the host response to the tumour, including hormones and mediators of inflammation (Fig. 1). The pathogenesis of cancer cachexia is discussed in detail in a later article in this issue (Van Cutsem and Arends, 2005).

The presence of abnormal, rapidly proliferating cancer cells can induce an inflammatory immune response, which is thought to start

Clinical consequences of cancer-associated malnutrition

The presence of cancer-associated malnutrition is associated with increased morbidity and mortality. Loss of muscle mass, impaired muscle function, fatigue, reduced physical activity and reduced functional capacity have been reported in malnourished patients with cancer (Zeiderman and McMahon, 1989; Stone et al., 1998; Barber et al., 1999a; al-Majid and McCarthy, 2001). A low level of physical activity leads to further muscle wasting and weakness, and is also associated with decreased appetite,

The ‘vicious circle’ of cancer-associated malnutrition

Disease and malnutrition are closely linked, and can rapidly develop into a ‘vicious circle’, in which illness causes decreased food intake, malabsorption and/or increased loss of nutrients, which in turn results in increased susceptibility to complications, as discussed above. These complications add to the level of illness of the patient, including decreased mobility, fatigue, poor response to therapy and more complications, which can further decrease nutritional status. Thus, the cachectic

Nutritional support

The aim of nutritional support is to halt nutritional decline and delay or prevent the development of malnutrition. In malnourished and cachectic patients with advanced cancer, nutritional support aims to improve nutritional status and quality of life (Ottery, 1995; Mercadante, 1998). As the consequences of poor nutritional status start before clinical signs are evident, early nutritional intervention and support can prevent the onset of malnutrition and the development of the vicious circle.

Conclusion

Cancer-associated malnutrition is a common problem, occurring in a large proportion of patients with cancer. Malnutrition in cancer differs from simple starvation, being associated with loss of lean body mass and muscle wasting, ultimately resulting in cachexia. Cancer-associated malnutrition is a multifactorial condition, and both tumour- and host-derived factors have been implicated in its pathogenesis. The presence of an inflammatory response has been correlated with poor outcome in cancer,

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