Correspondence *Department of Clinical Medicine, University La Sapienza, viale dell'Universitá 37, 00185 Rome, Italy

Email alessandro.laviano@uniroma1.it

Introduction

In recent years, our cumulative understanding of a number of scientific breakthroughs in the fields of tumor biology and genomics has translated into novel antineoplastic therapeutic approaches. Thus, the use of radiotherapy and chemotherapy is now complemented by gene-driven therapy that will yield improved response rates and prolonged survival, particularly in patients whose cancers are not susceptible to eradication.¹ Although many tumors can be treated, only a few patients with metastatic cancer are likely to be cured. Consequently, supportive care is a critical issue in the management of cancer patients, wherein oncologists positively influence not only survival, but quality of life and nutritional status.

The presence of a tumor can be clinically suspected when patients report anorexia accompanied by marked weight loss; both symptoms that frequently lead patients to seek medical advice. While anorexia is defined as the loss of the desire to eat, which frequently leads to reduced food intake, cachexia is characterized by profound loss (up to 80%) of both adipose tissue and skeletal muscle mass that eventually leads to hypoalbuminemia and asthenia, which, together with anemia, a frequent comorbidity in cancer patients, limit physical activity and consequently inhibit protein synthesis.² The weight loss caused by cancer differs from that observed during starvation, which is characterized by preservation of lean body mass. In contrast, both adipose tissue and, in particular, lean body mass are markedly depleted during cachexia.² Furthermore, in many cancer patients, particularly those with pancreatic or lung cancer, resting energy expenditure is not suppressed by progressive weight loss, but can even be increased, thus exacerbating the detrimental effects of wasting and reduced food intake on nutritional status.²

In cancer patients, anorexia and cachexia can co-exist, although the degree of weight loss cannot be ascribed completely to reduced food intake. Indeed, the muscle wasting observed in cancer patients occurs even in the presence of a normal food intake, and increased muscle proteolysis is detectable even before weight loss occurs.³ Consequently, in cachectic cancer patients, the mere provision of nutrients via artificial nutrition is not effective in preventing muscle wasting or restoring lean body mass.⁴ Anorexia per se reduces food intake and promotes weight loss, but when it accompanies cachexia it acts synergistically to impact on patients' morbidity, mortality and quality of life. To paraphrase the clinical consequences of this deadly combination, all that anorectic–cachectic patients can eat is themselves.

Pathogenesis of cachexia and anorexia

Although cancer-associated anorexia and cachexia have been documented since the first tumor studies, it is only recently that advances in the field of molecular biology have shed light on their pathogenesis. Under physiologic conditions, the homeostasis of skeletal muscle mass is a dynamic process, in which a balance of protein degradation and protein synthesis is achieved. During cancer, progressive reduction of skeletal muscle mass occurs, although visceral protein reserves are preserved and the liver mass may actually increase.² Whole-body protein turnover is increased,⁵ due to an increase in muscle protein catabolism⁶ and an overall decrease in protein synthesis,⁷ despite the increase in hepatic acute-phase protein synthesis.⁸ There are three main proteolytic pathways responsible for protein catabolism in skeletal muscle. These are the lysosomal system, which is involved in proteolysis of extracellular proteins and cell-surface receptors;⁹ the cytosolic calcium-regulated calpains, which are involved in tissue injury, necrosis and autolysis;¹⁰ and the ATP ubiquitin-dependent proteolytic pathway.⁹ Of these, ubiquitin-dependent proteolysis is considered to be the most important for protein degradation in cancer cachexia.⁹

Cancer cachexia is also characterized by a marked reduction in adipose tissue, which is due to an increase in lipolysis rather than a decrease in lipogenesis.¹¹ In addition, energy metabolism is dysregulated during tumor growth, leading to continual increased energy expenditure, possibly via changes in the expression of genes encoding the uncoupling proteins.¹² These are a family of mitochondrial membrane proteins that mediate proton leakage and decrease the coupling of respiration to ADP phosphorylation, resulting in the production of heat instead of ATP.

The dramatic metabolic changes that occur during tumor growth are triggered by a number of factors, including proteolysis-inducing factor, which induces protein degradation into amino acids in skeletal muscles,¹³ and lipid-mobilizing factor, which promotes breakdown of adipose tissue into free fatty acids.¹⁴ While proteolysis-inducing factor and lipid-mobilizing factor are produced by the tumor, other factors are released as a consequence of interactions between host cells and tumor cells, represented by a number of proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-), interleukin-1 (IL-1), and interleukin-6 (IL-6). Their role in cancer cachexia was first established in animal models, and supporting evidence in humans has been reported.¹⁵

The pathogenesis of anorexia is multifactorial and is related to disturbances of the central physiological mechanisms controlling food intake. Under normal conditions energy intake is controlled primarily in the hypothalamus by specific neuronal populations, which integrate peripheral blood-borne signals conveying information on energy and adiposity status.¹⁶ In particular, the arcuate nucleus of the hypothalamus transduces these inputs into neuronal responses, and, via second-order neuronal signaling pathways, into behavioural responses (Figure 1). Intuitively, anorexia might be considered secondary to defective signals arising from the periphery, perhaps due to an error in the transduction process or to a disturbance in the activity of the second-order neuronal signaling pathways. However, consistent data seem to suggest that cancer anorexia is mediated by the inability of the hypothalamus to respond appropriately to peripheral signals, indicating an energy deficit (Figure 2). Cytokines, including IL-1 and TNF-, appear to mediate this 'hypothalamic resistance', by hyperactivating anorexigenic neurons and suppressing prophagic neurons.¹⁷ Cytokine-driven deregulation of the hypothalamic monoamine system contributes significantly to modulating these effects.¹⁷

Figure 1 Diagram showing the modulation of food intake via the hypothalamus.

In the hypothalamus, the arcuate nucleus receives information from the periphery and integrates these inputs to modulate food intake via second-order neurons. According to the information conveyed to the brain, peripheral signals may differentially activate/inhibit POMC/CART and NPY/AgRP neurons. When an energy deficit is signaled, anorexigenic POMC/CART neurons are inhibited and prophagic NPY/AgRP neurons are activated, resulting in increased energy intake. When an energy surplus is signaled, NPY/AgRP neurons are inhibited and POMC/CART neurons are activated.¹⁶ AgRP, agouti-related protein; CART, cocaine-amphetamine-regulated transcript; NPY, neuropeptide Y; POMC, pro-opiomelanocortin.

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Figure 2 The balance between prophagic and anorexigenic signaling in the arcuate nucleus of the brain.

Under normal conditions, energy intake is determined by the hypothalamic integration of peripheral signals conveying inputs on adiposity status, digestive processes, and metabolic profile. Some of these signals, including adipocyte-derived leptin, duodenum-derived cholecystokinin, and gut-derived peptide YY, inhibit energy intake. Other signals stimulate energy intake, including pancreas-derived insulin and stomach-derived ghrelin.¹⁶ During cancer, tumor-host immune interaction leads to neuroimmune activation. Increased brain cytokine expression disrupts hypothalamic neurochemistry, particularly in the arcuate nucleus, where cytokines activate POMC/CART neurons, which mediate satiety and reduced food intake. This effect is at least in part mediated via increased serotonin synthesis and release. In addition, cytokines probably inhibit NPY/AgRP neurons, which mediate appetite and energy intake. These changes in hypothalamic neurochemistry lead to 'resistance' to peripheral signals informing the brain of ongoing energy deficits in the periphery. Consistent evidence indicates that cytokines may have a pivotal role in the long-term inhibition of feeding by mimicking the hypothalamic effect of excessive negative feedback signaling.⁵⁸ Tumor-induced changes in energy metabolism of hypothalamic neurons are not presented in the figure, but they are probably involved in the pathogenesis of cancer anorexia.¹⁷ AgRP, agouti-related protein; CART, cocaine-amphetamine-regulated transcript; NPY, neuropeptide Y; POMC, pro-opiomelanocortin.

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Diagnosis of cachexia and anorexia

Anorexia is defined as the loss of the desire to eat, and its diagnosis is based on reduced appetite. However, the presence of anorexia could be characterized more effectively by identifying objective symptoms, including early satiety, taste alterations and nausea, and by assessing its severity. Consequently, a visual analog scale is often used, which is a useful tool in epidemiologic or prospective studies but may prove unreliable if small changes in appetite need to be detected.¹⁸ Sometimes, the diagnosis of anorexia is based on the presence of reduced energy intake, but this could be misleading because the reduction of ingested calories might be the consequence of dysphagia or depression rather than because of anorexia. In addition, a number of symptoms interfering with food intake, which are likely to be linked to changes in the central nervous system energy intake control, have been identified (Box 1).¹⁹ The use of questionnaires to diagnose anorexia is increasing rapidly, thus highlighting their utility and reliability. However, considering that questionnaires provide only a qualitative assessment of the presence of anorexia, it is also advisable to quantify the degree of anorexia by using a visual analog scale.

In contrast, the diagnosis of cachexia could be more difficult because it is latent, and its development often proceeds for a long time before its clinical manifestation.^{20, 21} Cancer cachexia is biologically characterized by increased activity of intracellular proteolytic pathways, which is clinically manifest by loss of body weight, although the increased activity of the major muscular proteolytic system is observed even in the absence of any weight loss.³ Therefore, activation of the pathogenic mechanisms of cancer cachexia is an early phenomenon during tumor growth, and cachexia should be suspected even in the absence of weight loss, particularly in those patients whose tumors are known to negatively influence nutritional status (i.e. those of the pancreas, lung, esophagus, and stomach).²² Given these facts, cachexia should be treated in its preclinical stage, when the likelihood for effective prevention of muscle wasting is greater than during the advanced stages of the disease.

Clinical relevance

Owing to the difficulties in clearly defining and diagnosing cancer anorexia, its prevalence is yet to be precisely assessed. Based on different diagnostic tools, anorexia has been detected at the point of cancer diagnosis in 13–55% of patients.²³ Nevertheless, consistent evidence suggests that approximately 50% of cancer patients report abnormalities of eating behaviour at the time of first diagnosis,²⁴ and prevalence in terminally-ill cancer patients is even higher at approximately 65%.²⁵ The incidence of weight loss upon diagnosis varies greatly according to the tumor site (Table 1).^{22, 26} In less aggressive forms of Hodgkin's lymphoma, acute nonlymphocytic leukemia, and in breast cancer, the frequency of weight loss is 30–40%. More aggressive forms of non-Hodgkin's lymphoma, colon cancer, and other cancers are associated with a frequency of weight loss between 50–60%.^{27, 28, 29} Patients with pancreatic or gastric cancer have the highest frequency of weight loss at over 80%.

Table 1 Incidence of weight loss in cancers of different sites (adapted, with permission, from ref 22).

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The onset of anorexia–cachexia significantly influences the clinical course of the disease, and most antitumor therapies actually exacerbate anorexia and worsen body weight loss. As a consequence, the higher prevalence and greater severity of anorexia–cachexia syndrome in advanced cancer patients is mostly due to iatrogenic cause. The presence of early satiety at any stage of the disease can significantly increase the risk of death by 30%.³⁰ Similarly, the extent of body weight loss negatively influences survival not only per se, but also by delaying initiation and/or completion of aggressive antitumor therapy (Table 2).²⁶

Table 2 Effect of weight loss expressed as % of premorbid weight on median survival expressed in weeks (adapted, with permission, from ref 26).

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An interesting aspect of the clinical impact of cancer anorexia–cachexia syndrome that has recently emerged is its influence on quality of life. Supporting this view, it was recently documented that quality-of-life function scores are largely determined by nutrient intake and weight loss, accounting for 20% and 30% of the total score, respectively.³¹ Despite the well-known and much-documented clinical impact of anorexia and cachexia on prognosis and quality of life, oncologists have suboptimal awareness of how to treat this syndrome. A recent survey showed that almost all of the responding oncologists agreed that all advanced cancer patients should receive concurrent supportive care, even if they are receiving antitumor therapy.³² Yet only a minority reported consulting frequently with a supportive care specialist, and almost half of respondents indicated that they were inadequately trained in this aspect of patient care. Surprisingly, an astonishing 30% did not disagree with the statement that "palliative care specialists steal patients who would otherwise benefit from medical oncology". Therefore, it appears that most oncologists recognize the importance of supportive care for cancer patients. Despite this, many are inadequately trained, resulting in the delivery of suboptimal care.

During the past few years, the general awareness of the clinical relevance of anorexia–cachexia syndrome has increased, particularly because it is now clear that in cancer management it is important to add life to years and not just years to life. Therefore, it is expected that in the near future, cancer patients may start concurrent antitumor and anti-anorexia/cachexia therapies when a diagnosis is made. Such a combined therapy would have a synergistic effect on enhancing response rates and improving quality of life.

Therapy for anorectic–cachectic patients

The optimal therapy for anorexia and cachexia is curing the underlying cancer.²³ Unfortunately, this goal is often not attainable with currently available treatments. Thus, an integrated therapeutic approach should be devised to treat cancer anorexia and cachexia, and should include both nutritional counseling and pharmacologic approaches (Box 2).

Therapy: what's next?

Antiserotonergic agents

Cancer anorexia and cachexia can be therapeutically treated by interfering with the neurochemical events downstream of cytokine activation. Serotonergic hypothalamic neurotransmission may represent a suitable example. Synthesis of serotonin in the hypothalamus depends on the availability of its precursor, the amino acid tryptophan. Such availability is reduced by the oral administration of branched-chain amino acids (BCAA) because they compete with tryptophan for the same transport system located on the blood-brain barrier (Figure 3).⁴⁶ In a pilot study, oral supplementation with BCAA improved anorexia and energy intake in anorectic cancer patients.⁴⁷ Although not tested in larger clinical trials involving cancer patients, the prophagic effects of supplementation with BCAA have been confirmed in patients with uremia and liver cirrhosis.^{48, 49}

Figure 3 Anorexia improvements via oral supplements that compete with tryptophan to inhibit serotonergic signaling.

Oral supplementation with branched-chain amino acids, by competing with tryptophan for the same carrier located on the blood brain barrier, the L-system, leads to reduced brain tryptophan entry, which in turn results in reduced hypothalamic serotonergic activity and improved anorexia. BBB, blood–brain barrier; BCAA, branched-chain amino acids; TRP, tryptophan.

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Another mechanism of action of BCAA could be that they act centrally to influence appetite and energy intake, while simultaneously inhibiting peripheral muscle wasting. Serotonin has been shown to activate hypothalamic melanocortin receptors,⁵⁰ which have been linked to muscle wasting.⁵¹ It is postulated that melanocortin receptors are less activated as a result of reducing brain serotonergic activity via BCAA, leading to reduced peripheral muscle wasting. Furthermore, recent experimental data show that leucine, one of the three BCAA, has inhibitory effects on ATP-dependent ubiquitin activity.⁵²

Conclusion

The incidence of anorexia–cachexia syndrome is high in cancer patients. This is clinically relevant because it significantly affects the course of the underlying disease. Unfortunately, awareness of its relevance is suboptimal among the health professionals involved in clinical management of cancer patients. As a consequence, severely compromised nutritional status and wasting are still common features of cancer patients. It is important to recognize and treat this syndrome as early as possible, even concurrently with antitumor therapy, in order to prolong survival and positively influence quality of life.

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Subject areas under which this article appears: Palliative Care | Chemotherapy