Cancer cachexia--pathophysiology and management

Abstract

About half of all cancer patients show a syndrome of cachexia, characterized by anorexia and loss of adipose tissue and skeletal muscle mass. Cachexia can have a profound impact on quality of life, symptom burden, and a patient's sense of dignity. It is a very serious complication, as weight loss during cancer treatment is associated with more chemotherapy-related side effects, fewer completed cycles of chemotherapy, and decreased survival rates. Numerous cytokines have been postulated to play a role in the etiology of cancer cachexia. Cytokines can elicit effects that mimic leptin signaling and suppress orexigenic ghrelin and neuropeptide Y (NPY) signaling, inducing sustained anorexia and cachexia not accompanied by the usual compensatory response. Furthermore, cytokines have been implicated in the induction of cancer-related muscle wasting. Cytokine-induced skeletal muscle wasting is probably a multifactorial process, which involves a protein synthesis inhibition, an increase in protein degradation, or a combination of both. The best treatment of the cachectic syndrome is a multifactorial approach. Many drugs including appetite stimulants, thalidomide, cytokine inhibitors, steroids, nonsteroidal anti-inflammatory drugs, branched-chain amino acids, eicosapentaenoic acid, and antiserotoninergic drugs have been proposed and used in clinical trials, while others are still under investigation using experimental animals. There is a growing awareness of the positive impact of supportive care measures and development of promising novel pharmaceutical agents for cachexia. While there has been great progress in understanding the underlying biological mechanisms of cachexia, health care providers must also recognize the psychosocial and biomedical impact cachexia can have.

Fig. 1

A simplified model of the hypothalamic neuropeptide circuitry in response to starvation (a) and cancer cachexia (b). Full line arrows indicate the activation of the process, and broken line arrows indicate the inhibition of the process. 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 such as adipocyte-derived leptin inhibit energy intake, while other signals such as stomach-derived ghrelin stimulate energy intake. In the hypothalamus, the arcuate nucleus (ARC) 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 or inhibit POMC/CART and NPY/AgRP neurons. When an energy deficit (e.g., starvation) is signaled, orexigenic NPY/AgRP neurons are activated and anorexigenic POMC/CART neurons are inhibited, resulting in increased energy intake. When an energy excess is signaled, NPY/AgRP neurons are inhibited and POMC/CART neurons are activated. During cancer, cachectic factors such as cytokines elicit effects on energy homeostasis that mimic leptin in some respects and suppress orexigenic Ghrelin-NPY/AgRP signaling. Increased brain cytokine expression disrupts hypothalamic neurochemistry, particularly in the ARC where cytokines activate POMC/CART neurons, while inactivate NPY/AgRP neurons. The anorexia and unopposed weight loss in cachexia could be accomplished through persistent inhibition of the NPY orexigenic network and stimulation of anorexigenic neuropeptides, although the hypothalamic pathways participating in this response remain to be determined. AgRP Agouti-related peptide, MCH melanin-concentrating hormone, CART cocaine- and amphetamine-related transcript, NPY neuropeptide Y, POMC pro-opiomelanocortin, CRH corticotropin-releasing hormone, MC4R melanocortin-4 receptor, PVN paraventricular nucleus. LHA lateral hypothalamic area. Source: (5) with modification

Fig. 2

An abbreviated diagram of skeletal muscle in cancer cachexia. In adults, muscle mass remains fairly constant in the absence of stimuli (e.g., exercise) and thus protein synthesis and degradation generally remain in balance. However, in cachectic situation, the balance of skeletal muscle has been shifted towards protein breakdown, finally leading to the weight loss, weakness, and fatigue that characterize cancer cachexia. In recent years, it has become evident that catabolic factors are up-regulated (e.g., cytokines, myostatin and members of the ubiquitin–proteasome system), whereas anabolic factors (e.g., insulin-like growth factor 1) are down-regulated in cachexia muscle wasting. IGF-1 Insulin-like growth factor 1, FoxO forkhead box O, UPS ubiquitin–proteasome system, ROS reactive oxygen species, NF-κBPIF tumor-released proteolysis-inducing factor, mTOR mammalian target of rapamycin, p70S6K p70 S6 kinase

Fig. 3

The potential modalities of pharmacological intervention of cancer anorexia-cachexia syndrome. Agents were classified as those established (first-line) or those unproven/investigational (second-line), depending on their site or mechanism of actions. ①, inhibitors of production/release of cytokines and other factors; ②, gastroprokinetic agents with or without antinausea effect; ③, blockers of Cori cycle; ④ ⑤, blockers of fat and muscle tissue wasting; ⑥, appetite stimulants with or without antinausea effect; and ⑦, anti-anxiety/depressant drugs. These agents should be selected on an individual basis according to the cause of cachexia or the state of the patient. *The precise actions of statins on skeletal muscle still remain controversial. First-line treatments: glucocorticoids ① ⑥, progesterones ① ⑥. Second-line treatments: cannabinoids ⑥, cyproheptadine ⑥, branched-chain amino acids ⑤ ⑥, metoclopramide ② ⑥, eicosapentanoic acid ① ④ ⑤, 5′-deoxy-5-fluorouridine ①, melatonin ①, thalidomide ①, β2-adrenoceptor agonists ⑤, non-steroidal anti-inflammatory drugs ① ⑥, others anabolic steroids ⑤, pentoxifylline ①, hydrazine sulfate ③, statin ① ⑤*, angiotensin-converting-enzyme inhibitor inhibitor ⑤, selective androgen receptor modulator ⑤. Source: [99] with modification