Treatment of Cachexia in the Elderly

Chapter 11.1 Treatment of Cachexia in the Elderly

Shing-Shing Yeh,Michael W.Schuster

Treatment of Weight Loss and Cachexia in the intake in the elderly may be due to the following Elderly [10, 11] (Tables 1, 2): 1. Changes associated with normal aging Numerous studies have shown that weight loss is (reduced basal hunger, decreased gastric emp- associated with an increase in mortality [1–4]. tying time, failure to adjust food intake after Treating weight loss in the elderly can ameliorate periods of overfeeding or underfeeding) many medical conditions. For example, rehabilita- 2. Endocrine disturbances (hyperthyroidism, tion time following post-hip fractures has been hyperparathyroidism, hypoadrenalism) shown to decrease with nutritional supplementa- 3. Medications (theophylline, lithium, digoxin, tion [5]. In hospitalised geriatric patients, nutri- chemotherapy agents for cancer treatment, tional supplementation resulted in improvement in antibiotics, and many other medications that serum protein, nutritional status, and decreased distort normal smell and taste perception) mortality [6]. In a subset of geriatric inpatients, low 4. Dementia and related behavioural disturbances serum albumin with weight loss predicts those 5. Psychiatric problems (depression, anorexia patients at highest risk for dying during the subse- nervosa, alcoholism, late-life paranoia) quent 2 years [7]. Riquelme and Torres et al. [8] 6. Gastric, intestinal, and related problems (swal- carried out a multivariate analysis of risk and prog- lowing disorders, missing dentures, pain, mal- nostic factors in community-acquired pneumonia absorption, diarrhoea, constipation) in the elderly and found that age by itself was not a 7. Systemic-disease-related dysphagia (strokes, significant factor related to prognosis. Among the Parkinson’s disease, achalasia, scleroderma) significant risk factors, only nutritional status is 8. Dysgeusia (age-related decline in taste and amenable to medical intervention. In the cachectic smell) elderly, medical, cognitive, and psychiatric disor- 9. Chronic diseases (chronic obstructive pul- ders may diminish self-sufficiency in activities of monary disease, congestive heart failure, daily living (ADL), thus reducing the quality of life rheumatoid arthritis, HIV,cancers) and increasing the frequency of secondary proce- 10. Dysfunction (inability to feed oneself, limited dures, hospitalisations, and need for skilled care [2, income, poor eyesight, poor diet) 9]. The understanding of the pathophysiology of 11. Infections (acute and chronic diseases, HIV, geriatric cachexia has increased and has resulted in gastritis, cholecystitis). effective and safe nutritional measures. The Council for Nutritional Strategies in Long- Term Care has developed an algorithm for the assessment of undernutrition in long-term care Physiological Causes of Weight Loss in the settings. This algorithm was published in a supple- Elderly ment to the Annals of Long-Term Care, 2004, and addresses the diagnosis of weight loss. The first The regulation of food intake changes with age step in the management of weight loss in the eld- and involve mechanisms that are complex and erly is to attempt to identify and treat any specific multifactorial, making the treatment of weight loss underlying treatable or contributing conditions more challenging. Weight loss and poor food (e.g. endocrine diseases, medication, polypharma- 702 Shing-Shing Yeh,Michael W.Schuster

Table 1. Causes of involuntary weight loss in the elderly; These are some of the important issues that need the 9 ‘D’s’. (Adapted from [11]) to be addressed first.

Dysgeusia Dentition Nutritional Supplementation Dysphagia Depression Rolls and Dimeo found that even healthy elderly Drugs men consumed significant less baseline energy com- Dementia pared to young men [13–16]. Roberts et al. found that healthy elderly men had both a short-term (7 weeks) Diseases and a long-term (6 months) impairment in adjust- Diarrhoea (malabsorption) ing their food intake after an episode of either over- Dysfunction feeding or underfeeding.Encouraging the elderly to take in extra food (with verbal prompts, physical assistance, or appetite stimulants) at mealtime over a Table 2. Treatable causes of malnutrition (‘meals on period of 4–6 weeks, then allowing them to eat at wheels’). (Adapted from [10]) their own volition could promote weight gain. Since the elderly are not able to adjust their food intake af- M Medication effect ter a period of overfeeding for at least 6 months, E Emotional problems (depression) they will continue exceeding their eating needs and A Anorexia tardive (nervosa, alcoholism) thus, increase weight [14–16]. The elderly men in the study did not decrease food intake even after L Late-life paranoia they were given supplements before meals. As a re- S Swallowing disorders sult, they obtained 10–30% extra energy from the ‘preload’ (supplements) and still were able to take in O Oral factors (e.g., poorly fitting dentures, caries) their usual amount of food at mealtime. Providing an N No money energy-dense nutritional supplement 30–90 min before a meal can thus increase energy intake in elder- W Wandering and other dementia related behaviours ly people. H Hyperthyroidism, hypothyroidism, hyperparathy- McCrory et al. found that a wide variety of roidism, hypoadrenalism sweets, snacks, condiments, and high-carbohydrate E Enteric problems (malabsorption) entrees coupled with a smaller variety of vegeta- bles promoted long-term increase in energy intake E Eating problems (inability to feed oneself) and body fat [17]. Providing nutritional supple- L Low-salt, low-cholesterol diets ments consisting of a wide variety of sweets and S Stones, social problems (e.g., isolation, inability to carbohydrates may be helpful as the second step obtain preferred foods) for the treatment of weight loss. In addition, loss of taste and smell are common in the elderly, and medications and medical conditions play a major role in taste losses and distortions [18]. Thus, the use of flavour-enhanced food has a corresponding- cy, depression, dentition, constipation, dehydration ly positive effect on food intake. diarrhoea, systemic diseases, infections, and social Resistance at meal times in demented patients support for providing food and feeding). However, is widely reported [19],and behavioural distur- Kayser-Jones et al. found that a lack of attention to bances play a role in low body weight and weight individual food preferences, inadequate staffing, loss in demented patients [19]. Providing feeding and a lack of feeding assistance were major factors assistance and using feeding assistants may pro- accounting for weight loss in the elderly [12]. mote intake in the demented population [20]. 11.1 Treatment of Cachexia in the Elderly 703

Tube Feeding and (5) miscellaneous agents as metabolic stimulants or supplements (Table 3). Tube feeding has been indicated in persons with neuromuscular diseases (with impaired swallowing or gag reflex), postoperative patients, individu- Treatment with Appetite Stimulants als who are unable to eat, and patients using venti- Megestrol Acetate lators. Feeding-tube-associated side effects include aspiration, diarrhoea, and vomiting [21]. Megestrol acetate (MA) is a synthetic derivative of Numerous studies have been aimed at determining a naturally occurring progestational agent and is the benefits of tube feeding [22]. Mitchell et al. similar to progesterone. MA treatment of patients found no evidence that tube feeding prolonged with cancer increases appetite and non-fluid survival, especially if dysphagia is the main indica- weight gain in a dose-dependent manner, and is tion [23]. Only a small subset of nursing-home res- well-tolerated in patients with advanced malignant idents benefit from tube feeding [23]. diseases [39–44]. Von Roenn et al. found that treating patients with MA for AIDS-related anorexia/ cachexia not Parenteral Nutrition only increased weight, but also improved body image, sense of well-being, and pleasure from eat- Parenteral nutrition can be given to the elderly ing [45–47]. The Food and Drug Administration immediately after acute disease if they are inca- (FDA) has approved the use of MA for the treat- pable of taking in adequate calories or fluid for a ment of anorexia, cachexia, and/or an unexplained short period of time [24]. This must be only a tem- significant weight loss in patients with a diagnosis porary measure and cannot be sustained for more of AIDS. A few studies have shown that treating than a few weeks. Peripheral parenteral nutrition cachexia in the elderly with MA improved quality only provides a limited amount of calories and the of life and weight gain [48–51]. Lambert et al. infusion site has to be changed frequently; thus, its found that MA appears to have an anti-anabolic benefit is restricted [25, 26]. effect on muscle size, even when combined with testosterone replacement. Resistance exercise attenuated this reduction in muscle mass [52]. Pharmacological Interventions Although the mechanism(s) by which MA pro- motes weight gain is unknown, Hamburger et al. The effects of nutritional support on the preven- suggested that it either blocks tumour necrosis tion and treatment of cancer and AIDS cachexia factor (TNF) or reverses the effects of TNF by have been extensively investigated [27–33]. inducing adipocyte differentiation [53]. Reitmeier However, nonselective nutritional support with and Hartenstein found that MA increases body total parenteral nutrition (TPN) or percutaneous weight by increasing fat and body cell mass rather endoscopic gastrostomy (PEG)-tube insertion, than by fluid retention [54]. Beck and Tisdale [55] with their associated complications, has failed to reported that the weight gain associated with MA α provide benefit [34]. can be blocked by co-treatment with TNF- in Understanding the role of cytokines in mediat- NMRI mice. ing cachexia in cancer and AIDS may also provide It is not surprising that progesterone plays an new insights into nutritional therapy and pharma- important role in nutritional status. Lapp and cotherapy for the treatment of geriatric cachexia Thomas found, for example, that higher proges- [35–38]. terone concentrations are common in late preg- Pharmacological treatment agents for cachexia nancy and result in decreased interleukin (IL)-6 can be divided into five categories: (1) appetite levels to 40–50% of controls [56]. stimulants, (2) direct cytokine inhibitors, (3) ana- Mantovani et al. [57–60] reported that the bolic amino acids, (4) indirect cytokine inhibitors, appetite, weight, and sense of well-being of cancer 704 Shing-Shing Yeh,Michael W.Schuster

Table 3. Possible pharmacological treatment agents for geriatric cachexia

Appetite stimulant Direct cytokine inhibitors Indirect cytokine-inhibitors (metabolic stimulants) Dronabinol Pentoxifylline Testosterone Megestrol acetate Thalidomide Anabolic steroids N-3 fatty acids Growth hormone Fish oil Insulin-like growth factor-1 Monoclonal antibodies against specific cytokines N-acetylcysteine Specific cytokine-receptor antagonists

Anabolic amino acids Miscellaneous Ornithine oxoglutarate Cyproheptadine Branched-chain amino acids Hydralazine sulfate Glutamine and arginine Creatine Melatonin β-Blockers NSAID/COX inhibitors ACE inhibitors Ghrelin Anandamide Ponalrestat ATP Cyclic plasma perfusion Other cytokine-related substances

ACE, angiotensin-converting enzyme; ATP, adenosine 5’-triphosphate; COX, cyclooxigenase; NSAID, non-steroidal anti- inflammatory drug

patients improved with MA. In addition, cytokine Although prolonged use of MA appears to be levels in these patients decreased with MA treat- safe, therapy with this drug can result in clinical ment, but not with chemotherapy alone. They manifestations of glucocorticoid-like activity [65]. [57–60] also found that medroxyprogesterone Studies of the effects of long-term administration acetate reduces the in vitro production of pro- of MA have shown that it may cause venous inflammatory cytokines (IL-1, IL-6, TNF-α,and thromboembolism, hyperglycaemia, secondary serotonin) from peripheral mononuclear cells of adrenal suppression, and adrenal insufficiency cancer patients. Yeh et al. observed a correlation [66–75]. Short-term administration (12 weeks) of between cytokine levels, nutritional status, and MA in a preliminary pilot study of geriatric nurs- appetite in patients treated with MA [38, 61]. By ing-home residents with cachexia (69 patients) contrast, in a 6-week trial of MA, Loprinzi et al. did revealed the drug to be safe and without apparent not find evidence that MA down-regulates IL-6 in evidence of adrenal suppression [48, 51]. patients with cancer-associated anorexia and weight loss [62]. McCarthy et al. [63] showed that MA stimulates food and water intake, and this Dronabinol effect may involve neuropeptide Y (a potent feed- The use of dronabinol (a cannabinoid derivative) ing-stimulating substance). In another animal has been reported anecdotally to lead to weight study, Costa et al. [64] demonstrated that MA stim- gain and appetite stimulation [76, 77]. Volicer et al. ulation of appetite may involve calcium channels [78] found that dronabinol treatment increased in the ventromedial hypothalamus. the body weight of Alzheimer’s patients. Morley et 11.1 Treatment of Cachexia in the Elderly 705 al. [50] suggested that dronabinol has a particular- muscle mass, but with unknown clinically mean- ly good profile for persons with anorexia who are ingful changes in muscle function and disease out- at the end of life. The drug should initially be come in HIV-infected men [98–102]. Morley et al. given at a low dose (2.5 mg) in the evening. The safely administered testosterone to older men with dose should be increased to 5 mg per day if no hypogonadism and noted an increase in the upper- improvement in appetite is seen after 2–4 weeks. arm strength of this population [52, 103]. Dolan et Jatoi et al. found that MA provided superior al. found that testosterone administration anorexia palliation among advanced cancer increased muscle strength in low-weight HIV- patients compared with dronabinol alone and infected women and suggested that it may be a combination therapy did not appear to confer useful adjunctive therapy to maintain muscle additional benefit [79]. Dronabinol has been used function in this group of patients [104, 105]. by HIV patients and approved by the FDA as an In elderly men, an additional problem associat- appetite stimulant and anti-emetic in these ed with the use of testosterone-like drugs might be patients [76, 80, 81]. The main side effects are an exacerbation of prostate cancer, which would euphoria, somnolence, sedation, fatigue, and hallu- therefore limit its use. cinations [78]. Effects such as sedation, dizziness, and hallucinations make the drug less ideally suit- ed for the geriatric population. Growth Hormone and Insulin-Like Growth Factor-1 Growth hormone (GH) and insulin-like growth Indirect Cytokine Inhibitors (Metabolic Stimulants) factor (IGF)-1 stimulate amino-acid uptake and protein synthesis in muscle and improve myocyte Anabolic Agents and Testosterone proliferation and differentiation in animal studies The use of anabolic drugs, such as methyltestos- [106, 107]. The FDA recently granted accelerated terone, oxandrolone, and stanozolol, has been approval for a form of recombinant human GH explored in clinical trials with cachectic AIDS (rhGH) to treat AIDS wasting. Preliminary reports patients. Studies showed that nandrolone from Schambelan and co-workers in AIDS decanoate decreases the weight loss associated patients have all been positive [108–112]. The with cancer and HIV [82–84]. The main side combined GH and IGF-1 doses used in studies in effects were masculinisation, fluid retention, and adult males with HIV-associated weight loss had hepatic toxicity [83, 85–87]. The efficacy of nan- mixed results in producing a sustained anabolic drolone decanoate unknown in geriatric patients. response [113–120]. In fact, after trauma, the anti- However, Batterham and Garsia studied the effects catabolic action of rhGH is associated with a of nandrolone decanoate and MA in HIV patients potentially harmful decrease in muscle glutamine with weight loss and concluded that both drugs production and increased mortality [116]. Use of resulted in an increase in fat-free mass greater the rhGH for elderly patients with a low than that obtained with dietary counselling alone somatomedin C or IGF improved lean muscle [82]. Oxandrolone has been studied for treating mass, but not functional ability. Moreover, fre- weight loss in patients with HIV infection, cachec- quent side effects were seen [121]. Morley and co- tic chronic obstructive pulmonary disease (COPD) workers [122] demonstrated that rhGH, which is a patients, and cancer patients with weight loss [35, very expensive therapy, led to nitrogen retention 88–96]. Earthman et al. found that oxandrolone and weight gain in malnourished older patients. therapy in HIV infection improves weight, quality The effects of GH may be mediated through IGF- of life, and lean body mass, with minimal adverse 1. However, the combination of GH and IGF-1 did effects [97]. not result in consistent appetite stimulation [123]. Testosterone has been used as a treatment for Peripheral oedema, hyperglycaemia, carpal tunnel cachexia and weight loss in HIV patients with pos- syndrome, and gynecomastia were the major itive results concerning weight and gain of lean adverse effects. 706 Shing-Shing Yeh,Michael W.Schuster

Anabolic Amino Acids Direct Cytokine Inhibitors Ornithine Oxoglutarine Patients with advanced HIV infection or those with opportunistic infections have elevated TNF-α Brocker et al. randomised 194 elderly patients at levels, and there is a correlation with the develop- two centres to ornithine oxoglutarine (OrnOx) or ment of wasting [138, 139]. Pharmacological placebo and noted improved appetite and weight manipulation of TNF-α regulation has been pro- gain in the group of convalescing, ambulatory posed as a means of stabilising or reversing the patients who received the drug [124]. OrnOx works wasting process. by increasing amino acid and insulin levels; therefore, a major side effect may be hypoglycaemia. Pentoxifylline α Glutamine and Arginine Pentoxifylline decreases TNF- production by suppressing TNF-α mRNA transcription [140]. Glutamine is one of the most abundant amino Studies using pentoxifylline to treat cancer- and acids in the body. It is important for maintaining a HIV-associated cachexia demonstrated that it did healthy immune status, protein metabolism, and not improve appetite, weight, or sense of well- gastrointestinal mucosal integrity [125–128]. being [141–143]. It may have even have an adverse Arginine has been shown to stimulate the immune effect on the course of opportunistic infections. system, enhance wound healing, and decrease the Sathe and Sarai [144, 145] found that pentoxi- rate of tumour growth. Several prospective, ran- fylline treatment led to impairment in TNF-α domised, double-blind studies in cancer and HIV secretion and, thereby, increased the mycobacterial patients found positive weight gain after supple- load in macrophages of AIDS patients with dis- menting patients’ diets with glutamine and argi- seminated Mycobacterium avium-intracellulare nine [129–134]. Since glutamine is an essential complex infection. Gastrointestinal disturbances nutrient for cell growth, its exogenous supplemen- were among the major adverse effects. The failure tation might be used by rapidly growing tumour of pentoxifylline in the HIV-induced cachexia trial cells in patients with cancer. This, in turn, may does not rule it out as a possible agent for cachexia treatment in the elderly, but its potential effective- lead to increased levels of pro-inflammatory ness is less likely. cytokines that, in turn, may exacerbate cachexia [135]. The efficacy of glutamine in treating geriatric cachexia is unknown. Thalidomide Thalidomide also decreases TNF-α production by Branched-Chain Amino Acids increasing degradation of TNF-α mRNA [146]. It reduces serum C-reactive protein and IL-6 [147]. Other attempts at improving anorexia with nutri- Reyes-Teran et al. [148] carried out a double-blind, tional substrates such as branched-chain amino placebo-controlled study with 23 HIV-infected acids (BCAA), which have been used in TPN, are wasting patients and found a significant weight still under investigation. BCAA can compete with gain and improved Karnofsky scores in the tryptophan (the precursor of serotonin in the cen- thalidomide-treated group. There was no signifi- tral nervous system, thus reducing serotonin pro- cant change in viral load and absolute CD4+ cells duction and increasing food intake [136]. Tayek et count. However, 29% of the treatment group devel- al. found that BCAA-enriched formulas improved oped a rash. Other well-known side effects are albumin synthesis and may favourably influence peripheral neuropathy, somnolence, and constipa- protein metabolism in cancer cachexia [137]. Once tion. Vivid memories of thalidomide-induced ter- again, the efficacy of BCAA in the geriatric setting atogenicity several decades ago make it very diffi- is unknown. cult to revive this medication for general use. The 11.1 Treatment of Cachexia in the Elderly 707 exact role of thalidomide in the treatment of can- failed to show benefit in cancer cachexia [161, cer and cancer cachexia in the elderly remains to 162]. The efficacy of hydrazine sulfate in the geri- be elucidated [149, 150]. atric population has not been studied.

N-3 Fatty Acids and Fish Oil Melatonin N-3 fatty acids, mainly from fish oils, interfere Melatonin down-regulates TNF levels. In a ran- with the cyclooxygenase (PGE2 production) and domised trial of 100 patients with metastatic can- lipooxygenase metabolic pathways. They also cer [163], Lissoni et al. showed that melatonin, inhibit cytokine synthesis and activity [151, 152]. given at a dose of 20 mg orally every evening, Dinarello [153] and Endres [154] found that N-3 resulted in a statistically significant decrease in fatty acids improved food intake in rats with IL-1- TNF levels in patients treated with study drug induced anorexia. Tisdale and Dhesi also reported compared to the placebo group. Of even more that using omega-3 fatty acids stopped the weight interest was the fact that the melatonin-treated loss in an experimental cachexia model [155]. patients had significantly less weight loss. Its use While the role of N-3 fatty acids in the treatment in geriatric cachexia remains unknown. of cancer cachexia remains unclear [156], their potential role in the treatment of cancer cachexia is promising [157, 158]. Creatine Creatine is a physiologically active substance required for muscle contraction. The proper N-Acetylcysteine amount of creatine phosphate in the muscle allows This compound is effective in replenishing deplet- high rates of adenosine resynthesis; therefore, it ed glutathione levels and regulates levels of pro- plays a vital role in the performance of high- inflammatory cytokines, such as TNF, IL-1, and IL- intensity exercise. Creatine supplementation has 6 [159]. N-Acetylcysteine may therefore be of clini- not consistently been shown to enhance perform- cal benefit in the treatment of cachexia [159]. ance in exercise tasks, but it may increase performance in situations in which the availability of creatine phosphate is important [164, 165–168]. Miscellaneous Agents Short-term creatine supplementation appears to Cyproheptadine increase body mass in young males, although the initial increase is most likely water weight. Long- Cyproheptadine is both an antihistamine and an term creatine supplementation, in conjunction antiserotonergic reagent. It is effective in treating with physical training involving resistance exer- selected groups of children with anorexia and, cise, may increase lean body mass [169–171]. Its reportedly, affects central appetite centres. Yet, the use in geriatric cachexia is not yet known. results of clinical trials in cancer patients have been disappointing [160]. The side effects of sedation and dizziness make this drug less likely to be β-Blockers used in the geriatric population. Moreover, its effi- Wasting in cancer patients is multifactorial, but is cacy is unproven despite its widespread usage in caused, at least in part, by increased β(1)- and this group of patients. β(2)-adrenoceptor activity, as well as elevated basal metabolic rate and altered host metabolism [172–174]. Weight gain in response to β-blocker Hydrazine Sulfate therapy in the hypertensive population may be Hydrazine sulfate is an inhibitor of gluconeogene- attributable to decreased resting energy expendi- sis. Clinical trials in cancer patients, however, ture, inhibition of lipolysis, and decreased insulin 708 Shing-Shing Yeh,Michael W.Schuster

sensitivity [175, 176]. β-Blocker therapy has also energy expenditure [190]. Ghrelin, which is nega- been shown to reverse excess protein catabolism tively regulated by leptin and IL-1β, is secreted by after severe burns and may increase skeletal mus- the stomach and increases arcuate NPY expres- cle mass [176–178]. Hryniewicz et al. were able to sion, which in turn acts through Y(1) receptors to partially reverse cachexia by β-adrenergic-recep- increase food intake and decrease energy expendi- tor blocker therapy in patients with chronic heart ture. Gastric peptide ghrelin may, thus, functions failure [179]. β-Blocker treatment potentially pre- as part of the orexigenic pathway downstream vents further weight loss in cachectic geriatric from leptin and is a potential therapeutic target patients [180]; however, there may be an exacerba- not only for obesity, but also for anorexia and tion of sick sinus syndrome in some of these cachexia [190]. patients.

Anandamide NSAIDs/COX Inhibitors Hao et al. reported a possible role of the endo- Cachexia has also effectively been attenuated by cannabinoid anandamide on modulating the cyclooxygenase-2 (COX-2) inhibitor treatment in behavioural and neurochemical consequences of established animal cancer models [181–184], and semi-starvation in an animal study. They found this class of drugs may play an important role in that low-dose anandamide (0.001 mg/kg) could cachexia treatment [185, 186]. A study of cachectic improve food intake and cognitive function. cancer patients in Sweden who were given Anandamide-treated mice consumed 44% more indomethacin found a significant prolongation in food each day. The hypothalami of these animals their survival compared to placebo-treated contained significantly increased concentrations patients [187]. of norepinephrine, dopamine, and 5-hydrox- ytryptamine (5-HT). In the hippocampus, anandamide significantly increased norepinephrine Angiotensin-Converting-Enzyme (ACE) Inhibitors and dopamine, but decreased 5-HT. The fact that Body wasting is a clinical feature of a variety of low-dose anandamide improved food intake, cog- chronic illnesses like congestive heart failure. nitive function, and reversed some of the neuro- Treatment of cardiac cachexia with ACE inhibitors transmitter changes caused by diet restriction has been found to be somewhat successful [188, suggests its possible use in the treatment of 189]. The potential role of these inhibitors in the cachexia [191]. Phase II studies in humans have treatment of cachexia is promising but is still yet to be done. under investigation in cancer and HIV-infected patients. Ponalrestat Lipoprotein lipase (LPL) is a key regulatory Ghrelin enzyme responsible for the hydrolysis of triglyc- Ghrelin, an endogenous ligand for the GH secreta- eride (TG)-rich lipoproteins. The reduction in LPL gogue receptor, was recently identified in the rat activity is observed in tumour-bearing animals stomach. Ghrelin exhibits gastroprokinetic activity and cancer patients with cachexia, suggesting an with structural resemblance to motilin in addition involvement of LPL in inducing cancer cachexia to potent orexigenic activity through its action on [192]. Kawamura et al. demonstrated that tumour- hypothalamic neuropeptide Y (NPY) and Y(1) induced cachexia in mice is inhibited by ponalre- receptor; this effect was lost after vagotomy [190]. stat [193–195]. This suggests that ponalrestat, a Peripherally administered ghrelin blocked IL-1β- LPL-activating agent, has a therapeutic potential induced anorexia and produced positive energy for the treatment of cachexia, although no human balance by promoting food intake and decreasing trials have been conducted. 11.1 Treatment of Cachexia in the Elderly 709

Adenosine 5’-triphosphate (ATP) cytokine gene expression, cellular adhesion, cell- cycle activation, apoptosis and oncogenesis. Cancer cachexia is associated with elevated lipoly- Suppression of NF-κB results in attenuation of sis, proteolysis, and gluconeogenesis. ATP infusion cancer cachexia in a mouse tumour model has been found to significantly inhibit loss of body [205–207]. All studies involving cytokine-related weight, fat mass, and fat-free mass in patients with substances showed improved food intake, but no advanced lung cancer [196]. Agteresch et al. found single agent alone was able to reverse all the that regular infusions of ATP inhibited loss of changes seen in the tumour-bearing state. body weight and improved quality of life in Combinations of drugs, such as a PGE inhibitor patients with non-small-cell lung cancer (NSCLC) 2 with an anti-cytokine antibody, or IL-15 gene [196]. ATP treatment was associated with a signifi- transfer and anti-IL-6 antibody, or substances that cant increase in survival in the subgroup of act upon more than one pro-inflammatory weight-losing patients with stage IIIB NSCLC cytokine, may be needed to augment the anti- [197]. cachectic effect.

Cyclic Plasma Perfusion Anaemia-inducing substance (AIS) is a protein of Conclusions approximately 50000 molecular weight that is Weight loss is associated with increased mortality secreted by malignant tumour tissue and depress- and is a major problem in the geriatric population. es erythrocyte and immunocompetent cell func- Feelings of well-being and the pleasure derived tions. Ishiko and et al. reported enhanced AIS from eating positively affect the quality of life of activity and lipolytic activity as the tumours grew older individuals. The connection between eating and suggested that AIS is one of the substances and good health has been understood for hun- involved in the enhanced lipolytic activity seen in dreds of years and transcends all cultures. advanced-tumour-bearing rabbits [198]. AIS can Furthermore, it is understood that when the elder- be removed by cyclic plasma perfusion adsorption ly stop eating, their death is imminent. The first in animal studies [198, 199]. This mode of treat- step in management of elderly weight loss is to ment resulted in reduced muscle wasting and attempt to identify and treat any specific underly- increased lean body mass, and induced angiogene- ing treatable or contributing conditions. Providing sis in the adipose tissue in tumour-bearing rabbits an energy-dense nutritional supplement 30–90 [200, 201]. No human trials have been reported. min before a meal can increase energy intake in elderly people. Use of flavour-enhanced food also has a positive effect on food intake. Providing Other Cytokine-Related Substances feeding assistance and using feeding assistants Interleukin-1 receptor agonist A, IL-15, and Decoy may promote food intake in demented patients. nuclear factor κB [202, 203] have been employed to A better understanding of the role of pro- reverse cancer cachexia in animal models with inflammatory cytokines in mediating cancer- and some success. IL-15, which is known to favour HIV-induced cachexia may provide an explanation muscle-fibre hypertrophy, antagonised enhanced for geriatric cachexia and the increased levels of muscle-protein breakdown in a cancer cachexia negative regulatory cytokines, as well as possible model [203]. The alterations in protein-breakdown pharmacological treatment for this condition. rates induced by IL-15 were associated with an Overlapping physiological activities make it unlike- inhibition of the ATP-ubiquitin-dependent prote- ly that a single substance is the sole cause of cachex- olytic pathway and resulted in a preventive effect ia. Several different cytokines produce the same on muscle-protein wasting [203, 204]. The nuclear response. The potential involvement of IL-6, TNF-α, factor-κB (NF-κB) family of transcription factors IL-1, serotonin, PGE2, and other cytokines (IL-10, is involved in multiple cellular processes, including IL-4, IL-15) in the pathophysiology of ageing, 710 Shing-Shing Yeh,Michael W.Schuster

chronic diseases, and wasting calls for research on body, have demonstrated augmentation of the anti- ways to suppress the secretion, dysregulation, or cachexia effect. Further investigation with specific downstream effects of these compounds. nutritional manipulations, and the administration Anti-cytokine antibodies have been used to of specific steroids, neuropeptides, and peptide reverse cancer cachexia in animal models with hormones are promising. Further research will be some success. Studies showed improvement in food needed to fully evaluate the safety and efficacy of intake, but no single antibody alone was able to these interventions and to determine what their effect is in the treatment of geriatric cachexia. reverse all the changes seen in the tumour-bearing state. Combination studies, such as those that com- Aknowledgements bined a PGE2 inhibitor with an anti-cytokine anti- The authors thank Sherri Lovitts for her help in prepar- body or IL-10 gene transfer and an anti-IL-6 anti- ing the manuscript.

References

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