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Published on 21 September 2009

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Therapeutic approaches to cancer-related cachexia

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Cancer cachexia is a complex syndrome characterised by marked depletion of body weight associated with profound alterations of both nutritional status and metabolic homeostasis

Paola Costelli
Dipartimento di
Medicina e Oncologia
Sperimentale
Università di Torino, Italy

The management of cancer patients is frequently complicated by the onset of cachexia, a multifactorial syndrome that impairs survival, reduces the tolerance to antineoplastic therapies and results in poor quality of life. The hallmark of cancer cachexia is body weight loss, reported to occur in 54 to 70% of patients at diagnosis.[1] Disease- and therapy-associated wasting increases morbidity and mortality, also by enhancing drug-induced toxicity, frequently impairing completion of therapeutic schedules. In this regard, weight loss is a reliable predictor for both treatment toxicity and short survival[2], while a good performance status positively correlates with response rates to therapy and survival.[3] In addition to body weight loss, depletion of skeletal muscle and adipose tissue, asthenia, anorexia, altered metabolic and hormonal homeostasis occur in cachectic patients.

Approximately two million people die annually worldwide due to cancer-related cachexia.[1],[3] This syndrome remains a major problem in clinical oncology4, being basically refractory to therapy. In addition, cachexia is still considered a late event in the course of neoplastic disease, although body weight loss and both biochemical and molecular changes can be detected at the time of diagnosis in about 60-80% of lung or gastric cancer patients.[1],[5] On this line, cachexia should be regarded as an early phenomenon3 and targeted therapeutic interventions are due well before the occurrence of full-blown body wasting.[6]

Studies performed on different experimental models have shown that appropriate tools can be devised to effectively antagonise the development of cachexia.[7] Despite the difficulties in integrating experimental and clinical research, significant progresses have been made along this line or are underway. In this regard, the main improvement in the management of cancer cachexia will reflect therapy being shifted from symptomatic to mechanism based strategies.

Nutritional support
Recent findings show that preserving or restoring an adequate nutritional status allow neoplastic patients to recover and withstand aggressive therapeutic regimens. Previous studies showed that weight loss of cachexia, differently from that induced by starvation or caloric restriction, cannot be reverted simply by nutrient provision.[8] On this line, the maintainance of nutritional status in cancer patients is mandatory. The achievement of this goal mainly depends on the possibility to detect a condition of latent™ cachexia, allowing early interventions to be adopted. Indeed, late intervention in malnourished patients is quite ineffective, and belongs to terminal palliative cares rather than to treatment of cachexia.[9] In this regard, routine nutritional assessment, aimed to identify individuals at nutritional risk, is a valuable tool in defining the correct therapeutic approach to maintain the patient in good physical conditions as long as possible. Of particular relevance at this purpose is the follow up of patients by nutritional counselling (Muscaritoli et al, unpublished data).
Consistently, previous results have shown that both nutritional intake and quality of life improve in colon cancer patients maintained on regular foods and not just receiving protein and calorie supplementation.[10]

Cachexia is significantly associated with anorexia[11] and several drugs have been proposed in order to achieve an orexigenic effect. Significant increase in both food intake and body weight has been reported in patients treated with megestrol acetate or medroxyprogesterone acetate, although increased fat rather than lean body mass is observed.[12],[13]

Glucocorticoids have been shown to stimulate appetite to an extent comparable to megestrol acetate, although without significantly increase body weight.[14] Similarly, histamine antagonists endowed with antiserotonergic properties such as cyproheptadine or ondasetron, a type3 serotonergic receptor antagonist, stimulate appetite without increasing body weight.[15] A comparable effect has been shown for cannabinoids, dronabinol in particular, that is able to stimulate appetite, but fails to contrast the loss of body weight that
characterised the progression towards overt cachexia.[16] Ghrelin, a neuropeptide mainly secreted from gastric cells, improves appetite and stimulates the release of growth hormone, positively interfering with anabolic pathways dependent on both insulin and IGF1. Anorectic cancer patients respond to ghrelin infusion by increasing energy intake[17], and administration of a ghrelin analogue to cachectic cancer patients results in increased hand-grip strength and lean body mass, in the absence of body weight changes.[18]

Treatment with branched-chain amino acids (BCAA) has been shown to improve both anorexia and energy intake in cancer patients.[19] BCAA also exert anticatabolic effects since they stimulate protein synthesis and inhibit protein breakdown.[20] Beta-hydroxy-beta-methylbutyrate (HMB), a leucine metabolite, has been shown to effectively inhibit protein degradation. In addition on the promising data obtained in experimental models of cancer cachexia (Muscaritoli et al, unpublished data), HMB has been also successfully tested in clinical trials.[21]

Anti-inflammatory strategies
Among the factors contributing to cancer cachexia, inflammatory mediators appear crucially involved. For this reason, dietary supplements endowed with antiinflammatory properties have been proposed.[22] Particular attention has been devoted to the omega-3 polyunsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA) and docosahexaenoic acid that have been shown to suppress the production of proinflammatory cytokines, of molecules deriving from the arachidonic acid cascade, and of acute phase reactants such as C-reactive protein.[2], [23] Clinical trials performed in malnourished patients have shown that EPA promotes gain of both body weight and lean body mass, likely in force of its anti-inflammatory properties.[23],[24] These observations, however, have not been completely confirmed by a large multicenter study performed on pancreatic cancer patients.[25] The use of omega-3 PUFA in the clinical practice is still limited, since a poor compliance to prolonged supplementation has been reported and not all cancer patients benefit from treatment.[22] In addition, recent data show that EPA administration per se does not exert any statistically significant benefit in the treatment of cancer cachexia.[26]

The effectiveness of specific anti-cytokine treatments, either acting centrally, inhibiting cytokine production, or peripherally, antagonising their biological activity, has been largely investigated in experimental studies.[27] However, although specific anti-cytokine drugs are available, their clinical use is limited to chronic inflammatory pathologies such as rheumatoid
arthritis, inflammatory bowel disease and psoriasis.[28] This limitation is based on the observation that human cancer cachexia does not appear to depend upon a single inflammatory mediator. Rather, the cytokine profile is different according to tumor type and disease stage. Increased production of a single cytokine may not be a frequent feature in cancer patients, while the simultaneous release of multiple inflammatory mediators with overlapping biological activities is more likely. In this regard, recent reports have proposed that myeloidderived suppressor cells may contribute to both cytokine hyperproduction and at least some of the metabolic alterations associated with cancer cachexia.[28] Although still unexplored, the hypothesis that controlling the expansion of this cell population may help in preventing or delaying the onset of cachexia is intriguing.

Antioxidant treatments
The hypothesis that oxidative stress can contribute to the pathogenesis of cancer cachexia is supported by several experimental and clinical evidences, suggesting the usefulness of antioxidant therapeutic regimens.[29]

Few studies in the literature report about antioxidant treatment in human cancer cachexia. A phase III trial has evaluated the effectiveness of an approach integrating antioxidants, progestagens, nutraceuticals, and cyclo-oxygenase-2 inhibitors, showing improved food intake, body weight, lean body mass, and quality of life.[30] These results, however, do not allow to draw precise indications about the effects of antioxidants. The same research group has also shown that carnitine administration to cancer reduces fatigue and the levels of reactive oxygen species, while increasing appetite, lean body mass, and antioxidant systems.[31] However, despite the observation that oxidative stress generally occurs in wasting conditions, the extent of its contribution is still unclear. As an example, the effectiveness of treatment with dehydroepiandrosterone in correcting/ preventing muscle atrophy in experimental diabetes or cancer cachexia is quite different, being very marked in the former, while just partial, although significant, in the latter.[32]

These observations indicate that the results obtained with antioxidant treatments are contrasting. The observation that some studies demonstrate a certain degree of protection against cancer cachexia suggest that oxidative stress likely behaves as an additional factor, that certainly amplifies the wasting stimuli, but probably does not play a leading role.

Conclusions
The results obtained from both experimental and clinical studies demonstrate that cancer cachexia results from profound metabolic alterations due to the combined action of factors released either by the tumor or by the host, and that the underlying metabolic disturbances may occur very early in the course of the disease, well before any evidence of general wasting. On these bases, timely therapeutic approaches aimed at interfering pharmacologically with the onset of tissue wasting need to be pursued. A number of drugs selected because of their effectiveness in preventing experimental cachexia, are presently reaching the clinical trial stage.[2],[23] Combination protocols addressing simultaneously the different aspects of cachexia seem to be the better choice. Expectedly, the development of strategies aimed at preventing or reversing cachexia will also help in tailoring a more effective management of cancer patients by increasing their resistance to anticancer therapies.

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