Support of Energy Balance

The best way to improve energy balance is apparently to control tumour progression, which attenuates the metabolic abnormalities induced by the tumour and/or tumour-host interactions. When cure cannot be achieved, an obvious next option is to increase nutritional intake by oral nutritional support or artificial nutrition (Fig. 3). A number of studies have tried to achieve this, particularly on a short-term basis. However, few positive effects were reported in terms of anthropometric measures, response rate to therapy, survival, or quality of life. Parenteral nutrition is difficult to supply over extended periods of time and may be associated with a number of complications. A number of parenteral nutrition trials were carried out in the 1980s in cancer patients, who showed little benefit

Fig. 5. REE in weight-losing cancer patients randomised to either P-blockade (propranolol), indo-methacin,morphine,or placebo compared to healthy individuals on P-blockade (propranolol), as described by Hyltander et al. (Data from [21])

but significant problems with infection complications. A position paper of the American College of Physicians in 1989 stated that 'parenteral nutritional support was associated with net harm, and no conditions could be defined in which such treatment appeared to be of benefit' [29]. This statement was based on studies that appeared to have design flaws and used nutritional regimens regarded as suboptimal by current standards. The disappointing results of stand-alone conventional nutritional supplementation to cancer patients led to a focus on the metabolic changes in cancer cachexia, and attempts to manipulate the metabolic alterations with a variety of pharmacological agents.

Megestrol acetate and medroxyprogesterone acetate have been extensively used and studied, primarily as appetite stimulants in weight-losing cancer patients. Several randomised trials in various groups of weight-losing cancer patients demonstrated increased appetite and also, less frequently, improved dietary intake [6, 30]. While weight loss may be attenuated or even reversed, gain of lean tissue was not demonstrated; instead, the weight gained tended to consist of fat and water. At best, these agents may improve negative energy balance but not reverse it. The metabolic alterations in advanced cancer have many parallels to those seen in the chronic systemic inflammatory response and appear, in some respects, to be different from the metabolic changes that occur in pure starvation. Thus, strategies to counteract the inflammatory response would seem to be optional. Steroids have been widely used and have been shown to improve appetite. However, steroids will not reverse ongoing weight loss and muscle wasting, and symptomatic benefits are often short lived and associated with a number of adverse effects. Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce the acute-phase protein response and REE and to preserve body fat by support of food intake in patients with advanced cancer on long-term treatment [24] (Fig. 6, 7). Thus, indomethacin stabilised performance status and prolonged survival in a number of cancer patients [31]. Therefore, anti-inflammatory

Fig.6. Time-course changes of REE in unselected cancer patients treated with indomethacin (50 mg twice daily) compared to untreated cancer patients (p < 0.003). (Data from [32])
Fig. 7. Time-course changes of food intake in unselected cancer patients treated with indomethacin (50 mg twice daily) compared to untreated cancer patients (p < 0.0006). (Data from [32])

treatment seems to have a role in palliative care of cancer, although it is still difficult to predict responders and non-responders.

Based on current knowledge of metabolism and its control in weight-losing cancer patients, we evaluated the effect of nutritional support in combination with NSAID and erythropoietin treatment in 309 patients with progressive cachexia due to solid tumours, predominantly gastrointestinal malignancy [32]. As-treated analysis demonstrated that patients receiving nutritional support had prolonged survival, accompanied by improved energy balance, increasing body fat, and greater maximum exercise performance. The results support the conclusion that nutrition is a limiting factor for outcome in a majority of cancer patients with negative energy balance (Fig. 8), and treatments targeted towards both diminished nutritional intake and metabolic alterations are there-

Fig. 8. The relationship between caloric intake and maximum exercise capacity in weight-losing cancer patients (n = 419, p < 0.001)

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