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Thalidomide and cancer cachexia: old problem, new hope?
  1. M Stroud
  1. Correspondence to:
    Dr M Stroud
    Institute of Human Nutrition, Mail Point 113, F Level, Centre Block, Southampton General Hospital, Tremona Rd, Southampton SO16 6YD, UK; m.a.stroudsoton.ac.uk

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Thalidomide is safe and may be effective in attenuating severe weight loss in patients with advanced pancreatic cancer. This may also grant benefit in terms of improved physical function

The cancer cachexia syndrome is common. Significant weight loss occurs in approximately 50% of oncology patients, with even higher values in those with gastrointestinal tumours.1 In pancreatic cancer, approximately 80% of patients will become severely malnourished. The development of cachexia is not only distressing for patients and their families, it is also associated with a much worse clinical outcome. Malnourished patients undergoing surgery for cancer have morbidity and mortality rates of three to four times those of their better nourished counterparts,2 and wasted weakened patients also tolerate chemoradiation poorly. Ultimately, malnutrition itself can be considered to be the final cause of death in approximately 30% of cancer patients. It occurs once patients have lost about one third of their premorbid body weight.

Historical explanations for the causes of cancer induced wasting have been varied. Some experts have claimed that the dominant cause of weight loss is heightened energy demands, attributable to both the needs for tumour growth and tumour triggered changes in metabolism of tissues distant to the malignant process. However, although studies confirm that the resting metabolism of cancer patients is often elevated,3total energy requirements are frequently lower than normal as patients who feel unwell do little physical activity.4 Furthermore, as cancer patients lose weight, their metabolic requirements fall further still. This type of argument has led other authorities to suggest that anorexia is the prime cause of wasting5 but once again, this cannot provide a full explanation. Although appetite loss and consequent falls in dietary intake can be profound (especially with gastrointestinal tumours), augmenting intakes using nutritional supplements is remarkably ineffective at slowing, let alone reversing, the wasting process.6 Furthermore, the pattern of tissue loss in cachexia is very different from that induced by starvation alone. Loss of lean tissues is more marked and it appears that cancers can trigger specific proteolytic and lipolytic pathways, as well as activate neuroendocrine systems that upregulate metabolism.7,8 Indeed, the changes in many ways are similar to those seen in the catabolic response to acute injury or sepsis.

Greater comprehension of the mechanisms underlying cancer cachexia has come from examination of the systems that regulate cellular metabolism. As with the acute phase response, it appears to be alterations in cytokines that lead to altered metabolic activity. Cancer patients have been shown to have elevated production of proinflammatory cytokines such as tumour necrosis factor α, interleukin 1, and interleukin 6, either produced by the tumour itself or released as part of a host response.9 These cytokines directly influence appetite, metabolic demands, and relative substrate utilisation, and indeed it appears that survival time in pancreatic cancer may relate to varying genetic propensity for proinflammatory cytokine production.10 In addition to changes in cytokines, cancer patients also have alterations in both leukotriene and prostaglandin-type eicosanoids, which can effect tissue loss through local changes in inflammatory status and systemic effects from upregulation of the acute phase response.11

Improved understanding of the triggers and responses underlying cancer cachexia offers new targets for potential therapeutic intervention. These are sorely needed as most attempts to date have met with very little success. Although perioperative nutritional support in malnourished cancer patients can improve perioperative outcome,12 the benefits appear to accrue from improved wound healing and greater resistance to infection rather than through weight gain per se; trials of nutritional supplements in cancer cachexia patients who are not undergoing surgery show very little benefit in terms of body weight, functional capacity, quality of life, or survival.6 Some interventions however have shown promise. These include megesterol acetate13 and downregulation of proinflammatory cytokine and eicosanoid pathways using fish oil supplements,14 although in the latter studies the benefits appeared to be confined to a subgroup of patients (perhaps those with an increased genetic propensity for inflammation). Furthermore, the benefits of megesterol acetate and fish oil supplementation seem confined to modest reductions in rates of body weight loss, with little change in either quality or length of remaining life.

In this issue of Gut, Gordon and colleagues15 report on the use of thalidomide for the cachexia of pancreatic cancer (see page 540). Thalidomide has a number of actions that make it a potentially useful anticancer agent. These include inhibition of angiogenesis, modulation of adhesion molecules, inhibition of cyclooxygenase 2, and stimulation of immune responses.16 Previous studies have confirmed significant thalidomide activity in multiple myeloma and some activity in myelofibrosis and myelodysplastic syndromes. Its activity in solid tumours however is less definite.17 Although thalidomide appears to have some potential in the treatment of Kaposi’s sarcoma, malignant melanoma, renal carcinoma, and prostatic cancer, it has not proved effective in tumours of the head and neck, breast, or ovary.17 Nevertheless, the potential use of thalidomide in pancreatic cancer cachexia may relate to a completely different property of the drug which does not necessarily target the tumour itself. Thalidomide has quite powerful anti-tumour necrosis factor α effects which might alter the cytokine triggers of the wasting response.16

A small open label study of thalidomide in oesophageal cancer patients with weight loss was published last year, suggesting some attenuation of wasting.18 Now, Gordon and colleagues15 report a larger, double blind, randomised controlled trial of its use in advanced inoperable pancreatic cancer patients with more than a 10% decline in recent weight. This appears to show that this fairly cheap oral agent, thought to be reasonably safe if kept away from opportunities for causing birth defects, does ameliorate the wasting process and, furthermore, that maintaining better weight grants some benefit in terms of improved physical function.

Unfortunately, as with the studies of megesterol acetate and fish oil, the reduction in cancer related wasting reported in this new study of thalidomide had no definite effect on survival times. As death in many pancreatic cancer patients is frequently a direct result of malnutrition, this lack of benefit is a little surprising, and it should force consideration as to whether attenuating the cachectic process might result in disadvantages which offset any nutritional gains. From a teleological point of view, catabolism in general must grant survival advantage, perhaps through release of nutrients that are critical for normal immunological and acute phase responses. This may explain why measures which markedly reduce catabolism, such as growth hormone, appear to actually worsen rather than improve clinical outcome in severe injury or infection.19 However, although it is easy to see how catabolism might have evolved to grant survival advantage in injury and infection, the fact that most cancers affect individuals beyond their reproductive years and are fatal if left untreated makes it near impossible to imagine how natural selection could have led to the evolution of the cachexia response. Instead, it would seem more likely that it is an unfortunate “coincidence” of nature which, in turn, makes it reassuringly unlikely that turning off the cachectic response will have adverse effects on clinical outcome. Clearly, larger multicentre studies of thalidomide in pancreatic and other gastrointestinal cancers are required and should be undertaken as soon as possible.

Thalidomide is safe and may be effective in attenuating severe weight loss in patients with advanced pancreatic cancer. This may also grant benefit in terms of improved physical function

REFERENCES

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Footnotes

  • Conflict of interest: None declared.

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