Our study has shown that thalidomide attenuates weight loss in patients with cachexia secondary to pancreatic cancer and that this is associated with a reduction in loss of lean body mass. This is a clinically important finding as it has previously been shown that patients with unresectable pancreatic cancer show inexorable weight loss, as seen in our placebo group, with death occurring when patients have lost approximately 30% of their premorbid weight.24
However, our trial does have some potential limitations. Analysis and interpretation of results from studies involving patients with advanced cancer can be difficult due to the high attrition rate and resultant changing patient population. In our study, only 70% of patients were available for analysis at four weeks and 43% at eight weeks, raising the question that bias may have arisen due to selective attrition as the numbers in both groups were relatively small. Patients in the placebo arm were also on average 4 kg lighter than in the treatment arm, and although this difference was not significant it is possible that this could have contributed to differential weight loss between the two groups. However, the two groups were otherwise well matched for percentage weight loss, performance status, and inflammatory markers at the start of the trial, and the subsequent attrition rate and rate of weight loss in the placebo group was similar to that reported in previous studies, leading us to feel this was unlikely.24–26,28
Lean body mass was estimated indirectly using anthropometric measures which, although they have been shown to correlate well with other indirect measures of lean body mass such as bioelectrical impedance,29
are prone to intra-observer variation and can over or underestimate changes in nutritional status. To keep bias to a minimum, a single trained investigator (TJ) undertook all measurements throughout the study. Furthermore, the change in bone free arm muscle mass in both groups correlated well with weight loss suggesting this was a true effect. This is in keeping with previous trials in human immunodeficiency virus associated wasting where lean body mass was measured by bioelectrical impedance,30,17
and more recently in an open label study of thalidomide in the treatment of cachexia where thalidomide was shown to promote a gain in lean body mass, as measured by DEXA scanning.19
We were unable to demonstrate that the attenuation in loss of body weight led to an improvement in quality of life. This may reflect the fact that global and physical functioning scores in patients with terminal malignancy are not particularly sensitive to weight change. Alternatively, the relatively small sample size may have meant that the study was underpowered to detect small changes in quality of life. It is however clear that overall improvement in physical functioning does correlate strongly with weight gain (p
0.001) and there was also a trend to a less pronounced but positive correlation between global health score (which encompasses more emotional functioning) and weight gain.
Finally, although the trial was not powered to investigate survival benefit, it was encouraging to note that the median survival was longer in the thalidomide group than in the placebo group (148 v
110 days) and similar to that seen in recent trials using gemcitabine.31,32
To date, previous trials of nutritional or pharmacological therapy in cachexia have been largely ineffective in increasing lean body mass, and none have demonstrated a survival benefit. Increasing energy intake by means of enteral or parenteral feeding has not been successful in increasing either total weight or lean body mass, and does not improve functional status, quality of life, or survival. Likewise, treatment with appetite stimulants such as corticosteroids and cyprohexidine, and hormonal agents such as megestrol acetate, can lead to a temporary improvement in appetite and sense of well being but any weight gain appears to be due a combination of fat deposition and fluid retention, and are thus only of benefit in the palliation of the end stage symptoms of cachexia.2,3,11,33
Eicosapentaenoic acid (EPA), the major active component of fish oils, has recently attracted considerable attention as a treatment for cachexia due to its potential immunomodulatory properties. However, despite promising early pilot studies in which it appeared to increase lean body mass, two large multicentre trials have recently failed to demonstrate any beneficial effect of EPA over either oral high calorie supplements or megestrol acetate.28,34
The only controlled trial to demonstrate an increase in lean body mass to date used a nutritional supplement containing the three amino acid related nutrients glutamine, arginine, and β-hydroxy-β-methylbutyrate.35
However, at four weeks total weight change was not significantly different between the two groups and lean body mass was only significantly different when measured by bioelectrical impedance analysis and not when measured by air displacement plethysmography.
Although the mechanism by which thalidomide attenuates weight loss is unknown it is likely that it results from modulation of the inflammatory response. One possibility is that its predominant effect is through downregulation of proinflammatory cytokines such as TNF-α. However, in the only previous randomised controlled trial of anti-TNF-α therapy in cachexia, pentoxifylline, a phosphodiesterase inhibitor which inhibits TNF-α production from macrophages, did not promote weight gain.36
In this respect it is interesting that oxpentifylline has also been found to be ineffective in the treatment of Crohn’s disease where TNF-α is known to play a central role.37
These disparate results may be explained by the fact that pentoxifylline is a rather poor inhibitor of TNF-α production compared with thalidomide.
Alternatively, there are several other possible mechanisms through which thalidomide may modulate the immune response in patients with cachexia. Thalidomide has been shown to inhibit NFκB, a ubiquitous intracellular signalling molecule involved in the transcriptional regulation of proinflammatory cytokines. NFκB controls both TNF-α and PIF induced protein catabolism through upregulating the ubiquitin-proteasome pathway.38,39
Thalidomide can inhibit NFκB activity by suppressing inhibitor κB (IκB) kinase activity, inhibiting IκB degradation, and thus NFκB nucleolar translocation.40,41
. This may therefore represent a pathway through which thalidomide can downregulate both the proinflammatory host immune response and the activity of tumour derived catabolic factors. Thalidomide has also recently been shown to inhibit lipopolysaccharide mediated induction of cyclooxygenase 2 and prostaglandin E2
which may represent an alternative pathway by which it can promote an anti-inflammatory response.42
It is also feasible that thalidomide could directly affect cancer associated anorexia, in which cytokines are thought to play a key role, and thus influence the development of cachexia. However, in our study we did not find any significant difference in loss of appetite symptom scores between the thalidomide and placebo groups. Finally, it is possible that thalidomide has a direct effect on the pancreatic cancer itself as it has previously been shown to be active against a wide range of blood and solid organ malignancies.
In addition to the immunomodulatory effects of thalidomide, other properties may play a beneficial role in alleviating symptoms in patients with end stage cancer. In an uncontrolled study involving 37 patients with terminal malignancy, the antiemetic, analgesic, and sedative properties of thalidomide were shown to be effective in the palliation of otherwise intractable symptoms.43
In conclusion, we have demonstrated that thalidomide is safe and effective in attenuating severe weight loss in patients with advanced pancreatic cancer, and that this is associated with a reduction in loss of lean body mass. It remains to be seen whether these results can be generalised to all cancers and whether attenuation of weight loss leads to prolonged survival. In the future, combination of thalidomide with nutritional supplements and pharmacological agents may ultimately lead to a better clinical outcome.