Thalidomide in the treatment of cancer cachexia: a
randomised placebo controlled trial
J N Gordon, T M Trebble, R D Ellis, H D Duncan, T Johns, P M Goggin
See end of article for
Dr J N Gordon, Mailpoint
813, Level E, South Block,
SO16 6YD, UK;
Revised version received
28 June 2004
Accepted for publication
20 July 2004
Gut 2005;54:540–545. doi: 10.1136/gut.2004.047563
Background: Proinflammatory cytokines, especially tumour necrosis factor a (TNF-a), play a prominent
role in the pathogenesis of cancer cachexia. Thalidomide, which is an inhibitor of TNF-a synthesis, may
represent a novel and rational approach to the treatment of cancer cachexia.
Aims: To assess the safety and efficacy of thalidomide in attenuating weight loss in patients with cachexia
secondary to advanced pancreatic cancer.
Methods: Fifty patients with advanced pancreatic cancer who had lost at least 10% of their body weight
were randomised to receive thalidomide 200 mg daily or placebo for 24 weeks in a single centre, double
blind, randomised controlled trial. The primary outcome was change in weight and nutritional status.
Results: Thirty three patients (16 control, 17 thalidomide) were evaluated at four weeks, and 20 patients
(eight control, 12 thalidomide) at eight weeks. At four weeks, patients who received thalidomide had
gained on average 0.37 kg in weight and 1.0 cm3in arm muscle mass (AMA) compared with a loss of
2.21 kg (absolute difference 22.59 kg (95% confidence interval (CI) 24.3 to 20.8); p=0.005) and
4.46 cm3(absolute difference 25.6 cm3(95% CI 28.9 to 22.2); p=0.002) in the placebo group. At
eight weeks, patients in the thalidomide group had lost 0.06 kg in weight and 0.5 cm3in AMA compared
with a loss of 3.62 kg (absolute difference 23.57 kg (95% CI 26.8 to 20.3); p=0.034) and 8.4 cm3
(absolute difference 27.9 cm3(95% CI 214.0 to 21.8); p=0.014) in the placebo group. Improvement in
physical functioning correlated positively with weight gain (r=0.56, p=0.001).
Conclusion: Thalidomide was well tolerated and effective at attenuating loss of weight and lean body mass
in patients with cachexia due to advanced pancreatic cancer.
20% of cases.1 2Patients show profound wasting from both
fat and skeletal muscle compartments with death usually
occurring when weight loss reaches 30% of premorbid levels.
The complex metabolic disturbances in cachexia result in a
block in the accretion of lean body mass that nutritional
supplementation and appetite stimulants alone are unable to
reverse.2 3This appears to be mediated through a combina-
tion of the proinflammatory cytokine response of the host,
and the production of specific cytokines and catabolic factors
by the tumour. The cytokines tumour necrosis factor a (TNF-
a), interleukin 6 (IL-6), and interferon c (IFN-c) have all
been implicated in the pathogenesis of cachexia, and in
cachectic tumour bearing murine models treatment with
anti-TNF-a, anti-IL-6, and anti-IFN-c antibodies can attenu-
ate the disease process.4–10More recently, specific catabolic
factors such as lipid mobilising factor and proteolysis
inducing factor (PIF) which directly stimulate tissue break-
down have also been identified in cancer patients that are
losing weight.11 12
There is also some evidence that cytokines play a role in the
pathogenesis of anorexia, which is commonly associated with
cachexia.13It has been suggested that by mimicking the
hypothalamic effect of excessive negative feedback signalling
from leptin by persistent stimulation of anorexigenic peptides
such as corticotrophin releasing factor, or by inhibition of the
neuropeptide Y pathway, cytokines could induce anorexia.14
Thus modulating cytokine expression in cancer patients may
also affect cancer associated anorexia.
Thalidomide has complex immunomodulatory and anti-
inflammatory properties. It has been shown to downregulate
the production of TNF-a and other proinflammatory cyto-
ancer cachexia is a major cause of morbidity and
mortality, occurring in up to 80% of patients with
advanced cancer and contributing directly to death in
kines, inhibit the transcription factor nuclear factor kB
(NFkB), downregulate cyclooxygenase 2, and inhibit angio-
genesis.15 16In clinical trials it is effective in ameliorating
human immunodeficiency virus associated wasting and the
weight loss seen in subjects with active pulmonary tubercu-
losis.17 18We therefore hypothesised that thalidomide would
be effective in attenuating or reversing the weight loss seen in
patients with cancer cachexia. During the course of our trial,
an open label pilot study of thalidomide in the treatment of
cachexia in 11 patients with inoperable oesophageal cancer
has been reported. In this study, thalidomide reversed weight
loss over the two weeks of the trial and this was associated
with an increase in lean body mass.19To date, no other trial
evaluating the effect of thalidomide on cancer cachexia has
been undertaken. Thus the aim of our present study was to
assess the safety and efficacy of thalidomide in attenuating
weight loss in patients with cachexia secondary to advanced
PATIENTS AND METHODS
Between April 1999 and April 2003, we undertook a
prospective, randomised, double blind, placebo controlled
study at a single centre (Queen Alexandra Hospital,
Portsmouth, UK) in patients with cachexia due to inoperable
pancreatic cancer. Inclusion criteria were: diagnosis of
pancreatic cancer made on the basis of typical clinical and
Abbreviations: TNF, tumour necrosis factor; IL, interleukin; IFN,
interferon; PIF, proteolysis inducing factor; NFkB, nuclear factor kB; IkB,
inhibitor kB; MAC, mid upper arm circumference; TSF, triceps skinfold
thickness; AMA, arm muscle area; EPA, eicosapentaenoic acid; EORTC
QLQ, European Organisation for Research and Treatment of Cancer
Quality of Life Questionnaire
malignancy, the antiemetic, analgesic, and sedative proper-
ties 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.
We thank Mr Bernie Higgins (Senior Lecturer, Department of
Statistics, Portsmouth University, Portsmouth) for his help and
advice with statistical analysis.
J N Gordon, T M Trebble, R D Ellis, H D Duncan, T Johns, P M Goggin,
Department of Gastroenterology, Queen Alexandra Hospital,
Conflict of interest: None declared.
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Thalidomide in the treatment of cancer cachexia545