Thalidomide in the treatment of cancer cachexia: A randomised placebo controlled trial
Proinflammatory cytokines, especially tumour necrosis factor alpha (TNF-alpha), play a prominent role in the pathogenesis of cancer cachexia. Thalidomide, which is an inhibitor of TNF-alpha synthesis, may represent a novel and rational approach to the treatment of cancer cachexia. To assess the safety and efficacy of thalidomide in attenuating weight loss in patients with cachexia secondary to advanced pancreatic cancer. 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. 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 cm(3) in arm muscle mass (AMA) compared with a loss of 2.21 kg (absolute difference -2.59 kg (95% confidence interval (CI) -4.3 to -0.8); p = 0.005) and 4.46 cm(3) (absolute difference -5.6 cm(3) (95% CI -8.9 to -2.2); 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 cm(3) in AMA compared with a loss of 3.62 kg (absolute difference -3.57 kg (95% CI -6.8 to -0.3); p = 0.034) and 8.4 cm(3) (absolute difference -7.9 cm(3) (95% CI -14.0 to -1.8); p = 0.014) in the placebo group. Improvement in physical functioning correlated positively with weight gain (r = 0.56, p = 0.001). Thalidomide was well tolerated and effective at attenuating loss of weight and lean body mass in patients with cachexia due to advanced pancreatic cancer.
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-asynthesis, 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 cm
in 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
(absolute difference 25.6 cm
(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 cm
in 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 cm
(absolute difference 27.9 cm
(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.
Cancer 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
20% of cases.
Patients 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
This 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-cantibodies can attenu-
ate the disease process.
More 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
There is also some evidence that cytokines play a role in the
pathogenesis of anorexia, which is commonly associated with
It 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.
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-aand other proinflammatory cyto-
kines, inhibit the transcription factor nuclear factor kB
(NFkB), downregulate cyclooxygenase 2, and inhibit angio-
In clinical trials it is effective in ameliorating
human immunodeficiency virus associated wasting and the
weight loss seen in subjects with active pulmonary tubercu-
We 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.
To 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
radiological findings, operative appearance, and/or histologi-
cal diagnosis; patient deemed inoperable either on the basis
of tumour anatomy, inability to survive major surgery, or
patient preference; greater than 10% weight loss over the
preceding six months; and likely life expectancy of at least six
weeks based on clinical judgment. Exclusion criteria were:
any form of treatment for pancreatic cancer in the preceding
six weeks; weight less than 40 kg; concomitant use of
corticosteroids, anabolic drugs, hormonal agents, or other
appetite stimulants; age less than 18 years; subjective or
objective evidence of peripheral neuropathy; severe constipa-
tion, vertigo, or vestibular disease; or severe comorbidity.
Women of child bearing potential were required to have a
negative pregnancy test prior to starting the trial and use two
methods of contraception throughout the trial and for one
month afterwards. The trial was approved by the local ethics
committee and all patients gave written informed consent.
All procedures were carried out in accordance with the
declaration of Helsinki and the CONSORT guidelines.
At baseline, patients underwent a detailed medical history
and examination. Premorbid weight and duration of weight
loss were reported by the patient. Height (cm), weight (kg),
mid upper arm circumference (MAC, cm), triceps skinfold
thickness (TSF, mm), quality of life, full blood count, serum
biochemistry, liver function tests, C reactive protein, and
erythrocyte sedimentation rate were all recorded. All parti-
cipants were weighed without shoes in their underclothes on
the same set of spring balanced scales (SSEC, Germany).
MAC was measured using stretch resistant tape and TSF
using Harpenden skinfold callipers, as previously described.
Grip strength was measured from the non-dominant hand
using a digital hand grip dynamometer (Twinbird, Japan).
Quality of life was determined using the European
Organisation for Research and Treatment of Cancer
(EORTC) QLQ-C30 form, along with additional disease
specific pancreatic cancer module PAN26.
Participants were subsequently assessed every four weeks
for six months with the same measurements and blood tests
recorded at each visit. All measurements were undertaken by
the same investigator (TJ).
At enrolment, participants were randomised to receive
either thalidomide 200 mg daily or identical placebo.
Randomisation was undertaken in blocks of four using a
sequential series of sealed envelopes containing a computer
generated code. Randomisation envelopes were opened by a
third party who dispensed the trial drug in a double blind
Thalidomide was obtained from Penn Pharmaceuticals Ltd
(Gwent, UK) as 100 mg tablets, and prescribed in accordance
with the published guidelines for the clinical use and
dispensing of thalidomide.
The dose of thalidomide was
reduced to 100 mg in patients who suffered from unaccep-
table daytime somnolence, constipation, or developed a rash.
Patients in whom symptoms did not subsequently resolve
were then withdrawn from the trial. Compliance was
assessed by participant self reporting and tablet count at
The primary outcome measure was change in weight at four
weeks. Secondary outcome measures were change in bone
free muscle mass, grip strength, quality of life, and survival.
Bone free arm muscle area (AMA), a validated marker of lean
muscle mass, was calculated from MAC and TSF using the
formula (MAC 2pTSF)
/4pminus a correction factor of 10
for male sex or 6.5 for female sex.
Adverse event information was obtained at every clinic
visit by recording spontaneously reported complaints from
patients and by asking specifically about recognised side
Analysis was performed on an intention to treat basis. Data
are presented as means (SEM) and absolute differences (95%
confidence limits (CI)) when appropriate. Continuous vari-
ables were analysed using a two sample ttest, Mann-
Whitney U test, or the Pearson correlation test, as appro-
priate. Categorical data was analysed using Fisher’s exact test
as appropriate. Survival curves were plotted using Kaplan-
Meier survival estimates from the date of study enrolment.
Results were considered statistically significant if the p value
was less than 0.05.
Sample size calculations were undertaken based on
assumptions from published studies of weight loss in patients
with cancer cachexia.
To detect a mean difference in
weight of 2.5 kg at four weeks with 80% power and a 5%
significance level, 17 patients were required in each group.
This was inflated to 25 in each group to account for an
attrition rate of 25% at four weeks.
Statistical calculations were performed using SPSS version
11.5 software (SPSS, Chicago, USA).
Table 1 Baseline patient characteristics
(n = 24)
(n = 23)
Sex (M:F) 13:11 12:11
Age (y) 71(1.7) 69 (1.3)
Premorbid weight (kg) 73.0 (2.3) 77.1 (3.3)
Baseline weight (kg) 63.3 (2.2) 67.4 (2.7)
%Weight loss at baseline 13.2 (1.4) 12.2 (1.3)
Baseline MAC (mm) 27.1 (0.9) 27.6 (1.0)
Baseline Hb (g/dl) 12.1 (0.4) 12.4 (0.3)
Baseline Alb (g/dl) 35.0 (1.0) 37.1 (0.9)
Baseline ESR (mm/h) 62.0 (7.9) (n = 22) 54.7 (6.7) (n = 20)
Baseline C reactive protein (mg/l) 21.5 (4.8) 30.0 (9.5) (n = 22)
EORTC QLQ-C30 global health score*50 (4.6) 56 (4.7)
EORTC QLQ-C30 physical functioning*72 (5.1) 75 (5.1)
Values are mean (SEM).
MAC, mean arm circumference; Hb, haemoglobin; Alb, albumin; ESR, erythrocyte sedimentation rate.
*EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire.
High score represents high level of functioning (range 0–100).
There were no significant differences between the two groups.
Thalidomide in the treatment of cancer cachexia 541
A total of 50 patients were randomised and enrolled into the
study. One subject in the placebo arm and two in the
thalidomide arm were wrongly diagnosed and subsequently
excluded from further analysis. Both patient groups were well
matched at baseline with no significant difference between
any of the variables (p.0.05) (table 1). Concomitant drug use
was similar between the two groups: in the placebo group, 4/24
patients were taking Creon, 2/24 cholestyramine, 9/24 opiate
analgesics, 7/24 other analgesics, 4/24 antidepressants, 8/24
cardiovascular medications, and 4/24 acid suppressants com-
pared with 5/23, 3/23, 7/23, 10/23, 6/23, 11/23, and 6/23,
respectively, in the treatment group. Patients were also well
matched for global health score and physical functioning, as
measured by the EORTC QLQ-C30 questionnaire. There were
33 patients available for assessment at four weeks and 20 at
eight weeks. The predominant reason from withdrawal from
the trial was death or disease progression (fig 1). The high
attrition rate meant that after eight weeks there were too few
patients for meaningful comparison.
Weight and nutritional status
At the primary end point of four weeks there was a
significant difference in weight change, with patients in the
treatment group gaining a mean of 0.37 kg while those in the
placebo group lost a mean of 2.21 kg (absolute difference
22.59 kg (24.3 to 20.8); p = 0.005). At week 8 there was
still a significant difference between the two groups, with
patients in the treatment group losing 0.06 kg compared with
3.62 kg (absolute difference 23.57 kg (2-6.8 to 20.3);
p = 0.034) in the placebo group (fig 2).
Figure 1 Flow diagram of progress
through the trial.
Figure 2 Change in weight in pancreatic cancer patients randomised
to either thalidomide (n = 17, week 4; n = 12, week 8) or placebo
(n = 16, week 4; n = 8, week 8). Differences between groups: p = 0.005
at four weeks and p = 0.034 at eight weeks.
Figure 3 Change in bone free arm muscle area (AMA) in pancreatic
cancer patients randomised to either thalidomide (n = 17, week 4;
n = 12, week 8) or placebo (n = 16, week 4; n = 8, week 8). Differences
between groups: p = 0.002 at four weeks and 0.014 at eight weeks.
542 Gordon, Trebble, Ellis, et al
At week 4 there was a significant difference in change in
bone free AMA between the two groups. Patients in the
treatment group had gained an average of 1 cm
in bone free
AMA while those in the placebo group lost an average of
(absolute difference 25.6 cm
(28.9 to 22.2);
p =0.002). This remained significant at week 8, with patients
in the treatment group having lost an average of 0.5 cm
compared with 8.4 cm
(absolute difference 27.9 cm
(214.0 to 21.8); p = 0.014) in the placebo group (fig 3).
There was no significant difference in grip strength
between the two groups at any time point. Additionally, grip
strength did not differ significantly from baseline at any time
in either group (table 2).
Quality of life measurements
There was no significant difference in global health score or
physical functioning between the two groups or from
baseline in either group. However, change in physical
functioning correlated positively with change in weight
(r= 0.56, p = 0.001) and there was a trend suggesting change
in global health score correlated positively with change in
weight, although this was not significant (r= 0.22, p = 0.221)
(figs 4, 5)
Median duration of survival from entering the study was
148 days in the thalidomide group (95% CI 67–171)
compared with 110 days in the placebo group (95% CI 75–
136) although this was not statistically significant (p = 0.45).
Kaplan-Meier survival curves were not significantly different
between the two groups (fig 6).
Overall, thalidomide appeared to be well tolerated in this
study. Two patients (9%) complained of peripheral neuro-
pathy which resolved on stopping the drug, and two patients
(9%) developed a rash that necessitated withdrawing from
the trial. A further four patients (17%) complained of severe
daytime somnolence that required a reduction in drug dosage
in two patients and cessation of the drug in the other two.
In the symptom scales at four weeks, constipation was
significantly more common in the thalidomide group
compared with placebo (p = 0.04) and insomnia significantly
less common (p = 0.023). There was no significant difference
between the two groups in any of the other symptom scales
(fatigue, pain, nausea and vomiting, dyspnoea, appetite loss,
diarrhoea, or financial difficulties). Other side effects were
mild and did not differ significantly from placebo. Two
patients in the placebo group and one in the thalidomide
group developed deep vein thrombosis and were withdrawn
from the study. Thalidomide has previously been associated
with an increased risk of thromboembolism in patients with
Table 2 Change in patient weight and nutritional status at weeks 4 and 8
(95% CI for difference) Significance
Weight change (kg)
Week 4 22.21 0.37 22.59 (24.3 to20.8) p = 0.005, t = 3.05
Week 8 23.62 20.06 23.57 (26.8 to20.3) p = 0.034, t = 2.30
Change in AMA (cm
Week 4 24.6 1.0 25.6 (28.9 to22.2) p = 0.002, t = 23.39
Week 8 cm
28.4 20.5 27.9 (214.0 to21.8) p = 0.014, t = 22.72
Change in grip strength
Week 4 20.88 21.00 0.125 (22.10 to 2.35) p = 0.909, t = 0.12
Week 8 21.00 22.50 1.50 (21.87 to 4.87) p = 0.363, t = 0.93
AMA, bone free arm muscle mass.
Figure 4 Relationship between change in physical performance status
and change in weight at four weeks in patients with pancreatic cancer
(n = 34, p = 0.001).
Figure 5 Relationship between change in global health status and
change in weight at four weeks in patients with pancreatic cancer
(n = 34, p = 0.221).
Figure 6 Kaplan-Meier survival curve for patients with pancreatic
cancer treated with thalidomide (n = 23) or placebo (n = 24). Median
survival 148 days in thalidomide group versus 110 days in the placebo
group (p = 0.45).
Thalidomide in the treatment of cancer cachexia 543
although this finding was not confirmed
in the study.
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.
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.
Lean body mass was estimated indirectly using anthropo-
metric measures which, although they have been shown to
correlate well with other indirect measures of lean body mass
such as bioelectrical impedance,
are prone to intra-observer
variation and can over or underestimate changes in nutri-
tional 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
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.
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 v110 days) and similar to that seen in
recent trials using gemcitabine.
To date, previous trials of nutritional or pharmacological
therapy in cachexia have been largely ineffective in increas-
ing 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.
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.
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
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 plethysmogra-
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-a. However, in the
only previous randomised controlled trial of anti-TNF-a
therapy in cachexia, pentoxifylline, a phosphodiesterase
inhibitor which inhibits TNF-aproduction from macro-
phages, did not promote weight gain.
In this respect it is
interesting that oxpentifylline has also been found to be
ineffective in the treatment of Crohn’s disease where TNF-a
is known to play a central role.
These disparate results
may be explained by the fact that pentoxifylline is a
rather poor inhibitor of TNF-aproduction compared with
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 NFkB, a ubiquitous intracellular signalling
molecule involved in the transcriptional regulation of
proinflammatory cytokines. NFkB controls both TNF-aand
PIF induced protein catabolism through upregulating the
Thalidomide can inhibit
NFkB activity by suppressing inhibitor kB(IkB) kinase
activity, inhibiting IkB degradation, and thus NFkB nucleolar
. 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 E
may represent an alternative pathway by which it can
promote an anti-inflammatory response.
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 thalido-
mide, 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
544 Gordon, Trebble, Ellis, et al
malignancy, the antiemetic, analgesic, and sedative proper-
ties of thalidomide were shown to be effective in the
palliation of otherwise intractable symptoms.
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.
1Dunlop R. Clinical epidemiology of cancer cachexia. In: Bruera E, Higginson I,
eds. Cachexia-anorexia in cancer patients, vol 5. Oxford: Oxford University
2Tisdale MJ. Cachexia in cancer patients. Nat Rev Cancer 2002;2:862–71.
3Barber MD, Ross JA, Fearon KC. Cancer cachexia. Surg Oncol
4Oliff A, Defeo-Jones D, Boyer M, et al. Tumors secreting human TNF/
cachectin induce cachexia in mice. Cell 1987;50:555–63.
5Langstein HN, Doherty GM, Fraker DL, et al. The roles of gamma-interferon
and tumor necrosis factor alpha in an experimental rat model of cancer
cachexia. Cancer Res 1991;51:2302–6.
6Strassmann G, Fong M, Kenney JS, et al. Evidence for the involvement of
interleukin 6 in experimental cancer cachexia. J Clin Invest 1992;89:1681–4.
7Costelli P, Carbo N, Tessitore L, et al. Tumor necrosis factor-alpha mediates
changes in tissue protein turnover in a rat cancer cachexia model. J Clin Invest
8Murray S, Schell K, McCarthy DO, et al. Tumor growth, weight loss and
cytokines in SCID mice. Cancer Lett 1997;111:111–15.
9Matthys P, Heremans H, Opdenakker G, et al. Anti-interferon-gamma
antibody treatment, growth of Lewis lung tumours in mice and tumour-
associated cachexia. Eur J Cancer 1991;27:182–7.
10 Strassmann G, Kambayashi T. Inhibition of experimental cancer cachexia by
anti-cytokine and anti-cytokine-receptor therapy. Cytokines Mol Ther
11 Tisdale MJ. Cancer anorexia and cachexia. Nutrition 2001;17:438–42.
12 Wigmore SJ, Todorov PT, Barber MD, et al. Characteristics of patients with
pancreatic cancer expressing a novel cancer cachectic factor. Br J Surg
13 Ramos EJ, Suzuki S, Marks D, et al. Cancer anorexia-cachexia syndrome:
cytokines and neuropeptides. Curr Opin Clin Nutr Metab Care
14 Inui A. Cancer anorexia-cachexia syndrome: are neuropeptides the key?
Cancer Res 1999;59:4493–501.
15 Sampaio EP, Sarno EN, Galilly R, et al. Thalidomide selectively inhibits tumor
necrosis factor alpha production by stimulated human monocytes. J Exp Med
16 Gordon JN, Goggin PM. Thalidomide and its derivatives: emerging from the
wilderness. Postgrad Med J 2003;79:127–32.
17 Kaplan G, Thomas S, Fierer DS, et al. Thalidomide for the treatment of AIDS-
associated wasting. AIDS Res Hum Retroviruses 2000;16:1345–55.
18 Tramontana JM, Utaipat U, Molloy A, et al. Thalidomide treatment reduces
tumor necrosis factor alpha production and enhances weight gain in patients
with pulmonary tuberculosis. Mol Med 1995;1:384–97.
19 Khan ZH, Simpson EJ, Cole AT, et al. Oesophageal cancer and cachexia: the
effect of short-term treatment with thalidomide on weight loss and lean body
mass. Aliment Pharmacol Ther 2003;17:677–82.
20 Heymsfield SB, McManus C, Smith J, et al. Anthropometric measurement of
muscle mass; revised equations for calculating bone-free arm muscle area.
Am J Clin Nutr 1982;36:680–90.
21 Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for
Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for
use in international clinical trials in oncology. J Natl Cancer Inst, 1993 Mar 3,
22 Fitzsimmons D, Johnson CD, George S, et al. Development of a disease
specific quality of life (QoL) questionnaire module to supplement the EORTC
core cancer QoL questionnaire, the QLQ-C30 in patients with pancreatic
cancer. EORTC Study Group on Quality of Life. Eur J Cancer
23 Powell RJ, Gardner-Medwin JM. Guideline for the clinical use and dispensing
of thalidomide. Postgrad Med J 1994;70:901–4.
24 Wigmore SJ, Plester CE, Richardson RA, et al. Changes in nutritional status
associated with unresectable pancreatic cancer. Br J Cancer 1997;75:106–9.
25 Barber MD, Ross JA, Voss AC, et al. The effect of an oral nutritional
supplement enriched with fish oil on weight-loss in patients with pancreatic
cancer. Br J Cancer 1999;81:80–6.
26 McMillan DC, Wigmore SJ, Fearon KCH, et al. A prospective randomized
study of megesterol acetate and ibuprofen in gastrointestinal cancer patients
with weight loss. Br J Cancer 1999;79:495–500.
27 Bennett CL, Schumock GT, Desai AA, et al. Thalidomide-associated deep vein
thrombosis and pulmonary embolism. Am J Med 2002;113:603–6.
28 Fearon KC, Von Meyenfeldt MF, Moses AG, et al. Effect of a protein and
energy dense N-3 fatty acid enriched oral supplement on loss of weight and
lean tissue in cancer cachexia: a randomised double blind trial. Gut
29 Kushner RF, Haas A. Estimation of lean body mass by bioelectrical impedance
analysis compared to skinfold anthropometry. Eur J Clin Nutr
30 Haslett P, Hempstead M, Seidman C, et al. The metabolic and
immunologic effects of short-term thalidomide treatment of patients infected
with the human immunodeficiency virus. AIDS Res Hum Retroviruses
31 Colucci G, Giuliani F, Gebbia V, et al. Gemcitabine alone or with cisplatin for
the treatment of patients with locally advanced and/or metastatic pancreatic
cancer: a prospective, randomized phase III study of the Gruppo Ocologia
dell’Italia Meridionale. Cancer, 2002 15, 94:902–10.
32 Berlin JD, Catalano P, Thomas JP, et al. Phase III study of gemcitabine in
combination with fluorouracil versus gemcitabine alone in patients with
advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial
E2297. J Clin Oncol 2002;20:3270–5.
33 Barber MD. Cancer cachexia and its treatment with fish-oil-enriched
nutritional supplementation. Nutrition 2001;17:751–5.
34 Jatoi A, Rowland KM, Loprinzi CL, et al. An eicosapentainoic acid (EPA)-
enriched supplement versus megestrol acetate (MA) versus both for patients
with cancer-associated wasting. A collaborative effort from the North Central
Cancer Treatment Group (NCCTG) and the National Cancer Institute of
Canada. Proc Am Soc Clin Oncol 2003;22:743.
35 May PE, Barber A, D’Olimpio JT, et al. Reversal of cancer-related wasting
using oral supplementation with a combination of beta-hydroxy-beta-
methylbutyrate, arginine, and glutamine. Am J Surg 2002;183:471–9.
36 Goldberg RM, Loprinzi CL, Mailliard JA, et al. Pentoxifylline for treatment of
cancer anorexia and cachexia?A randomized, double-blind, placebo-
controlled trial. J Clin Oncol 1995;13:2856–9.
37 Bauditz J, Haemling J, Ortner M, et al. Treatment with tumour necrosis factor
inhibitor oxpentifylline does not improve corticosteroid dependent chronic
active Crohn’s disease. Gut 1997;40:470–4.
38 Li YP, Reid MB. NF-kappaB mediates the protein loss induced by TNF-alpha in
differentiated skeletal muscle myotubes. Am J Physiol Regul Integr Comp
39 Whitehouse AS, Tisdale MJ. Increased expression of the ubiquitin-proteasome
pathway in murine myotubes by proteolysis-inducing factor (PIF) is associated
with activation of the transcription factor NF-kappaB. Br J Cancer
40 Keifer JA, Guttridge DC, Ashburner BP, et al. Inhibition of NF-kappa B activity
by thalidomide through suppression of IkappaB kinase activity. J Biol Chem
41 Jin SH, Kim TI, Hans DS, et al. Thalidomide suppresses the interleukin 1beta-
induced NFkappaB signaling pathway in colon cancer cells. Ann N Y Acad
42 Fujita J, Mestre JR, Zeldis JB, et al. Thalidomide and its analogues inhibit
lipopolysaccharide-mediated induction of cyclooxygenase-2. Clin Cancer Res
43 Bruera E, Strasser F, Palmer JL, et al. Effect of fish oil on appetite and other
symptoms in patients with advanced cancer and anorexia/cachexia: a
double-blind, placebo-controlled study. J Clin Oncol 2003;21:129–34.
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