JAMDA 15 (2014) 866e872

JAMDA
journal homepage: www.jamda.com

Review Article

Treatment of Cachexia: An Overview of Recent Developments

Stephan von Haehling MD, PhD a, b, *, Stefan D. Anker MD, PhD a
a
Division of Innovative Clinical Trials, Department of Cardiology and Pneumology, University Medical Centre Göttingen, Göttingen, Germany
b
Applied Cachexia Research, Department of Cardiology, Charité Medical School, Campus Virchow-Klinikum, Berlin, Germany

a b s t r a c t

Keywords: Body wasting in the context of chronic illness is associated with reduced quality of life and impaired
Cachexia survival. Recent clinical trials have investigated different approaches to improve patients’ skeletal muscle
cancer mass and strength, exercise capacity, and survival in the context of cachexia and body wasting, many of
wasting
them in patients with cancer. The aim of this article was to summarize clinical trials published over the
therapy
past 2 years. Therapeutic approaches discussed include appetite stimulants, such as megestrol acetate,
L-carnitine, or melatonin, anti-inflammatory drugs, such as thalidomide, pentoxyphylline, or a mono-
clonal antibody against interleukin-1a as well as ghrelin and the ghrelin agonist anamorelin; nutritional
support, and anabolics, such as enobosarm and testosterone.
Ó 2014 AMDA e The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. This
is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

Changes in body composition that occur with chronic diseases are development of sarcopenia can be associated with poor survival as
usually considered unwanted and are associated with loss of skeletal well. The 2 conditions have seen much attention in recent years: first,
muscle mass, fat mass, or both.1,2 The loss of lean and fat tissue may with regard to their definition4,6; second, with regard to their
in turn be associated with weight loss. Such involuntary weight loss pathophysiology12e14; and third, with regard to their treatment.15,16
has been termed cachexia. Much confusion exists with regard to the In fact, pathophysiological pathways of the 2 clinical entities can,
different terminology.3 A recent consensus definition suggests to but do not necessarily have to, overlap. For clinicians actively
diagnose cachexia when there is loss of more than 5% of body weight involved in the care of patients at risk of cachexia or muscle wasting
over 12 months or less in the presence of a chronic illness such as (ie, surgeons, oncologists, nephrologists, cardiologists, and many
heart failure, chronic obstructive pulmonary disease (COPD), chronic more), the available terms often create more confusion than help,
kidney disease, or cancer,4 altogether providing the basis for an making the diagnosis of cachexia and muscle wasting a rarity.17 This
estimated 9 million subjects being affected by cachexia in industri- is unfortunate, in particular because both require medical attention,
alized countries alone.5 The mere loss of skeletal muscle mass in the and treatment approaches are currently under way that will hope-
limbs that exceeds 2 SDs of the mean of a healthy young reference fully enable physicians to maintain their patients’ muscle mass and
population has been termed sarcopenia.6e8 Some researchers have body weight and therefore their ability to maintain activities of daily
suggested to restrict the use of the term sarcopenia to apparently living for longer than is currently possible. The aim of this article was
healthy elderly subjects who lose muscle mass as a consequence of to highlight clinical intervention trials that have been published over
the aging process. In the context of chronic illness, the terms muscle the past 2 years with the primary purpose of treating cachexia.
wasting, myopenia, or even muscle wasting disease have been used Studies that have shown beneficial results in animal experiments
or proposed.9,10 In contrast to cachexia, sarcopenia and muscle only using approaches such as myostatin blockade,18 use of green
wasting are not usually associated with weight loss, but with reduced tea,19 ursodeoxycholic acid,20 or inhibition of nuclear factor-kB21 are
exercise capacity and reduced quality of life.11 Although the devel- not discussed.
opment of cachexia is mostly associated with impaired survival, the
Appetite Stimulants

The authors declare no conflicts of interest. Loss of appetite appears in many patients with cancer, which is
Note: This article is also to be published in the International Journal of not only frequent, but also associated with poor prognosis and
Cardiology. reduced quality of life. The origin of appetite loss has been deemed
* Address correspondence to Stephan von Haehling, MD, PhD, Division of
Innovative Clinical Trials, Department of Cardiology and Pneumology, University
multifactorial, and a recent study failed to show a genetic association
Medicine Centre Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany. of appetite loss in patients with cancer.22 However, overexpression of
E-mail address: [email protected] (S. von Haehling). proinflammatory cytokines, such as interleukin (IL)-1, IL-6, tumor
http://dx.doi.org/10.1016/j.jamda.2014.09.007
1525-8610/Ó 2014 AMDA e The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/3.0/).
 S. von Haehling, S.D. Anker / JAMDA 15 (2014) 866e872 867

necrosis factor, or interferon-g, as well as macrophage inhibitory study were younger than 18 years of age and presented with weight
cytokine-1/growth differentiation factor 15 (MIC-1/GDF-15) appear to loss of 5% or more secondary to cancer and/or cancer treatment.
be involved.23,24 Activation of these factors has effects on peripheral Children on megestrol acetate experienced an average weight gain
(lipolysis, proteolysis, insulin resistance) as well as on central path- of þ19.7% compared with a mean weight loss of 1.2% in the placebo
ways (hypothalamic appetite regulation).23,25 Megestrol acetate, a group (P ¼ .003).32 All patients in the megestrol acetate group
synthetic, orally active derivative of the hormone progesterone, was developed at least one undetectable early morning serum cortisol
originally synthesized in 1963 as a contraceptive drug.26 Beginning in level during the study; this occurred only in 1 patient on placebo.
1967, it was used in the treatment of breast cancer. Beginning in 1993, Severe adrenal suppression was reported in 2 patients on megestrol
it was approved in the United States and in several European coun- acetate. Other adverse effects were not different between this and the
tries for the treatment of the anorexia-cachexia syndrome.26 It has placebo group.32
recently been argued that the use of megestrol acetate also may be Melatonin has been shown to improve appetite in animal exper-
helpful in patients with muscle wasting without weight loss.15 iments. 33 Del Fabbro et al 34 performed a randomized, placebo-
Wen et al27 recently studied 102 patients with cancer-related controlled trial in patients with advanced lung or gastrointestinal
anorexia/cachexia syndrome who were randomly assigned to cancer. Unfortunately, the trial was stopped early for futility. This
receive, for 8 weeks, either a combination therapy of oral megestrol result came as a surprise, because the dosage used in this trial, oral
acetate at a dosage of 160 mg twice daily plus oral thalidomide 50 mg melatonin 20 mg at night, was similar to that used in previous trials
twice daily or megestrol acetate 160 mg twice daily alone (all studies and is much higher than that used for conditions such as jet lag
discussed in the text are summarized in Table 1). Patients in either (typically 0.5e5.0 mg). A total of 73 patients were enrolled, but it was
group showed an increase in their appetite score (both P < .03). The stopped after 48 subjects had finished the study, because an interim
increase in body weight and the improvement in quality of life were analysis showed that the intervention was unlikely to be of significant
more pronounced in the group that received combination therapy benefit. In fact, none of the assessed end points improved: the Ed-
than in the group on megestrol acetate alone. Serum values of IL-6 monton Symptom Assessment Scale (ESAS), the Functional Assess-
and tumour necrosis factor decreased only in the combination ther- ment of Cancer Illness TherapyeFatigue (FACIT-F), or the Functional
apy group, just as handgrip strength was only improved in this Assessment of Anorexia/Cachexia Therapy (FAACT) scores. Also, there
group.27 Another small study28 used a combination therapy of oral was no change in body weight to suggest any benefit of melatonin
formoterol (80 mg/d) and megestrol acetate tablets (480 mg/d) for up over placebo (all P > .15).34
to 8 weeks in 13 patients with advanced malignancy and involuntary
weight loss. Six of 7 patients who completed the study showed an Inflammation
improvement in muscle size and muscle function as assessed using
quadriceps strength and magnetic resonance imaging. In fact, quad- Inflammatory processes have been shown to maintain the
riceps volume increased significantly (P < .02); in addition, there was wasting process in cachexia. Hong et al35 used a novel approach to
a trend toward an increase in the patients’ quadriceps and handgrip target inflammation and its consequences in patients with advanced
strength.28 cancer. For this purpose, they designed a dose-escalation and
Just as with thalidomide, several workers have tried to enhance expansion approach using a first-in-class monoclonal antibody
the effects of megestrol acetate on appetite using different ap- (MABp1) cloned from a human being that targets IL-1a. The first,
proaches. L-carnitine, for example, plays a central role in fatty acid dose-escalation part of the study identified an optimal intravenous
metabolism and possesses antioxidant and anti-inflammatory prop- dose of 3.75 mg/kg every 2 weeks. Using this dose, the following
erties.29 Madeddu et al30 randomized 60 patients with advanced phase II study was performed. In the 42 patients in this open-label,
cancer at any site and weight loss of at least 5% to receive either L- uncontrolled study, median plasma IL-6 concentrations decreased
carnitine 4 g per day plus celecoxib 300 mg per day or the same from baseline to week 8 (P ¼ .08). Of the 34 patients who were re-
regimen plus megestrol acetate 320 mg per day. After 4 months of staged, 1 patient had a partial response and 10 had stable disease.
treatment, no significant difference was noted between the 2 treat- Among 30 patients with an assessment of body composition, lean
ments with regard to an increase in lean body mass, total daily mass increased significantly by 1.02
2.24 kg (P ¼ .02). Overall, the
physical activity, handgrip strength, or 6-minute walk distance. drug was well tolerated.35
However, when the 2 arms were analyzed separately, significant in- Two recent interventional studies used thalidomide to treat
creases were noted in each arm for lean body mass (by about 2.5 kg, cachexia. Unfortunately, thalidomide is a drug associated with trag-
both P < .04) and 6-minute walk distance (approximately 50 m, both edy, because a single dose can induce malformation of the unborn in
P < .04). No change was noted for physical activity or grip strength. pregnant women.36 Despite these effects, it has been rediscovered for
Resting energy expenditure decreased significantly in both groups. its anti-inflammatory properties, and reports dating back more than
Body weight was increased in the group that received megestrol 20 years have demonstrated successful treatment of erythema no-
acetate only (from 54.7
10.8 to 57.2
11.8 kg, P ¼ .05). dosum leprosum.37 Yennurajalingam et al38 studied 31 patients with
L-carnitine on its own also has been successfully used in 72 pa- advanced cancer with weight loss of more than 5% in the previous
tients with advanced pancreatic cancer as part of a prospective, 6 months who also reported anorexia and fatigue. Patients were, in a
multicenter, placebo-controlled, randomized, and double-blinded double-blinded fashion, randomized to receive 100 mg thalidomide
trial.31 Patients received oral L-carnitine at a dose of 4 g or placebo. daily (n ¼ 15) or placebo for a comparatively short duration of
At study entry, patients reported a mean weight loss of 12.0
2.5 kg. 14 days. Only 21 patients completed the study. Statistically significant
During 12 weeks of treatment, body mass index increased by decreases were noted for fat mass (median: e1.5 kg, P ¼ .03) and fat-
3.4%
1.4% under L-carnitine and decreased by 1.5%
1.4% in con- free mass (e4.8 kg, P ¼ .024) after 14 days of treatment with
trols (P < .05). Likewise, body fat and body cell mass increased in the thalidomide. Some changes with regard to cytokine levels were noted
L-carnitine group only. as well; however, no effect was noted for the ESAS, FAACT, the FACIT-
The appetite stimulant megestrol acetate also has been success- F, the Hospital Anxiety Depression Scale, or the Pittsburgh Sleep
fully used in children. Cuvelier et al32 randomized, in a double-blind Quality Index. Another small phase II trial was conducted by Davis
fashion, 26 children to receive an oral suspension of megestrol ace- et al39 using 50 mg of thalidomide administered orally at bedtime;
tate (7.5 mg/kg/d) or placebo for 90 days. Patients enrolled into the however, this trial was uncontrolled and unblinded. Nonresponders
Table 1
868
Cachexia Intervention Trials Published Between 2012 and 2014

Reference Study Design Disease No. of Patients* Duration Intervention Groups Main Results
Appetite stimulation
Wen et al 201227 Single-center, randomized, controlled, Cancer with loss of 5% 102 (93) 8 wk (1) Megestrol acetate 160 mg twice Increases in body weight, quality of life,
open-label of body weight daily po plus thalidomide 50 mg appetite, and grip strength.
twice daily po
(2) Megestrol acetate 160 mg twice Increases in body weight and appetite.
daily po
28
Greig et al 2014 Single-center, nonrandomized, Cancer 13 (7) 8 wk Formoterol 80 mg/d po plus megestrol Six responders with an increase in
uncontrolled, open-label acetate 480 mg/d po quadriceps volume; trend for
increases in quadriceps and hand grip
strength.
Maddedu et al 201230 Single-center, randomized, controlled, Cancer with weight loss of 5% 60 4 mo (1) L-carnitine 4 g/d po plus celecoxib Increases in lean body mass and
open-label 300 mg/d po 6-minute walk distance. No
(2) L-carnitine 4 g/d po plus celecoxib significant difference between
300 mg/d po plus megestrol acetate the 2 groups.
320 mg/d po
Kraft et al 201231 Multicenter, randomized, placebo- Advanced pancreatic cancer 72 (26) 12 wk (1) L-carnitine 4 g/d po Weight gain due to increases in body
controlled, double-blind cell mass and body fat.
(2) Placebo No effect.
Cuvelier et al 201432 Single-center, randomized, placebo- Cancer with weight loss 5% 26 children 90 d (1) Megestrol acetate suspension Increases in body weight, body mass
controlled, double-blind 7.5 mg/kg/d po index, and mid upper arm
circumference.
(2) Placebo Weight loss.
Del Fabbro et al 201334 Single-center, randomized, placebo- Cancer with weight loss 5% 73 (48) 28 d (1) Melatonin 20 mg at bedtime po Terminated early for futility.
controlled, double-blind (2) Placebo
Inflammation
Hong et al 201435 Single-center, non-randomized, Cancer 52 (42) 8 wk Monoclonal anti-interleukin-1a Decrease in serum interleukin-6,
uncontrolled, open-label antibody (MABp1) 3.75 mg/kg IV increase lean body mass, partial
response in 1 of 34, stable disease in
10 of 34 patients.
Yennurajalingam Single-center, randomized, placebo- Cancer with weight loss 5% 31 (21) 14 d (1) Thalidomide 100 mg/d po Decrease and fat mass and fat-free
et al 201238 controlled, double-blind mass.
(2) Placebo No effect.
Davis et al 201239 Single-center, nonrandomized, Cancer 35 (33) 14 d Thalidomide 50 mg po at bedtime, Improvments in appetite, insomnia, and
uncontrolled, open-label uptitrated to 100 or 200 mg po at quality of life.
bedtime in nonresponders
S. von Haehling, S.D. Anker / JAMDA 15 (2014) 866e872

Rattanasompattikul Single-center, randomized, placebo- Maintenance dialysis with 93 (74) 16 wk (1) One can of nutritional support plus 1 Significant increases in serum albumin
et al 201341 controlled, double-blind hypoalbuminemia can of anti-inflammatory, levels.
antioxidant nutrition plus
pentoxyphylline 400 mg 3 times
weekly po
(2) One can of nutritional support plus 1
can of anti-inflammatory,
antioxidant nutrition plus placebo
(3) Two cans of nutritional placebo plus
pentoxyphylline 400 mg 3 times
weekly po
(4) Two cans of nutritional placebo plus No change.
placebo tablet
Ghrelin
Miki et al 201261 Multicenter, randomized, placebo- COPD and cachexia 33 3 wk (1) Ghrelin 2 mg/kg IV twice daily Increase in 6-minute walk distance
controlled, double-blind after 7 wk.
(2) Placebo No effect after 7 wk.
Temel et al 201362 Multicenter, randomized, placebo- Cancer 226 12 wk (1) Anamorelin 50 mg/d po Weight loss.
controlled, double-blind (2) Anamorelin 100 mg/d po Weight gain.
(3) Placebo Weight loss.
 S. von Haehling, S.D. Anker / JAMDA 15 (2014) 866e872 869

with regard to appetite were uptitrated every 2 weeks to 100 mg,

No significant effect on quality of life.

then to 200 mg once daily. Of 33 patients with active cancer and loss
Increase in total lean mass and stair

Increase in lean and fat mass and in

Weight gain, increase in appetite.

of appetite as assessed using a numerical rating scale, 64% showed

Increase in hand grip strength.

improved appetite. In addition, patients’ insomnia and quality of life
Increase in lean body mass.

categorical scale values increased significantly.

Wasting plays a major role not only in patients with cancer, but

hand grip strength.

also in patients with chronic kidney disease.40 Rattanasompattikul
et al41 randomized 93 patients on maintenance dialysis in a double-
climb power.

blind fashion to 1 of 4 groups, receiving either (1) 1 can of nutri-

Weight loss.

No effect.

No effect.

No effect.
tional support and 1 can of an anti-inflammatory, antioxidant
nutrition along with 1 tablet of pentoxyphylline (400 mg, 3 times
weekly), which is known to possess anti-inflammatory properties as
well; (2) 2 cans of active nutrition as described before plus a placebo
tablet; (3) 2 cans of nutritional placebo plus a pentoxyphylline tablet;
(1) Espindolol 2.5 mg twice daily po
(2) Espindolol 10 mg twice daily po
Injection of testosterone 150 or

(4) 2 cans of nutritional placebo plus 1 placebo tablet. At inclusion, all

patients had been hypoalbuminemic for at least the previous
(1) Anamorelin 50 mg/d po

3 months, defined as serum albumin values lower than 4 g/dL. After

200 mg every 14 d IM
Enobosarm 1 mg/d po
Enobosarm 3 mg/d po

Enobosarm 3 mg/d po

16 weeks of treatment, significant increases in serum albumin were

found after all 3 interventions, but not in the placebo group. None of
the groups showed a significant decline in the inflammatory markers
C-reactive protein, IL-1b, or IL-6.41
(2) Placebo

Placebo

Placebo

(2) Placebo

(3) Placebo

Ghrelin
(1)
(2)
(3)
(1)
(2)
(1)

Ghrelin is a 28-amino acid peptide hormone mostly produced in

Up to 113 d

the stomach, but also in other gastrointestinal tissues.11,42 It induces

16 wk

the release of growth hormone from the pituitary gland and stimu-
5 mo

4 wk
3d

lates food intake.43,44 Ghrelin also inhibits the production of the

proinflammatory cytokines IL-1a, IL-6, and tumor necrosis factor, but
induces the anti-inflammatory cytokine IL-10.45 Overall, the meta-
bolic changes induced by ghrelin lead to an increase in body weight
159 (100)

and body fat mass, but also in lean tissue mass, the latter possibly
641

mediated by a reduction in myostatin plasma levels. Even though

16

29

87

gender-specific differences have been reported in men and

women,46,47 overall ghrelin plasma levels have been shown to be
decreased in obesity and elevated in cachexia. In addition, ghrelin has
been suggested to link nutrition and reproduction, because animal
Cancer with weight

Cancer with weight

experiments have shown that ghrelin administration leads to inhib-

*Number of patients enrolled and, in parentheses, number of patients in final analysis.

itory responses in the secretion of luteinizing hormone and testos-

terone, thus potentially contributing to hypogonadism.48
loss 2%

loss 5%

Ghrelin administration has therapeutic appeal for its anabolic

Cancer

Cancer

Cancer

activities,49 and ghrelin plasma levels have been assessed in several

observational studies of cachexia in chronic diseases.50e52 Ghrelin
agonists, such as anamorelin, carry potential in the treatment of
cachexia as they mimic a natural ligand for the growth hormone
Single-center, randomized, placebo-
Multicenter, randomized, placebo-

Multicenter, randomized, placebo-

Multicenter, randomized, placebo-

Multicenter, randomized, placebo-

secretagogue receptor and thus stimulate food intake and appetite.53

Starting in 2004, a small number of interventional studies have used
oral, intravenous, or subcutaneous ghrelin administration45 for the
controlled, double-blind

controlled, double-blind

controlled, double-blind

controlled, double-blind

controlled, double-blind

treatment of wasting in chronic heart failure,54 COPD,55 cancer,56e58

or end-stage renal disease.59,60 The most recent additions to the
ghrelin intervention portfolio have been performed in COPD and
IM, intramuscular; IV, intravenous; po, per os.

cancer. Miki et al61 performed a multicenter, randomized, double-

blind, controlled trial including 33 cachectic patients with COPD
who were randomly assigned to receive placebo or intravenous
Enobosarm and other anabolics

ghrelin at a dose of 2 mg/kg of body weight twice daily for 3 weeks.

Patients on ghrelin treatment displayed an increase in their 6-minute
76

walking distance after 3 weeks (placebo [m
SE]: þ35
12 m vs

Crawford et al 201475

Del Fabbro et al 2013

ghrelin: þ40
17 m, both P < .05 vs baseline) that was maintained

Garcia et al 201364

Dobs et al 201374

out to 7 weeks (placebo: þ47
17 m [P < .05 vs baseline] vs

et al 201480
Stewart Coats

ghrelin: þ18
11 m). No change was noted in the patients’ peak

oxygen consumption value. Unfortunately, the beneficial findings on
patients’ 6-minute walk distance could not be pathophysiologically
explained, as there were no changes noted in body weight, total lean
mass, serum IL-6, tumor necrosis factor, or hand grip strength.
870 S. von Haehling, S.D. Anker / JAMDA 15 (2014) 866e872

More promising results were obtained in a clinical trial in 226 consisting of either enobosarm or placebo for 5 months. The study’s
patients with stage 3 or 4 nonesmall cell lung cancer who received coprimary end points, as assessed after 84 days of treatment, were
anamorelin in an international, randomized, double-blind, 12-week physical function response assessed by stair-climb power and
phase II study.62 Patients were randomized to placebo (n ¼ 76) or lean body mass as measured by DEXA. Compared with placebo,
oral anamorelin 50 mg (n ¼ 76) or 100 mg (n ¼ 73) per day. A enobosarm treatment was associated with an increase in the stair-
beneficial effect on body weight was observed as early as 1 week climb power and the lean body mass in the platinum plus taxane
after anamorelin treatment initiation. Over 12 weeks, the group treatment arm, whereas in the platinum plus nontaxane arm,
that received 100 mg anamorelin gained on average 0.14 kg there was only a significant increase in the patients’ lean body mass
compared with baseline, whereas mean losses of 0.3 kg and 1.32 kg (all P < .02).
occurred in the 50-mg and placebo group (P ¼ .0005). No effect was Using intramuscular testosterone replacement, Del Fabbro et al76
noted on hand-grip strength or survival. The larger ROMANA 2 performed a randomized, double-blind, placebo-controlled trial
phase III trial that included 495 patients with nonesmall cell lung in 29 patients with advanced cancer, low bioavailable testosterone,
cancer was recently finished, but results have not been reported so and a fatigue score higher than 3 of 10 on the ESAS. Unfortunately,
far.63 Garcia et al64 performed a multicenter, double-blind, placebo- 4 weeks of treatment did not change patients’ FACIT score values
controlled crossover trial that evaluated the effects of anamorelin in the testosterone group (n ¼ 13, administered every 2 weeks)
in 16 cachectic patients with different cancers. Patients were as compared with the placebo group (n ¼ 16). Improvements
randomly assigned to receive oral anamorelin at a dosage of 50 mg were noted in the testosterone group with regard to the Sexual
per day or placebo for 3 days. Compared with placebo, treatment Desire Inventory score (P ¼ .05) and the patients’ performance
with anamorelin induced significant increases in body weight status (P ¼ .02). The authors therefore concluded that “four weeks
(placebo: e0.33 kg vs anamorelin: þ 0.77 kg, P ¼ .02), appetite of intramuscular testosterone replacement in hypogonadal male
(P < .02), and serum levels of growth hormone and insulin-like patients with advanced cancer did not significantly improve quality
growth factor-1. of life.”76
Another novel anabolic agent has recently been tested in a ran-
domized, double-blind, controlled trial. MT-102, also known as
Enobosarm and Other Anabolics
espindolol, is a novel anabolic/catabolic transforming agent that ap-
pears to possess 3 potential pharmacological targets in cancer
Anabolic steroids have been effectively used to treat muscle
cachexia: (1) reduced catabolism through nonselective b-blockade,
wasting65,66; for example, in chronic heart failure where almost 20%
(2) reduced fatigue and thermogenesis through central 5-HT1a
of patients are affected by this problem.67 In patients with heart
antagonism, and (3) increased anabolism through partial b-2 receptor
failure, low levels of circulating anabolic hormones are associated
agonism.77 Animal experiments in 19-month-old male Wistar Han
with poor outcomes.68,69 The problem with the administration of
rats have shown that espindolol can abolish the effects of aging-
anabolic steroids is that their risks often outweigh their potential
associated body and muscle wasting.78 Indeed, although placebo-
benefits. Selective androgen receptor modulators (SARMs) belong to a
treated animals progressively lost body weight, lean and fat mass,
relatively new class of therapeutics currently under development that
espindolol-treated animals showed increases in all these parameters
possesses anabolic properties without adverse effects on prostate,
without affecting cardiac function. Key regulators of muscle catabo-
skin, or hair, frequently associated with testosterone treatment.70,71
lism showed reduced expression under espindolol treatment.
Enobosarm, an orally bioavailable nonsteroidal SARM with tissue-
Another animal study showed that the beneficial effects of espindolol
specific anabolic and androgenic activity, has shown improvements
on wasting were more pronounced than those of other beta-
in lean mass and physical function in healthy younger as well as in
blockers.79 The ACT-ONE trial was designed to test whether MT-102
healthy elderly men and postmenopausal women.72 The latter study
(espindolol) will positively impact the rate of change of body
was published in 2011, highlighting a large unmet clinical need.1
weight in cancer cachexia. The trial’s preliminary results were
Recently, collagen VI fragment has been suggested as a marker of
recently published in abstract form.80,81 It enrolled a total of 87 pa-
anabolic response that could be useful in patients treated with
tients with nonesmall cell lung cancer or colorectal cancer from 17
SARMs.73
centers who were in stage 3 or 4 of the disease. Patients were ran-
Dobs et al74 conducted a randomized, double-blind, placebo-
domized in a 3:1:2 fashion to 1 of 2 doses of espindolol (10.0 or
controlled phase II trial to assess the efficacy and safety of enobosarm
2.5 mg twice daily) or placebo and treated for 16 weeks. Only the
in 159 male and postmenopausal female patients with cancer who
higher dose of espindolol improved lean and fat mass. Hand grip
had lost at least 2% of body weight in the 6 months before random-
strength increased significantly after 16 weeks in the low-dose and
ization. Patients were randomized to receive oral enobosarm at a
high-dose treatment groups, but stair climbing power and 6-minute
dosage of 1 (n ¼ 53) or 3 mg (n ¼ 54) or placebo (n ¼ 52) once daily
walking distance did not.
for up to 113 days at centers in the United States or Argentina. The
primary end point was defined as the change in total lean body mass
from baseline as assessed by dual-energy X-ray absorptiometry Conclusions
(DEXA). After study termination, significant increases in total lean
mass were noted in both enobosarm groups (enobosarm 1 mg: me- Muscle wasting and cachexia remain great challenges in clinical
dian 1.5 kg, range e2.1 to 12.6, P ¼ .001 vs baseline, enobosarm 3 mg: practice. Clinical trials in this field remain small, and most are
1.0 kg, e4.8 to 11.5, P ¼ .046). The study drug was well tolerated. undertaken in oncology patients. Much research has focused on
POWER (Prevention and treatment Of muscle Wasting in patients appetite stimulation (mostly using megestrol acetate), anti-
with cancER) was a double-blind, randomized, placebo-controlled inflammatory pathways, and anabolics. Ghrelin has shown some
phase III trial of enobosarm 3 mg once daily that aimed to assess potential in clinical trials as has enobosarm. Results of the POWER
lean body mass and physical function after treatment. Preliminary trial with enobosarm, one of the few large-scale trials to improve
results were recently presented in abstract form.75 A total of 641 muscle mass and function in patients with advanced cancer, are
patients with stage 3 or 4 nonesmall cell lung cancer were ran- eagerly awaited. In addition, results of the ACT-ONE trial using
domized into 1 of 2 trials at initiation of first-line chemotherapy the anabolic/catabolic transforming agent espindolol have shown
(platinum plus taxane or platinum plus nontaxane) plus add-on, promising results.
 S. von Haehling, S.D. Anker / JAMDA 15 (2014) 866e872 871

Acknowledgments 30. Madeddu C, Dessì M, Panzone F, et al. Randomized phase III clinical trial of a
combined treatment with carnitine þ celecoxib
megestrol acetate for pa-
tients with cancer-related anorexia/cachexia syndrome. Clin Nutr 2012;31:
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