Review Article

Treatment of Cachexia in Oncology

EM Tazi, H Errihani
Department of Medical Oncology, National Institute of Oncology, Rabat, Morocco

Address for correspondence: Dr. Elmehdi Tazi; E-mail: [email protected]

ABSTRACT

Cachexia is a complex metabolic syndrome associated with many chronic or end-stage diseases, especially
cancer, and is characterized by loss of muscle with or without loss of fat mass. The management of cachexia
is a complex challenge that should address the different causes underlying this clinical event with an
integrated or multimodal treatment approach targeting the different factors involved in its pathophysiology.
The purpose of this article was to review the current medical treatment of cancer-related cachexia, in
particular focusing on combination therapy and ongoing research. Among the treatments proposed in the
literature for cancer-related cachexia, some proved to be ineffective, namely, cyproheptadine, hydrazine,
metoclopramide, and pentoxifylline. Among effective treatments, progestagens are currently considered
the best available treatment option for cancer-related cachexia, and they are the only drugs approved
in Europe. Drugs with a strong rationale that have failed or have not shown univocal results in clinical
trials so far include eicosapentaenoic acid, cannabinoids, bortezomib, and anti-TNF-alpha MoAb. Several
emerging drugs have shown promising results but are still under clinical investigation (thalidomide, selective
cox-2 inhibitors, ghrelin mimetics, insulin, oxandrolone, and olanzapine). To date, despite several years
of coordinated efforts in basic and clinical research, practice guidelines for the prevention and treatment
of cancer-related muscle wasting are lacking, mainly because of the multifactorial pathogenesis of the
syndrome. From all the data presented, one can speculate that one single therapy may not be completely
successful in the treatment of cachexia. From this point of view, treatments involving different combinations
are more likely to be successful.

Key words: Cachexia, Oncology, Treatment

INTRODUCTION loss in adults (corrected for fluid retention). Anorexia,

inflammation, insulin resistance, and increased muscle
Cachexia is a complex metabolic syndrome associated protein breakdown are frequently associated with
with underlying illness and characterized by loss of cachexia. Cachexia is distinct from starvation, age-related
muscle with or without loss of fat mass. Cachexia can loss of muscle mass, primary depression, malabsorption,
occur as part of many chronic or end-stage diseases and hyperthyroidism, and is associated with increased
such as infections, cancer, AIDS, congestive heart morbidity.[1] Cachexia defines a distinct clinical syndrome
failure, chronic renal failure, rheumatoid arthritis, where the activation of proinflammatory cytokines has
tuberculosis, and chronic obstructive pulmonary disease. a direct effect on muscle metabolism and anorexia. [2]
The prominent clinical feature of cachexia is weight Multiple mechanisms appear to be involved in the
development of cachexia, including anorexia, decreased
Access this article online physical activity, decreased secretion of host anabolic
Quick Response Code: hormones, and altered host metabolic response with
Website:
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abnormalities in protein, lipid, and carbohydrate
metabolism. Basically, cachexia is dependent from
DOI: cytokine-driven dysregulation of the peripheral signals
10.4103/0973-1075.73644 (mainly leptin, ghrelin, and serotonin), reaching the
brain hypothalamic region, which plays a central role
Indian Journal of Palliative Care / Sep-Dec 2010 / Vol-16 / Issue-3 129
 Tazi and Errihani: Treatment of cachexia - An update

in balancing the orexigenic and anorexigenic signals, action of progestagens in CACS has not been completely
leading to decreased food intake and increased resting elucidated. It may be related to glucocorticoid activity,
energy expenditure (REE). Indeed, an increased REE making these drugs similar to corticosteroids. Moreover,
may contribute to the loss of body weight in cachectic there is evidence that progestagens may stimulate appetite
patients and may explain the increased oxidation of fat by inducing the release of neuropeptide Y in the CNS
tissue. Futile energy-consuming cycles, such as the Cori (ventromedial hypothalamus). Furthermore, they act, at
cycle, may also play a role in the increased energy demand. least in part, by downregulating the synthesis and release of
Unlike starvation, body weight loss in cachectic patients proinflammatory cytokines.[7] Historically, Mantovani and al
arises mainly from loss of muscle mass, characterized by study,[8] including only a small number of patients, has been
increased catabolism of skeletal muscle and decreased one of the first to demonstrate the clinical effectiveness
protein synthesis. of MA and correlate it to the downregulation and reduced
release of proinflammatory cytokines. Eleven male patients
Management of cancer cachexia with head and neck cancer in advanced stage were enrolled
in the study and received MA at a dose of 320 mg/day
The best management of cancer cachexia is to cure the for two months during the interval of chemotherapy
cancer as this will completely reverse the cachexia syndrome. treatment. Weight and appetite increased significantly, and
Unfortunately, this remains an infrequent achievement in the Spitzer’s quality of life improved significantly, whereas
adults with advanced solid tumors. A second option could proinflammatory cytokines levels decreased significantly.
be to counteract weight loss by increasing nutritional intake,
but since in the majority of cachectic patients, anorexia in In a subsequent in vitro study,[9] they showed that MPA
only a part of the problem, nutrition as a unimodal therapy was also able to reduce the production of cytokine and
was not completely able to reverse the wasting associated to serotonin by PBMC of advanced stage cancer patients.
cachexia. Indeed, a large number of randomized controlled Among progestagens, megestrol has been the drug most
trials of nutritional intervention did not show a significant widely studied for its effect on CAC, with eight randomized,
benefit with regard to weight change or quality of life. These double-blind, placebo-controlled trials compared with
results have led to attempts to manipulate the process of medroxyprogesterone (two placebo-controlled studies).[7]
cachexia with a variety of pharmacological agents, with the
main purpose of providing symptomatic improvement. Table 1: Currently available different
To date, however, despite several years of coordinated therapeutic approaches, emerging drugs, and
efforts in basic and clinical research, practice guidelines future trends for the treatment of cancer-related
for the prevention and treatment of cancer-related muscle anorexia–cachexia syndrome
wasting are lacking, mainly because of the multifactorial Level of evidence

pathogenesis of the syndrome.[3] Drugs commonly used

Progestagens: megestrol acetate/Medroxyprogesterone acetate 1

Table 1 summarizes the currently available different Corticosteroids 1

Drugs with a strong rationale that failed or did not show
therapeutic approaches, emerging drugs, and future trends univocal results in clinical trials
for the treatment of Cancer-Related Anorexia–Cachexia Omega-3 fatty acids—EPA 1
Syndrome (CACS). Cannabinoids (dronabinol) 1
Bortezomib 3
Effective treatments Emerging drugs with some effective results but still under
clinical evaluation

Progestagens Thalidomide 2
Ghrelin 2
Progestagens, that is, Medroxyprogesterone Acetate (MPA) COX-2 inhibitors 2
and Megestrol Acetate (MA) are currently considered the Insulin 2
best available treatment option for CACS, and they are BCAA NA
approved in Europe for treatment of cancer- and AIDS- Oxandrolone 2
related cachexia. However, progestational agents are Future trends
nonetheless limited in their ability to treat cancer cachexia. Melanocortin antagonists NA
Fewer than 30% of patients treated with MA experience β2 agonists (formoterol) NA
short-term appetite stimulation,[4] and although weight and Anti-myostatin peptibody NA

appetite improve, there is no demonstrated improvement in Anti-IL-6 NA

quality of life or survival.[5,6] The proposed mechanism of SARMs NA

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 Tazi and Errihani: Treatment of cachexia - An update

Simons et al., carried out a randomized placebo-controlled although for long-term use, corticosteroids have more
study[10] to investigate the effects of MPA on food intake, side effects:[5] protein breakdown, insulin resistance, water
body composition, and REE on 54 patients with non- retention, and adrenal suppression are the most serious
hormone-sensitive cancer. Patients received either MPA, adverse effects of corticosteroid long-term treatment.
500 mg, or placebo twice daily for 12 weeks. Compared Therefore, corticosteroids are not suitable for long-term use
with placebo, 12 weeks of MPA led to an increase in energy and should be used during the pre-terminal phase of cachexia.
intake that was significantly associated with an increase in
fat mass. Fat-free mass was not significantly influenced and Drugs with a strong rationale that have failed or have
REE increased in the MPA arm. Berenstein and Ortiz[11] not shown univocal results in clinical trials so far
undertook a literature review to evaluate the efficacy,
effectiveness, and safety of MA in palliating anorexia– Drugs able to inhibit the synthesis and/or release of
cachexia syndrome in patients with cancer, AIDS, and cytokines (i.e. eicosapentaenoic acid (EPA), melatonin,
other underlying pathologies. Thirty trials were included etc.), the cytokine action (i.e. anti-cytokine antibodies,
in the original review, four new trials were identified anti-inflammatory cytokines interleukin (IL)-12, and IL-
for this update, but only two met the inclusion criteria 15), and drugs able to inhibit the proteasome activity (i.e.
(4123 + 703 patients). Twenty-two trials compared MA bortezomib) have been tested in experimental models
at different doses with placebo, five compared different of cachexia, with some positive results. Unfortunately,
doses of MA versus other drugs, two compared MA with most clinical trials in humans have provided limited or
other drugs and placebo, and five compared different doses disappointing results. N-3 fatty acids, especially EPA,
of MA. For all patient conditions, meta-analysis showed may have anticachectic properties. The first study by
a benefit of MA compared with placebo, particularly Fearon[15] suggests that if taken in sufficient quantity,
with regard to appetite improvement and weight gain only the omega-3 fatty acid enriched energy and protein
in cancer patients. Analyzing quality of life, clinical and dense supplement results in net gain of weight, lean
statistical heterogeneity was found and discussed. There tissue, and improved quality of life. Later, a study by Jatoi
was insufficient information to define the optimal dose et al.,[16] comparing EPA supplement versus MA versus
of MA. In summary, this review demonstrates that MA both in cachectic cancer patients showed that the EPA
improves appetite and weight gain in patients with cancer supplement either alone or in combination with MA does
while no overall conclusion about quality of life could be not improve weight or appetite more than MA alone.
drawn due to heterogeneity. Femia et al.,[12] carried out a A third study, carried out by Fearon,[17] compared EPA
study to assess whether MA delivered by nanoscrystal oral diethyl ester with placebo in cachectic cancer patients.
suspension could have the potential to improve outcomes The results of the trial indicated no statistically significant
in cachexia. MA nanocrystal oral suspension was designed benefit from single agent EPA in the treatment of cancer
to optimize drug delivery and improve bioavailability, cachexia. The Cochrane meta-analysis published in 2007[18]
enhancing the performance of drugs with poor water concluded that there were insufficient data to establish
solubility. It was shown that by rapidly increasing plasma whether oral EPA was better than placebo. Furthermore,
MA concentrations, this formulation could have the comparisons of EPA combined with a protein energy
potential to produce a more rapid clinical response. It supplementation versus a protein energy supplementation
was approved by FDA for the treatment of AIDS-related (without EPA) in the presence of an appetite stimulant
cachexia, and it is currently under evaluation for approval (Megestrol Acetate) provided no evidence that EPA
in cancer cachexia. Comprehensively, progestagens have improves symptoms associated with the cachexia syndrome
shown to be effective as regards body weight increase often seen in patients with advanced cancer. Among the
(mainly water and fat mass) and improvement of cenestesis potentially effective approaches against CACS, there are
and quality of life, but have not proved to be effective in cannabinoids but unfortunately two different randomized
increasing lean body mass (LBM), which is a critical target studies carried out by Jatoi et al.,[6] and Strasser et al.,[19]
in the treatment of cancer cachexia. Moreover, no benefit have failed to show better results as compared to MA or
on oxidative stress (OS) has been reported. placebo, respectively. Bortezomib, an NF-kB and ubiquitin-
proteasome inhibitor, although potentially promising, in
Corticosteroids preliminary results published by Jatoi[20] showed negligible
Among orexigenic agents, corticosteroids are widely used. favorable effects on cancer-associated weight loss in
In randomized controlled studies, they have been shown patients with metastatic pancreatic cancer. The authors
to improve appetite and quality of life compared with concluded that further study of bortezomib specifically
placebo.[13,14] MA and corticosteroids seem equally effective, in this setting and for this indication were not warranted.
Indian Journal of Palliative Care / Sep-Dec 2010 / Vol-16 / Issue-3 131
 Tazi and Errihani: Treatment of cachexia - An update

The approach with an anti-TNF-alpha MoAb (infliximab) functional capacity in patients with cardiopulmonary-
was shown to be ineffective. Indeed, the clinical study associated cachexia and to improve energy intake in anorexic
carried out by Wiedenmann et al.,[21] showed that the cancer patients. Based on the animal studies and short-term
addition of infliximab to gemcitabine to treat cachexia in human trials, there appears to be much promise for further
advanced pancreatic cancer patients was not associated studies to investigate the use of ghrelin and GHS-R agonists
with statistically significant differences in safety or efficacy for the treatment of cachexia caused by multiple underlying
when compared to placebo. conditions. Significant questions remain to be answered,
however, before its widespread use, most prominently
Emerging drugs with some effective results but still whether the gains produced by GHS R agonists maintain
under clinical evaluation safety and efficacy with long-term use in human diseases.
Clearly, more long-term research is needed.[24]
Thalidomide
Thalidomide has multiple immunomodulatory and Emergence of ghrelin as a treatment for cachexia
antiinflammatory properties; its inhibitory effect on syndrome
TNF-α and IL-6 production may be responsible for its Administration of ghrelin to humans with cachexia has
apparent anticachectic activity. Thus, thalidomide has shown no univocal efficacy in increasing food intake with
been used for treatment of cachexia associated with single dose intravenous administration.[25,26] In a study
acquired immunodeficiency syndrome, tuberculosis, and carried out by Strasser et al.,[25] 21 adult patients were
cancer. In the current literature, there are few studies randomized to receive ghrelin on days 1 and 8 and placebo
that have assessed the anabolic effects of thalidomide in on days 4 and 11 or vice versa, given intravenously over a
gastrointestinal cancer cachexia. Gordon et al.,[22] undertook 60-min period before lunch: 10 received 2 mg kg/1 (lower
a randomized placebo-controlled study to assess the safety dose) ghrelin and 11 received 8 mg kg/1 (upper-dose)
and efficacy of thalidomide in attenuating weight loss in ghrelin. Nutritional intake and eating-related symptoms,
patients with cachexia secondary to advanced pancreatic measured to explore preliminary efficacy, did not differ
cancer and concluded that thalidomide was well tolerated between ghrelin and placebo. Ghrelin is well tolerated and
but it was only able to attenuate loss of weight and LBM in safe in patients with advanced cancer. For safety, tolerance,
patients with cachexia due to advanced pancreatic cancer. and patient preference for treatment, no difference was
observed between the lower and upper-dose group.
Selective COX-2 inhibitors
Neary et al.,[26] carried out an acute, randomized, placebo-
Research on experimental animal models has shown
controlled, cross-over clinical trial to determine whether
that non-steroidal anti-inflammatory drugs, including
ghrelin (5 pmol/kg/min for 180 min i.c.) stimulates appetite
cyclooxygenase-2 (COX-2) inhibitors, may palliate cachexia
in cancer patients with anorexia. Seven cancer patients who
through the suppression of systemic inflammation.
reported loss of appetite were recruited from oncology
Lai et al.,[23] carried out a placebo-controlled study with clinics at Charing Cross Hospital. A marked increase in
celecoxib on 11 cachectic patients with head and neck or energy intake was observed with ghrelin infusion compared
gastrointestinal cancer. Patients receiving celecoxib showed with saline control, and every patient reported food intake
a statistically significant increase in weight and body mass increase. The meal appreciation score was greater by 28.8%
index compared with placebo. The results of this pilot study with ghrelin treatment. No side effects were observed.
are consistent with prior animal experiments and should Garcia et al.,[27] carried out a study on GHS-R agonist RC-
stimulate larger clinical trials investigating the role of COX-2 1291 (Anamorelin; Sapphire Therapeutics, Bridgewater,
inhibitors in the treatment of cancer cachexia. Indeed, more NJ, USA), a small-molecule orally active compound. The
studies are needed to confirm the findings of this pilot study. compound was administered in a randomized, placebo-
controlled trial over a 12-week period to 81 subjects with
Ghrelin mimetic with orexigenic and anabolic activity a variety of cancers (predominantly lung cancer). Over
Recently, much research interest has focused on ghrelin, a this 12-week course, RC-1291 produced an improvement
28 amino acid peptide produced by the P/D1 cells of the in total body mass and a trend toward increased lean
stomach. Not only does ghrelin stimulate GH secretion mass. A measurement of quality of life – an important
(via the GH secretagogue-1a (GHS-1a) receptor) but it consideration for any late-term cancer treatment – was
also promotes food intake (via the orexigenic NPY system) unchanged between the groups receiving RC-1291 and
and decreases sympathetic nerve activity. Synthetic human placebo. However, it has to be underlined that the above
ghrelin has been shown to improve muscle wasting and studies are small phase I and phase II trials, and therefore,
132 Indian Journal of Palliative Care / Sep-Dec 2010 / Vol-16 / Issue-3
 Tazi and Errihani: Treatment of cachexia - An update

their result should be treated with caution. Further in LBM, a reduction in fat mass, and reduced self-reported
controlled randomized studies are warranted before the anorectic symptoms.[32]
use of ghrelin can be translated into clinical practice.
Olanzapine
Insulin Olanzapine, an atypical neuroleptic with safe therapeutic
Lundholm et al.,[28] carried out a study to evaluate whether window for several psychotic diseases, induces significant
daily insulin treatment for weight-losing cancer patients weight gain and positive metabolic effects. Preliminary
attenuates the progression of cancer cachexia and improves data from a phase I pilot study by Braiteh et al.,[33] suggest
metabolism and physical functioning in palliative care. One that lower doses of OAZ are very well tolerated with
hundred and thirty-eight unselected patients with mainly promising clinical activity on weight, nutrition, and function
advanced gastrointestinal malignancy were randomized in advanced cancer patients with cachexia. The trial is
to receive insulin (0.11±0.05 units/kg/day) plus best ongoing.
available palliative support [anti-inflammatory treatment
(indomethacin), prevention of anemia (recombinant Combined approach
erythropoietin), and specialized nutritional care (oral
supplements+home parenteral nutrition)] according to From all the data presented, one can speculate that one
individual needs. Control patients received the best available single therapy may not be completely successful in the
treatment of cachexia. From this point of view, treatments
palliative support according to the same principles. Insulin
involving different combinations are more likely to be
treatment significantly stimulated carbohydrate intake,
successful.[34] Cerchietti et al.,[35] carried out a pilot study
decreased serum-free fatty acids, and increased whole body
using a multitargeted therapy in a homogeneous group of
fat, particularly in trunk and leg compartments, whereas
15 lung adenocarcinoma patients, with evidence of
fat-free lean tissue mass was unaffected. Insulin treatment
‘Systemic Immune-Metabolic Syndrome (SIMS)’ defined
improved metabolic efficiency during exercise, but did
by authors as a particular variety of distressing systemic
not increase maximum exercise capacity and spontaneous
syndrome characterized by dysregulation of the psycho-
physical activity. The authors concluded that insulin is a
neuro-immune endocrine homeostasis, with overlapping
significant metabolic treatment in multimodal palliation of
clinical manifestations: SIMS was defined as the presence
weight-losing cancer patients.
of weight loss, anorexia, fatigue, performance status ≥2,
and acute-phase protein response. Patients received MPA
Branched-chain amino acids
(500 mg twice daily), celecoxib (200 mg twice daily), plus
Branched-chain amino acids are neutral amino acids with oral food supplementation for 6 weeks. The results suggest
interesting and clinically relevant metabolic effects: They that patients with advanced lung adenocarcinoma, treated
interfere with brain serotonergic activity and inhibit the with MPA, celecoxib, and dietary intervention, might have
overexpression of critical muscular proteolytic pathways. considerable improvement in certain SIMS outcomes. In
The potential role of branched-chain amino acids as a subsequent study, Cerchietti et al.,[36] aimed to test the
antianorexia and anticachexia agents was proposed many hypothesis that by modulating systemic inflammation
years ago, but only recent experimental studies and clinical through an eicosanoid-targeted approach, some of the
trials have tested their ability to stimulate food intake and symptoms of the SIMS could be controlled. Twelve
counteract muscle wasting in anorectic, weight-losing patients were evaluated for compliance and were assigned
patients.[29] In experimental models of cancer cachexia, to one of the four treatment groups (15-, 12-, 9-, or 6-g
BCAAs were able to induce a significant suppression in dose, fractionated every 8 h). For patients assigned to 15-
the loss of body weight, producing a significant increase and 12-g doses, the overall compliance was very poor and
in skeletal muscle wet weight[30] as well as in muscle unsatisfactory for patients receiving the 9-g dose. The
performance and total daily activity.[31] maximum tolerable dose was calculated to be around two
capsules tid (6 g of fish oil per day). In consequence, this
Oxandrolone dose was used for the randomized trial. Then, a second
Recently, a prospective, randomized, phase III trial cohort of 22 patients with advanced lung cancer and SIMS
comparing the effects of oxandrolone (10 mg bid) and MA were randomly assigned to receive either fish oil, 2 g tid,
(800 mg q.d.) on weight, body composition, and quality plus placebo capsules bid (n=12) or fish oil, 2 g tid, plus
of life (QOL) in 155 adult patients with solid tumors and celecoxib 200 mg bid (n=10). All patients in both groups
weight loss receiving chemotherapy demonstrated that received oral food supplementation. After 6 weeks of
patients treated with oxandrolone experienced an increase treatment, patients receiving fish oil+placebo or fish oil +
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 Tazi and Errihani: Treatment of cachexia - An update

celecoxib showed significantly more appetite, less fatigue, approach, although supported by a good rationale, are all
and lower C reactive protein (C-RP) values than their phase II studies enrolling a small number of patients and
respective baselines values (P<0.02 for all the comparisons). hence are to be considered preliminary and warrant further
Additionally, patients in the fish oil+celecoxib group also confirmation in phase III studies. On the basis of these
improved their body weight and muscle strength compared results, we started a phase III randomized clinical trial to
to baseline values (P<0.02 for all the comparisons). establish which was the most effective and safest treatment
Comparing both groups, patients receiving fish oil + of CACS and oxidative stress in improving selected key
celecoxib showed significantly lower C-RP levels (P = variables as primary endpoints: increase of LBM, decrease
0.005, t-test) and higher muscle strength (P=0.002, t-test), of REE, increase of total daily physical activity, decrease
and body weight (P=0.05, t-test) than patients receiving of IL-6 and tumor necrosis factor-α, and improvement of
fish oil+placebo. The addition of celecoxib improved the fatigue. All patients were given basic treatment polyphenols
control of the acute-phase protein response, total body plus antioxidant agents alpha-lipoic acid, carbocysteine,
weight, and muscle strength. In the context of combined and vitamins A, C, and E, all orally administered. Patients
approaches, one of the most intriguing ones was our open were then randomized to one of the following five arms:
phase II trial.[37,38] The aim of the study was to test the (1) medroxyprogesterone acetate (500 mg/day)/megestrol
safety and efficacy of an integrated treatment based on acetate (320 mg/day), (2) pharmacologic nutritional
diet, pharmaconutritional support administered per os, and support containing eicosapentaenoic acid (2 g/day), (3)
drugs in a population of advanced cachectic cancer patients l-carnitine 6 (4 g/day), (4) thalidomide (200 mg/day), or
with cancer at different site. The following variables were (5) medroxyprogesterone acetate/megestrol acetate plus
assessed: clinical response, nutritional and functional pharmacologic nutritional support plus L-carnitine plus
variables, laboratory variables (as indicators of CACS/OS), thalidomide. Treatment duration was 4 months. The sample
and QOL, particularly fatigue. The ultimate goal of our size was 475 patients. The different single agents were
study was that of translating the results obtained on CACS/ selected on the basis of the following rationale. The
OS symptoms found in advanced cancer patients into a antioxidant agents were shown to be effective in our
prevention trial in a population of individuals at risk of previous studies. [39-44] The polyphenols, in particular
developing CACS/OS. The treatment consisted of diet quercetin, were included for their high activity as
with high polyphenols content (400 mg), antioxidant antioxidants.[45] Synthetic progestogens, MA/MPA, are
treatment (300 mg/day alpha-lipoic acid+2.7 g/day currently the only approved drugs for CACS in Europe.
carbocysteine lysine salt+400 mg/day vitamin E+30,000 Several randomized studies in mixed groups of weight-
IU/day vitamin A+500 mg/day vitamin C), and losing patients with cancer have suggested that MA/ MPA
pharmaconutritional support enriched with two cans per improves appetite and stabilizes weight to an extent greater
d ay ( n − 3 ) - P U FA ( e i c o s a p e n t a e n o i c a c i d a n d than placebo.[4,46-49] The ω-3 polyunsaturated fatty acids
docosahexaenoic acid), 500 mg/day medroxyprogesterone (EPA and docosahexaenoic acid) have been shown to
acetate, and 200 mg/day selective cyclooxygenase-2 inhibit the production of proinflammatory cytokines and
inhibitor celecoxib. The treatment duration was 4 months. thereby to act positively on cancer cachexia. In experimental
Thirty nine patients completed the treatment and were tumor models, EPA has demonstrated antitumor and
assessable. Body weight increased significantly from anticachectic effects. Studies on weight-losing patients with
baseline as did LBM and appetite. There was an important pancreatic cancer receiving EPA have shown suppression
decrease of proinflammatory cytokines IL 6 and tumor of IL-6 production by peripheral blood mononuclear
necrosis factor-α, and a negative relationship worthy of cells. [50-52] Barber et al.,[53] demonstrated that an EPA-
note was only found between LBM and IL-6 changes. As enriched supplement added to the diet may reverse cachexia
for quality of life, there was a marked improvement in the in patients with advanced pancreatic cancer. A double-
European Organization for Research and Treatment of blinded randomized study[15] in 200 patients with pancreatic
Cancer QLQC30, Euro QL-5D(VAS), and fatigue assessed cancer demonstrated a significant positive correlation
by MFSI-SF scores. The results have demonstrated the between the assumption of the nutritional supplement and
treatment to be both safe (without significant adverse the increase of weight and LBM, provided EPA
events) and effective in 17 patients and highly effective in supplementation was ≥1.5 cartons a day. Carnitine is a
five patients as for increase of body weight, increase of cofactor required for transforming the free long-chain fatty
LMB, decrease of proinflammatory cytokines, improvement acids into acyl-carnitine and for their subsequent transport
of quality of life parameters, amelioration of fatigue into the mitochondrial matrix to produce acetyl-coenzyme
symptom. Overall, these trials based on a combined A through the β-oxidation pathway. The relation between
134 Indian Journal of Palliative Care / Sep-Dec 2010 / Vol-16 / Issue-3
 Tazi and Errihani: Treatment of cachexia - An update

coenzyme A and carnitine is pivotal for cell energy predominantly anabolic activity in muscle and bone with
metabolism: Coenzyme A is required for β-oxidation, minimal androgenic effects in most other tissues. Evans
metabolism of several amino acids, pyruvate dehydrogenase et al.,[60] carried out a randomized phase II proof of concept
synthesis, and thus for triggering the tricarboxylic acid study of Ostarine, the first-in-class SARM, in healthy
cycle. [17,54] Patients with cancer are especially at risk for postmenopausal women and elderly men prior to initiating
carnitine deficiency; they frequently present with decreased a phase II study in cancer patients. The primary end point
caloric intake, and numerous antineoplastic drugs can was change from baseline to 3 months in total LBM
interfere with the absorption and synthesis of carnitine. measured by dual energy X-ray absorptiometry. Ostarine
Thalidomide has multiple immunomodulatory and anti- was shown to improve LBM and physical performance in
inflammatory properties; its inhibitory effect on TNF-α healthy older men and women. Ostarine had no unwanted
and IL-6 production may be responsible for its anticachectic androgenic side effects. A phase II study is planned to
activity. Thus, thalidomide has been used for treatment of evaluate the safety and efficacy of Ostarine in patients
cachexia associated with acquired immunodeficiency with cancer cachexia. Myostatin has been implicated in
syndrome, tuberculosis, and cancer. An interim analysis on several forms of muscle wasting, including cancer cachexia.
125 patients was published,[55] and the results obtained thus Anti-myostatin strategies are, therefore, promising and
far, although to be considered with caution, seem to suggest should be considered in future clinical trials involving
that the most effective treatment for cancer-related cachectic patients.[61] Recent experiments have shown that
anorexia/cachexia syndrome should be a combination blockade of melanocortin signaling using antagonists to the
regimen. However, the study is still in progress until melanocortin MC4 receptor attenuates disease-associated
completion of a planned accrual. In summary, there is not anorexia and wasting in rodent models of cancer and
yet a consolidated treatment for cancer cachexia. As renal failure.[62] Predictive or early biomarkers of cachexia
progestagens and corticosteroids, the only approved drugs could be developed, which would aid in the selection of
for CACS, are only partially effective; research interest is patients for early therapeutic intervention.[63] Key defining
currently shifting toward the use of different approaches features of cachexia in humans (weight loss, reduced food
addressing the potential targets involved in the intake, and systemic inflammation) now provide not only
pathophysiology of CACS. a framework for classification but also a rationale for
targets for therapeutic intervention. The role of age and
Future trends immobility in muscle wasting also provides a rationale for
the nature of nutritional support in cachexia. Multimodal
Current new trends include anti-IL-6 humanized approaches that address these key issues can stabilize and
monoclonal antibody which in murine models appear to even improve the nutritional status, function, and quality
inhibit cancer cachexia;[56] IL-15, a cytokine expressed in of life of at least a proportion of cachectic cancer patients.
skeletal muscle, is able to suppress the increased DNA The current evidence justifies new enthusiasm for the
fragmentation associated with muscle wasting in tumor- design of complex intervention studies in the management
bearing rats[57] and also to have muscle anabolic effects in of cancer cachexia.[64]
vitro and slow muscle wasting in rats with cancer cachexia.
[58]
Formoterol, a β2-adrenergic agonist, is a very efficient In summary, based on current views on the cachexia
agent preventing muscle weight loss in tumor-bearing syndrome in cancer patients, we put forward the following
rats.[59] Recently, several promising androgen analogs have recommendations:
been developed, as potential selective androgen receptor 1. Wasting is a predictable event in many cancer patients,
modulators (SARMs), which claim to preferentially act readily diagnosed by assessment of weight, change in
on skeletal muscle. They bind to the androgen receptor appetite, and food intake. Often these patients will
(AR) with high affinity and exert strong pharmacological also have anemia and low albumin, with a concomitant
activity in selective tissues, although the mechanism is not increase in C-reactive protein. The above simple
well understood. In cellular and animal models, androgen- assessments should form a consistent part of the
activated AR modulates myoblasts proliferation, promotes record of all advanced cancer patients.
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offer patients nutritional counseling (they should have
A new class of nonsteroidal SARMs is being developed access to a nutrition team with a special interest in
for use in cancer cachexia. SARMs are designed to have wasting disorders), encourage them to take part in a
Indian Journal of Palliative Care / Sep-Dec 2010 / Vol-16 / Issue-3 135
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