Critical Reviews in Oncology/Hematology 94 (2015) 251–259

Cachexia: A preventable comorbidity of cancer. A T.A.R.G.E.T. approach

Maurizio Muscaritoli ∗ , Alessio Molfino, Simone Lucia, Filippo Rossi Fanelli
Department of Clinical Medicine, Sapienza University of Rome, Italy
Accepted 28 October 2014

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
2. Is cancer cachexia preventable? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
3. Cachexia: a cancer comorbidity? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
4. The T.A.R.G.E.T. approach to cancer cachexia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256
Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256
Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258

Abstract
Although relevant achievements in the treatment of cancer have been obtained, some barriers still remain in the prevention and treatments
of cancer comorbidities, including cachexia. Indeed, the enormous advances in the understanding of the pathogenesis of cancer cachexia have
not been paralleled by effective strategies aimed at modifying the cultural approach to this devastating condition. Too little attention is still paid
to the nutritional and metabolic changes occurring in cancer, despite their negative effects on patients’ tolerance to antineoplastic treatments
and outcome. We propose a T.A.R.G.E.T. approach as a novel strategy, encompassing active interventions and research development within
the different domains influencing the onset and the progression of cancer cachexia. Moreover, based on the most recent clinical evidences,
we suggest that cachexia should be considered a comorbidity of cancer.
© 2014 Elsevier Ireland Ltd. All rights reserved.

Keywords: Cachexia; Cancer; Comorbidity; Prevention; Therapy

1. Introduction States will develop cancer in their lifetime [1,2]. Besides,

cancer survivors, defined as any person who has been diag-
Cancer is a major public health problem in the world, nosed with cancer, are increasing, largely due to population
particularly in western countries, representing the second aging, earlier diagnosis and improvement in treatments
leading cause of death after heart disease and accounting for [1]. The increasing number of cancer survivors makes
23% of all deaths. It has been estimated that 13.7 million current clinical practice in need of embracing new clinical
Americans with a history of cancer were alive on January 1, issues, such as nutritional and metabolic support, in the
2012 and that one in 3 women and one in 2 men in the United attempt to improve life expectancy and quality of life (QoL).
Indeed, until quite recently and before the introduction
of effective cancer screening and treatment, cancer was
∗ Corresponding author at: Department of Clinical Medicine, Viale
frequently diagnosed in a late stage, when patients may
dell’Univesrità 37, 00185 Roma, Italy. Tel.: +39 06 49972016;
fax: +39 06 49972016.
have already experienced weight loss and cachexia [3], and
E-mail address: maurizio.muscaritoli@uniroma1.it (M. Muscaritoli). cancer cachexia was considered a terminal cancer event,

http://dx.doi.org/10.1016/j.critrevonc.2014.10.014
1040-8428/© 2014 Elsevier Ireland Ltd. All rights reserved.
252 M. Muscaritoli et al. / Critical Reviews in Oncology/Hematology 94 (2015) 251–259
uniquely amenable to palliative support. During the recent
years, however, the better understanding of its multifactorial
pathogenesis has led to consider cancer cachexia an early
phenomenon, worth of early, preventative, diagnostic and
therapeutic interventions [4–6].
Significant progress has been achieved in the recent years
regarding the re-definition and classification of cachexia
in cancer [7] and chronic diseases [8,9]. Currently, cancer
cachexia is defined as “a multifactorial syndrome charac-
terized by an ongoing loss of skeletal muscle mass (with
or without loss of fat mass) that cannot be fully reversed
by conventional nutritional support and leads to progressive
functional impairment. Major hallmarks of cachexia include
anorexia, fatigue, metabolic and endocrine alterations, and
loss of lean body mass. The pathophysiology is character-
ized by a negative protein and energy balance driven by a
variable combination of reduced food intake and abnormal
metabolism [7]. Cancer cachexia negatively impacts on QoL,
tolerance and response to anti-neoplastic treatments, morbid-
ity and mortality rates, and it has been estimated that more
than 50% of cancer patients die with the presence of cachexia,
with a relevant percentage (up to 20%) of deaths directly due
to cachexia [6,10].
The spectrum of cancer cachexia ranges from non-
symptomatic inflammatory alterations with minimal weight
and muscle loss at an early stage, to severe muscle wasting
and low performance status in more advanced stages [7], sup-
porting the view that metabolic and nutritional issues should
be taken into account as early as the diagnosis of a cancer
disease is made [11]. Based on the currently available evi-
dence, it is clear that, since cancer cachexia recognizes a
multifactorial pathogenesis, it requires a multimodal therapy
[7,12]. However, although conceptually sound, this thinking
is still rarely transferred into clinical practice. The enormous
advances in the understanding of the pathogenesis of cachexia
seem not to have been paralleled by effective strategies aimed
at modifying the cultural approach to this devastating condi-
tion.
The aim of the present review is to propose a novel and
holistic approach to cancer cachexia, based on the most recent
advances in the pathogenic mechanisms, terminology and
classification.
2. Is cancer cachexia preventable?
International scientific effort has recently focused on
translating the understanding of the molecular mechanisms
underlying cachexia into patients’ care. The recently devel-
oped classification of cancer cachexia into three stages,
namely pre-cachexia, cachexia, and refractory cachexia [7]
will improve ease of cachexia recognition by clinicians,
through objective and standardized criteria. Pre-cachexia is
defined by unintentional weight loss ≤5% of usual body
weight during the last 6 months, anorexia and metabolic
change [7]. Recently, Blum et al. showed that pre-cachexia is
more clinically relevant when it is defined based on inflam-
mation or anorexia, rather than by minimal, if any, weight loss
[13]. More importantly, Blauwhoff-Buskermolen et al. [14]
reported a very low prevalence of pre-cachexia when diag-
nosed by the criteria of the International Consensus [8]. This
underscores the importance of still working on the diagnostic
framework of pre-cachexia.
Cachexia is defined by weight loss >5% over past 6 months
in absence of simple starvation or the combination of ongoing
weight loss >2% with BMI < 20 or sarcopenia. Refractory
cachexia, instead, is a clinically refractory stage featured by
a low performance score and a life expectancy <3 months,
only liable for psychosocial support and symptom palliation
[7].
Such a dynamic view of the cancer cachexia process
implies that the progression from cancer to-pre cachexia and
cachexia may be variably modulated by timely appropriate
and effective interventions (i.e., nutrition and/or drugs) and
that at least cachexia and pre-cachexia may be considered
reversible conditions.
Recent data obtained in head/neck, lung and colorec-
tal cancer patients [15–19], strongly argue in favor of this
view and consistently show that an early and tailored nutri-
tional counseling and intervention may maintain nutritional
status and dramatically improve treatment tolerance and clin-
ical outcome. Head and neck cancer patients are at high
risk of malnutrition in part because of preexisting unhealthy
lifestyles (e.g., ethanol and smoking addiction) and in part
due to local tumor interference with chewing and swal-
lowing leading to dysphagia and determining a reduced
food intake. Moreover, cancer therapy (including surgery,
radiation and chemotherapy) can further negatively affect
nutritional status and treatment tolerance. Indeed, anticancer
therapies are often prematurely interrupted because of the
occurrence of severe side effects, including weight and mus-
cle loss, malnutrition, leukopenia, and hand-foot syndrome
[15,20], while intensive and early nutritional intervention
(before chemotherapy) maintains body weight, reduces hos-
pital admissions and the number of radiotherapy in head
and neck cancer patients [15]. In a retrospective study, the
use of prophylactic gastrostomy in patients with head and
neck cancer at high risk for malnutrition was shown to
decrease hospital length of stay and to reduce healthcare costs
[16], while in a prospective study failed to ensure daily rec-
ommended energy intake until six months after treatment
initiation [21].
In lung cancer patients, early nutritional intervention
determines a significant improvement of the nutritional sta-
tus and reduction of the inflammatory response [18], with
body weight stabilization during chemotherapy being asso-
ciated with reduced toxicity and a longer overall survival [22].
Moreover, specialized nutritional support enriched with fish-
oil n-3 polyunsaturated fatty acids may beneficially affect
quality of life, performance status and physical activity in
patients with NSCLC non-small cell lung cancer undergoing
multimodality antineoplastic treatment [23].
 M. Muscaritoli et al. / Critical Reviews in Oncology/Hematology 94 (2015) 251–259
Similar evidences were reported in colorectal and
oesophageal cancer patients receiving controlled nutritional
support. Patients presented lower infectious complication
rates, maintenance of body weight, lean body mass and qual-
ity of life [19,24,25].
3. Cachexia: a cancer comorbidity?
Given the high risk that cancer patients develop
disease-related or treatment-related metabolic and nutritional
impairment throughout the course of the disease, possibly
leading to the clinical picture of cachexia, the question then
arises whether cachexia itself should be innovatively, and
operationally, considered a comorbidity of cancer.
According to a meaningful definition given by Fried et al.,
comorbidity is “the presence of two or more medically diag-
nosed diseases in the same individual, with the diagnosis
of each contributing disease based on established, widely
recognized criteria” [26].
In cancer, comorbidities may influence survival by
delaying cancer diagnosis, by determining suboptimal
chemotherapy dosage, by enhancing treatment-related tox-
icity, not allowing provision of best supportive care, or by
acting as a competing cause of death [27–29].
Overall survival of patients affected by the most prevalent
tumors, e.g., prostate [30], lung [31], colon [32] and breast
[27] cancer as well as by other malignancies [33–35], is neg-
atively affected by the presence of comorbidities, supporting
the view that comorbidities of cancer represent and act as
independent prognostic factors.
In relation to the index (i.e., principal) disease, comor-
bidities have been classified into 4 types: (1) causal, when
a common pathophysiology is recognizable; (2) complicat-
ing, when disease-specific complicating illness is present; (3)
concurrent, when a causal relation to the index disease can-
not be determined; (4) intercurrent, when represented by a
concomitant acute illness [36].
In this perspective, cancer cachexia may be identified as
both a causal and a complicating comorbidity of cancer,
because of its strict association with the pathophysiologi-
cal changes induced by the tumor in the host. Unlike other
comorbidities, however, there is now compelling evidence
suggesting that cancer cachexia may be prevented or at least
delayed in its presentation, provided that a comprehensive
tailored medical approach is adopted. This innovative method
is described in the following sections.
4. The T.A.R.G.E.T. approach to cancer cachexia
Targeting cancer cachexia and its complex pathophysio-
logy has been the focus of a large number of experimental
and clinical studies during the last decades [4–7].
According to novel pathophysiological knowledge, a
new cachexia therapy mainly aimed at acting on specific
253
molecular targets such as myostatin, ghrelin, interleukin-
6, interleukin-1␣, and skeletal muscle androgen receptor
has been proposed. Although numerous single agents are
currently under investigation, the only available interven-
tion is nowadays represented by a multimodal approach, in
which gradual resistance training, aerobic exercise, targeted
nutrients supplementation and pharmacological intervention
are administered, thus implementing a multimodal strategy
aimed at counteracting the development of cancer cachexia.
In this light, the T.A.R.G.E.T. approach, encompassing
both active actions and further research within different
domains, namely Teaching, Awareness, Recognition, Genet-
ics, Exercise/Early intervention and Treatment of cancer
cachexia is proposed here.
This innovative approach will be described below and is
summarized in Table 1.
T: Teaching.
Teaching of nutrition and metabolic alterations during
chronic diseases, such as cancer, is still insufficient in medical
schools [37,38], even if slight improvements are in progress
[39]. Thus we strongly suggest to facilitate the knowledge of
the negative impact of nutritional and metabolic alterations in
cancer patients, for medical students, residents and fellows,
nurses, dieticians and caregivers.
Already in 2001 the Council of Europe (the Committee of
Experts on Nutrition, Food Safety and Consumer Health of
the Partial Agreement in the Social and Public Health Field)
identified a lack of sufficient education as a determinant in
impairing food and nutritional care in hospitals [40].
More emphasis should be given to teaching nutrition and
metabolism as an important component of medical educa-
tion. Furthermore, refresher courses and regular continuing
medical education for practicing physicians and other health-
care workers would help in active retention of nutritional
knowledge and thereby in better practice of nutritional care.
A reasonable outcome of teaching is increased awareness.
A: Awareness.
Poor nutritional status is significantly correlated with poor
clinical outcomes including increased risk of infections, falls,
fractures and pressure ulcers development, reduced auton-
omy and quality of life and increased mortality [41].
Nutrition and hydration concerns on the list of evalu-
ation and treatment priorities in residential staff members
often rank low [42]. The majority of oncology fellows
demonstrated low levels of knowledge in nutrition, prob-
ably determining lack of confidence in identifying cancer
cachexia and malnutrition [43]. Major barriers identified to
make nutritional practice effective included lack of guide-
lines, knowledge and time [43].
Enhancing awareness among healthcare professionals,
will have earlier and prompt recognition of cancer cachexia
as an outcome.
R: Recognition.
The recently proposed criteria for definition and classifi-
cation of cancer cachexia will, with no doubt, significantly
contribute to improve recognition of this devastating
254 M. Muscaritoli et al. / Critical Reviews in Oncology/Hematology 94 (2015) 251–259

Table 1
The rationale of the T.A.R.G.E.T approach to cancer cachexia.
Domain where active interventions and/or Comment Refs.
research should be implemented
T Teaching Teaching of nutrition and metabolic alterations in chronic diseases and [37]–[40]
cancer is insufficient worldwide. Improving teaching would increase
awareness among HCPs.
A Awareness Increased awareness of the negative impact of cancer cachexia may [41]–[43]
translate into improved recognition.
R Recognition Criteria for diagnosis and staging of cancer cachexia are now available and [7,12]
their use in clinical practice will make its recognition easier.
G Genetics Susceptibility to cancer cachexia is genetically determined. Some [44]–[50]
genotypes are associated with exaggerated inflammatory response,
predisposing to cachexia and reduced survival.
Early Evidence exists that early recognition and treatment of cachexia improve [15,51–54]
E
patients’ outcome.
Exercise Physical activity is fundamental and recommended since the early phases [3,55–60]
of cancer in order to maintain/restore muscle mass.
T Treatment Cancer cachexia is preventable and treatable. Multimodal interventions [61–71]
should include appropriate nutrition and drugs capable of improving
appetite, body composition and physical performance.
Abbreviations: HCPs: Healthcare Professionals.

condition since its first appearance [7]. The agreed diag-
nostic criterion for cachexia is the presence of weight loss
greater than 5%, or weight loss greater than 2% in individuals
already showing depletion according to current body weight
and height (body-mass index [BMI] <20 kg/m2 ) or skeletal
muscle mass (sarcopenia). Physicians should also promptly
recognize anorexia and/or reduced food intake, muscle mass
and strength reduction and impaired physical function. While
the techniques providing a reliable assessment of muscle
mass (e.g., DXA, bioimpedance analysis, CT-Scan) may not
be easily available in daily practice, functional assessment of
patients’ muscularity may be easily performed with hand-grip
dynamometry and/or assessing the activities of daily living.
A personalized intervention will be based on the patient’s
baseline characteristics and aimed at counteracting, and pos-
sibly reversing, the mechanisms most likely contributing to
body weight loss and cachexia [7].
In this light, nutritional counseling, oral nutritional sup-
plements, artificial nutrition, exercise and physical therapy
should be timely considered and prescribed [12]. The recently
proposed “Parallel Pathway” would represent a reasonable
option in preventing or delaying cancer-related malnutrition,
enhancing the efficacy of anti-cancer therapies and improving
patients’ clinical outcome [12].
G: Genetics.
Cancer cachexia is the result of the interaction between
the host response and the presence of the tumor. Cytokines
play a key pathogenic role both when are produced directly
by cancer and by tumor environment. The impact of genetic
background may influence the host’s response to the tumor
and even the onset of molecular mechanisms finally leading
to cachexia [6]. Although host cytokine genotype was asso-
ciated with adverse prognosis and systemic inflammation in
gastro-oesophageal cancer [44], only few studies have evalu-
ated the associations between cachectic features and genetic
variability [45]. In cancer patients with elevated markers
of inflammation (C Reactive Protein, CRP), cachexia was
found associated with specific Vitamin D Receptor (VDR)
polymorphisms thus representing a possible early clinical
predictor phenomenon for the development of a more
aggressive form of cachexia [46]. In a large scale genetic
association study, the C allele of the single-nucleotide
polymorphism (SNP) (rs6136), encoding for the P-selectin,
was found to be associated with weight loss >10% [47].
Guthrie et al. showed that tumor necrosis is associated
with elevated IL-6 circulating levels, thereby modulating
local and systemic inflammation including angiogenesis that
may promote tumor progression and metastases [48]. In
this light, the European Palliative Care Research Collab-
orative Group indicated that polymorphisms resulting in
an increase in systemic inflammation, including increased
levels of IL-6, IL-1␤, IL-10 and tumor necrosis factor-␣,
a decrease in lean or fat mass and decreased survival in
cancer are likely to be cachexia prone variants [49,50]. Con-
versely, polymorphisms that result in a decrease in systemic
inflammation, an increase in body mass and improved sur-
vival in cancer are likely to be cachexia resistant variants
[49].
To date, no SNPs has been found in association with cancer
cachectic patients [45]. Thus, it is not yet possible to iden-
tify those patients who are at risk to enter and/or to progress
through the spectrum of cachexia stages. However, this lack
of knowledge does not rule out the putative role of genes in the
development of cancer cachexia, but rather it should encour-
age further larger clinical trials since the identification of a
genetic susceptibility to cachexia may offer to cancer patients
significant therapeutic advantages.
E: Early/Exercise
Early: In head and neck cancer patients the early admin-
istration of nutritional support showed to improve treatment
tolerance and outcomes [15]. The authors strongly suggested
to administer nutritional support before chemo-radiotherapy
 M. Muscaritoli et al. / Critical Reviews in Oncology/Hematology 94 (2015) 251–259
and to continue supplementation after treatment completion
[15].
Hence, early intervention structured in a multimodal
approach may help to counteract and prevent the detrimental
effects of cancer cachexia. Safety profile and the efficacy of
each intervention should be well balanced in order to obtain
clinical improvements. A multitargeted therapy of cancer
cachexia should involve drugs able to interfere with its main
pathophysiologic alterations, such as activation of systemic
inflammation, altered energy intake, altered resting energy
expenditure [51] and increased muscle and lipid catabolism.
With the multimodal intervention becoming a novel,
potentially effective, approach to counteract cancer cachexia,
increasing studies are investigating the efficacy of different
approaches in selected group of patients. In the ACCeRT
Study [52], authors designed a randomized feasibility study to
investigate, in non-small cell lung cancer (NSCLC) patients,
the efficacy of EPA plus Cox-2 inhibitor versus EPA and
Cox-2 inhibitor plus progressive resistance exercise training
(PTR) followed by ingestion of essential amino acids mixture
rich in leucine. EPA seems to affect LBM via several mecha-
nisms including effects on proteolysis, on protein synthesis,
on enhancing chemotherapy response and preserving from
treatment side effects, although controversial in advanced
cancer patients [53,54].
Exercise.
It is now well-recognized that exercise is effective in pre-
venting cancer [55], safe during active cancer treatments [56]
and healthy for cancer survivors [3] as well. It improves bone
health, muscle strength, quality of life, fatigue, psychosocial
distress, depression, and self-esteem [3].
The risk of comorbidities, typically detected in a large
amount of cancer survivors, can be significantly reduced
through increased physical activity. Moreover, exercise is
associated with reduced risk of cancer recurrence and
improved overall mortality [3].
Physical activity may attenuate the effects of cachexia
by modulating muscle metabolism, insulin sensitivity and
inflammation [57–59]. In particular, exercise has been
shown to have anti-inflammatory properties, through the up-
regulation of the anti-inflammatory cytokines both in skeletal
muscle and adipose tissue and to counteract the oxidative
stress enhancing both the non-enzymatic antioxidant effects
and the antioxidant enzyme activities (like the super-oxide
dismutase, SOD, the glutathione peroxidase, GPx, and the
catalase). Exercise also preserves muscle mass and function
enhancing protein synthesis, decreasing protein catabolism
and contributing to a better muscle performance [59].
Considering that some patients may not tolerate exercise
training, often physicians delay the initiation of physi-
cal activity because of possible chemotherapy-related side
effects.
Patients with diagnosis of cancer necessarily experience
a new frail psychosocial and clinical phase. So that it is
commonly impossible for them to carry out several actions
and activities earlier considered easy to perform. Therefore,
255
exercise programs need to be tailored and personalized
to cancer patient, maybe with the assistance of a special-
ized health care team able to plan the exercise intervention
taking care of the global clinical condition and personal
preferences.
Particular attention should be given to patients with
indwelling catheters or feeding tubes, and multiple or uncon-
trolled comorbidities such as compromised immune function,
anemia, fatigue, peripheral neuropathies or ataxia. For such
patients exercise might start with low-intensity activities such
as stretching and brief, slow walks and progress slowly, with
careful attention to balance and safety in order to reduce the
risk of falls and injuries.
Exercise should be recommended in the earliest phase of
the disease [57] and may include incremental intensity [62].
However, the goal for any cancer patient should be to be active
as much as possible, possibly with the helpful presence of a
caregiver or exercise professional during exercise sessions.
T: Treatment.
Current and emerging treatments for cancer cachexia
prevention and therapy are based on nutritional intervention,
appetite stimulation, anti-inflammatory agents, growth fac-
tors and anabolic agents [61]. Recently, particular attention
was given to Omega-3 fatty acids, amino acids and micronu-
trients supplementation [62]. Controversy still exists on these
substrates efficacy, but their anti-inflammatory, immunomod-
ulating and restoring properties in cancer cachexia appear
useful [62]. No single pharmacological agent showed clear
efficacy in counteracting depletion of muscle mass and in
attenuating cancer cachexia symptoms. A randomized phase
III clinical trial of 5 different arms of treatment showed that
the combination of a progestational agent (i.e., medoxypro-
gesterone acetate or megestrol acetate), EPA-enriched
nutritional supplement, l-carnitine and thalidomide is more
effective than each single treatment alone in improving
nutritional and performance status [63]. The multimodal
treatment efficacy was also evaluated in a recent study assess-
ing the ability of l-carnitine, celecoxib (a Cox-2 inhibitor)
and megestrol acetate in improving total daily physical activ-
ity, cancer cachexia symptoms, and functional status as well
as increasing lean body mass [64]. Multimodal interventions
should be scheduled in parallel with anti-cancer therapies and
may consist in nutritional intervention [65,66], exercise and
rehabilitation program [3,55,56,67], and multi-target drug
therapies. Nutritional intervention should be individualized
to single patient providing oral nutritional supplements,
enteral or parental nutrition [66]. Enteral nutrition should
be started if undernutrition already exists or if food intake is
markedly reduced for more than 7–10 days. Standard formu-
las for EN are recommended [68]. When nutritional needs
by enteral nutrition cannot be fulfilled, parental nutrition
may be co-administered as supporting nutritional strategy
or, otherwise, may cover for total nutritional requirements
[65,69].
Drugs for cancer cachexia may be classified into four
different categories, according to the level of evidence:
256 M. Muscaritoli et al. / Critical Reviews in Oncology/Hematology 94 (2015) 251–259
1. Effective (e.g., progestagens); 2. Ineffective (e.g., cypro-
heptadine, hydrazine, metoclopramide, and pentoxifylline);
3. Drugs with a strong rationale that failed or did not
show univocal results in clinical trials (e.g., eicosapentaenoic
acid, cannabinoids, bortezomib, infliximab); 4. Emerging
drugs with some effective results but still under clinical
evaluation (e.g., thalidomide, selective cyclooxygenase- 2
inhibitors, branched-chain amino acids, ghrelin mimetics,
insulin, oxandrolone, and olanzapine) [70]. Furthermore,
ongoing/programmed drug clinical trials in cancer cachexia
have been mainly focused on:
• Appetite stimulants (Molecules targeting the
melanocortin-4 receptor, MC-4R; Anamorelin, a synthetic
orally active ghrelin receptor agonist) [71];
• Drugs targeting inflammatory cytokines (Thalidomide;
Lenalidomide, a derivative of Thalidomide; Humanized
monoclonal anti-IL-6 antibody, ALD 518; Peptide nucleic
acid, PNA, immunomodulator drug OHR/AVR118, target-
ing IL-6 and TNF-alfa simultaneously) [71];
• Anabolic drugs (Selective Androgen Receptor Modulator
(SARMS) Ostarine (GTx-024); Myostatin/activin
inhibitors; Eicosapentaenoic Acid (EPA); Beta-
adrenoceptor agonists; MT-102 a beta-1 and beta-2
antagonism and orexygenic agent; Human antibody BYM
338) [71].
5. Conclusions
Despite its detrimental consequences on the prognosis
and quality of life of cancer patients, cancer cachexia is still
poorly recognized, prevented and treated. As a consequence,
up to 1 out of five cancer patients still dies because of the
direct effects of cachexia. While the incidence of some tumors
is slowly decreasing, the prevalence of cancer is steadily
increasing, due to the progress achieved in cancer early diag-
nosis and treatment. The population of cancer survivors is
expanding worldwide, with the ‘cancer journey’ progres-
sively becoming a long-term experience in which the burden
of comorbidities negatively affects both patients’ health and
healthcare systems efficacy.
Given the high risk that cancer patients develop
disease-related or treatment-related metabolic and nutri-
tional derangements, ultimately and frequently leading to
cachexia, we suggest that cachexia should be considered a
comorbidity of cancer. This view has practical and opera-
tional implications, since it might favor early recognition,
diagnosis and therapeutic interventions for cancer cachexia,
positively impacting on survival, quality of life and health-
care expenses. In this perspective, the T.A.R.G.E.T. approach,
encompassing active interventions and research develop-
ment within the different domains influencing onset and
progression of cancer cachexia, may represent a novel and
effective strategy to implement early multimodal interven-
tions aimed at counteracting this devastating comorbidity of
cancer.
Conflict of interest
All the authors declare no conflict of interest.
Reviewers
M. Cerqueira Leite Seelaender, PhD, Livre-Docência,
Professor of Cell and Tissue Biology, Universidade de São
Paulo, Department of Histology and Embryology, Av. Prof.
Lineu Prestes 1524, Sao Paulo, São Paulo CEP05508-900,
Brazil.
Professor Alessandro Laviano, Sapienza University,
Department of Clinical Medicine, viale dell’Università 37,
I-00185 Rome, Italy.
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Biographies
Maurizio Muscaritoli received his M.D. cum laude in
1982 at Sapienza University of Rome. He completed his resi-
dency in Internal Medicine and in Nephrology between 1982
and 1991. He was assistant Professor of Internal Medicine
from 1991 and is Associate Professor of Internal Medicine
from 2001. Research Fellow at the State University of New
York, in Syracuse, USA, 1991–1992. He is currently Head of
the Clinical Nutrition Unit at the Sapienza University Hospi-
tal, Rome, Italy.
Alessio Molfino received his M.D. cum laude in 2003 at
Sapienza University of Rome, Italy, and he concluded cum
laude in 2008 his residency/fellowship in Internal Medicine.
In 2012 he received his Ph.D. in Clinical and Preventive
Nutrition at University of Rome “Tor Vergata” and he is cur-
rently a post-doctoral reseach fellow at Sapienza University
of Rome, Italy. Since 2010 until now he helds the position
of Research Associate at University of California, Davis,
U.S.A. His principal fields of research are protein-energy
malnutrition, metabolism, anorexia and cachexia associated
with chronic diseases, such as cancer and hemodialysis. He
received several awards from national and international soci-
eties of Internal Medicine and from a prestigious international
Foundation devoted to cancer research.
Simone Lucia received his M.D. cum laude in 2010 at
Sapienza University of Rome, Italy. His main clinical and
research interests within Internal Medicine are malnutri-
tion, metabolism, cancer cachexia, pathogenic mechanisms
of muscle wasting in cancer and other chronic diseases. He
is currently Resident in Internal Medicine at Sapienza Uni-
versity of Rome, Italy.
Filippo Rossi Fanelli received his M.D. cum laude from
the University of Rome in 1971. Hewas Junior (1971–72) and
Senior (1972–74) Assistant Resident, Department of Inter-
nal Medicine, University of Rome. Assistant Professor of
Medicine from 1974 to 1982 at University of Rome. He
was Research Fellow at Harvard Medical School and Mas-
sachusetts General Hospital from June 1976 to May 1977.
 M. Muscaritoli et al. / Critical Reviews in Oncology/Hematology 94 (2015) 251–259
From 1982 to 1988 he was Associate Professor of Medicine
and Chief, Laboratory of Clinical Nutrition, Department
of Internal Medicine, University of Rome. From 1988 to
present is Professor of Medicine, Sapienza University of
Rome. From November 1996 to present is Chief, Division
of Internal Medicine, Department of Clinical Medicine, Uni-
versity of Rome. From November 2000, Head, Dept. Clinical
Medicine, Sapienza University of Rome. His research topic
is mainly represented by anorexia-cachexia syndrome during
259
chronic disease, in particular in cancer patients. His main
clinical interests within Internal Medicine are malnutrition,
metabolism, and metabolic-nutritional support in patients
with solid and hematologic tumours. Metabolic alterations in
cancer, cancer cachexia, pathogenic mechanisms of muscle
wasting in cancer and other chronic diseases and nutri-
tional and metabolic support in neurodegenerative disorders
such as amyotrophic lateral sclerosis are his main fields of
research.