Critical Reviews in Oncology / Hematology 127 (2018) 91–104

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Critical Reviews in Oncology / Hematology

journal homepage: www.elsevier.com/locate/critrevonc

Cancer cachexia: Diagnosis, assessment, and treatment T

a,b,c b,c d e
Mohammadamin Sadeghi , Mahsa Keshavarz-Fathi , Vickie Baracos , Jann Arends ,
⁎
Maryam Mahmoudib,f,g, Nima Rezaeih,i,j,
a
Molecular Medicine Interest Group (MMIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
b
Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran
c
School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
d
Department of Oncology, Division of Palliative Care Medicine, University of Alberta, Edmonton, AB, Canada
e
Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany
f
Dietitians and Nutrition Experts Team (DiNET), Universal Scientific Education and Research Network (USERN), Tehran, Iran
g
Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
h
Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
i
Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
j
Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Sheffield, UK

A R T I C LE I N FO A B S T R A C T

Keywords: Cancer cachexia is a multi-factorial syndrome, which negatively affects quality of life, responsiveness to che-
Cancer cachexia motherapy, and survival in advanced cancer patients. Our understanding of cachexia has grown greatly in recent
Nutrition years and the roles of many tumor-derived and host-derived compounds have been elucidated as mediators of
Palliative medicine cancer cachexia. However, cancer cachexia remains an unmet medical need and attempts towards a standard
Biomarker
treatment guideline have been unsuccessful. This review covers the diagnosis, assessment, and treatment of
Pharmacologic treatment
Nutritional treatment
cancer cachexia; the elements impeding the formulation of a standard management guideline; and future di-
Exercise rections of research for the improvement and standardization of current treatment procedures.
Psychological treatment

1. Introduction indirectly to the death of a significant proportion of cancer patients.

Cachexia is a multifactorial and multi-organ syndrome that is one of
the main causes of morbidity and mortality in late stages of chronic
conditions such as AIDS, chronic obstructive pulmonary disease
(COPD), congestive heart failure, multiple sclerosis, tuberculosis, and
cancer. More than 50 percent of cancer patients suffer from cachexia at
death, with the distribution varying by tumor type; the incidence is
highest in patients with gastric and pancreatic cancer (∼80%) while
patients with breast cancer and leukemia demonstrate the lowest fre-
quency (∼40%) of affliction with cachexia (Argiles et al., 2005;
Muscaritoli et al., 2006; Tisdale, 2005). Furthermore, one estimate of
the role of cachexia as a major contributor to cancer deaths stands at
almost 20 percent (Warren, 1932). Other studies, however, have found
this proportion to be lower (Sesterhenn et al., 2012; Ambrus et al.,
1975; Inagaki et al., 1974), whereas some have considered this estimate
conservative (Langer et al., 2001)(Sesterhenn et al., 2012) achieved this
estimate even though they had studied head and neck cancer patients
who are known to be at an especially high risk for malnutrition (Gorenc
et al., 2015). Nevertheless, cachexia can contribute directly or
Moreover, cachexia negatively affects quality of life, responsiveness to
chemotherapy, and survival (Bachmann et al., 2008; Dewys et al., 1980;
Penet and Bhujwalla, 2015). In 2011, an international consensus
statement defined cancer cachexia as:” a multifactorial syndrome
characterized by ongoing loss of skeletal muscle mass (with or without
loss of fat mass) that cannot be fully reversed by conventional nutri-
tional support and leads to progressive functional impairment (Fearon
et al., 2011).” The main clinical presentation of cachexia in cancer
patients is involuntary weight loss. Anorexia, systemic inflammation,
insulin resistance, and increased resting energy expenditure (REE) are
also usually associated with the condition.
The wide variety of symptoms observed in cachexia is mediated
through a spectrum of both tumor-derived and host-derived factors.
Zinc alpha 2-glycoprotein (ZAG) is a well-recognized procachectic
factor secreted by tumor cells (Wyke and Tisdale, 2005; Felix et al.,
2011; Hirai et al., 1998). Moreover, cytokines secreted by tumor cells
may complement the host inflammatory response to the tumor (Tan
et al., 2014; Argiles et al., 2009). Pro-inflammatory cytokines (IL-1, IL-
6, TNF-α, IFN-γ) act through both centrally-mediated and peripheral

⁎
Corresponding author at: Research Center for Immunodeficiencies, Children’s Medical Center, Dr Qarib St, Keshavarz Blvd, 14194 Tehran, Iran.
E-mail address: rezaei_nima@tums.ac.ir (N. Rezaei).

https://doi.org/10.1016/j.critrevonc.2018.05.006
Received 30 May 2017; Received in revised form 16 April 2018; Accepted 9 May 2018
1040-8428/ © 2018 Elsevier B.V. All rights reserved.
M. Sadeghi et al.
pathways. These factors, either independently (Faggioni et al., 1997) or
through dysregulation of the leptin response pathway (Janik et al.,
1997; Grunfeld et al., 1996), cause the persistent stimulation of anor-
exigenic pathways (Grossberg et al., 2010). These cytokines also lead to
the many metabolic changes observed in cachexia. These changes
characterize the state of hypercatabolism (lipolysis (Petruzzelli et al.,
2014; Kir et al., 2014), muscle degradation (Fearon et al., 2013), and
acute phase response (Fearon et al., 1999)) observed in cachectic pa-
tients. In addition to the numerous molecular mediators of cachexia,
mechanical or digestive factors have been identified (Fearon et al.,
2013; Tuca et al., 2013). Tumor burden or chemotherapy may lead to
nausea, dysphagia, mucositis, pancreatic insufficiency, and malab-
sorption (Deutsch and Kolhouse, 2004), resulting in reduced food in-
take and subsequently weight loss (Wigmore et al., 1997).
Although the aforementioned consensus-definition for cachexia has
been validated (Blum et al., 2014), diagnosis remains a challenge due to
several confounding factors such as cachexia-like complications of
cancer therapy and sarcopenic obesity (Fearon et al., 2013). Even
though our knowledge of cancer cachexia has increased considerably
during the last decade, cachexia remains an unmet medical need. The
condition is rarely recognized in clinical settings as weight loss is not
routinely assessed (Churm et al., 2009) and treatment is usually in-
adequate (Sun et al., 2015; Spiro et al., 2006). Furthermore, hetero-
geneity in the clinical presentation of cachexia (Fearon et al., 2012),
difficulties in consistent diagnosis of the disease at early stages (pre-
cachexia) (Blum et al., 2014; Argiles et al., 2014), the advanced age of
many patients (Dodson et al., 2011), and the complexity of the multi-
modal approach needed to manage cachexia (Fearon, 2008) have
hampered efforts towards a standardized and effective treatment. In
this review, we focus on the clinical management of cancer cachexia
(diagnosis, assessment, and treatment) and the latest advances in this
field. We will also propose future directions towards the development
of an effective and standard guideline for the treatment of cachexia.
2. Diagnosis
Recent advances in the field of cancer-associated cachexia have
elucidated the pathophysiology of the disease to a great extent. As a
result, a general consensus has formed within circles of health care
professionals and experts in cancer cachexia on the main symptoms of
the condition, namely: weight loss, loss of appetite, failure to thrive,
and muscle wasting (Muscaritoli et al., 2016). However, the hetero-
geneity in the clinical presentation of the condition has impeded efforts
towards a single unifying definition of cachexia (Fearon et al., 2012).
Nevertheless, several attempts towards this goal have been made
(Fearon et al., 2011; Bozzetti and Mariani, 2009; Fearon et al., 2006a;
Evans et al., 2008; Muscaritoli et al., 2010; Argiles et al., 2011)(Fearon
et al. (2006a))(Evans et al. (2008)), and an international panel of ex-
perts under the auspices of the European Palliative Care Research
Collaborative (EPCRC) (Fearon et al., 2011). In the end, a definition
proposed by the SCRINIO working group is also mentioned (Bozzetti
and Mariani, 2009). The main diagnostic criteria of these three fra-
meworks are listed in Table 1.
It is important to note the basic differences between these three
frameworks. The second framework has been proposed for cachexia
associated with all types of underlying chronic disease (generic fra-
mework) while the other two frameworks have been formed specifically
for cancer-associated cachexia (cancer-specific framework). Moreover,
compared to the other two definitions, the second definition puts less
emphasis on body weight loss. Instead, through the use of additional
criteria, it tries to take into account other metabolic and nutritional
aspects of the disease (Vanhoutte et al., 2016). Furthermore, the Evans
et al. framework does not consider sarcopenia to be a diagnostic factor,
which is in stark contrast with the EPCRC framework.
On the other hand, even though the authors of the EPCRC definition
acknowledge blood CRP levels as an indication of catabolic drive, their
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Critical Reviews in Oncology / Hematology 127 (2018) 91–104
Table 1
Consensus-based definitions of cancer cachexia.
Number Study Criteria
1 Fearon et al. ≥ 2 out of next 3 criteria:
Weight loss (≥ 10%)
Low food intake (≤1500 kcal/d)
Systemic inflammation (C-reactive protein [CRP] ≥
10 mg/L)
**
2 Evans et al. Weight loss > 5% over past 12 months and underlying
chronic disease
Or
BMI < 20
And
3 out of next 5 criteria:
Abnormal Biochemistry
CRP > 5 mg/L
HB < 12 g/dL
Albumin < 3.2 g/dL
Fatigue
Anorexia
Decreased Muscle Strength
Lean Muscle Depletion
3 EPCRC Weight loss > 5% over past 6 months without
starvation
And/or
Weight loss > 2% and BMI < 20
And/or
Weight loss > 2% and sarcopenia
** This definition is not specific for cancer cachexia and has been proposed
for cachexia associated with all types of underlying chronic disease.
criteria does not directly measure systemic inflammation (assessed by
CRP levels) as a diagnostic factor due to the lack of contemporary data
sets for blood CRP levels in cancer cachectic patients (Fearon et al.,
2011). The importance of contemporary data sets was highlighted in a
study seeking to formulate a robust risk assessment method based on
cancer-associated weight loss percentage in 2015. In this study, the
demographic shift in cancer patients towards obesity and overweight in
recent times required the analysis of contemporary patient groups for
truly valid results. In the opinion of the consortium, the risk assessment
method proposed in the 2015 study supersedes the weight criteria
originally proposed in the 2011 definition. In addition, this study de-
monstrated that the prognostic value of percent weight loss is limited
when considered independently from BMI (Martin et al., 2015). Finally,
in comparing these three definitions, it must be noted that unlike the
first two, the EPCRC definition has been validated in a large patient
group in an international multicenter study (Blum et al., 2014).
Although few in number, several studies have sought to evaluate
these proposed frameworks. In a study conducted by Vanhoutte et al.,
the third definition was shown to give a higher prevalence of cachexia
in comparison to the second one. However, the difference of survival
rates between cachectic and non-cachectic patients was more sig-
nificant when using the second definition, leading the authors to con-
clude that it may identify more severe cases of the disease (Vanhoutte
et al., 2016). In another study, the generic framework was similarly
reported to better differentiate between survival rates. However, unlike
the Vanhoutte et al. study, more cachectic patients were identified
using the general framework (van der Meij et al., 2013). A similar lack
of concordance between different definitions was observed in compar-
isons of the first and third definitions (Wesseltoft-Rao et al., 2015;
Thoresen et al., 2013; Wallengren et al., 2013). Although there are
many drawbacks to comparing data accrued based on different sets of
criteria, the observed contradiction of data between the studies may be
attributed to the heterogeneity of patient groups, small sample sizes,
and long time-spans between measurement and assessment of different
features (Wesseltoft-Rao et al., 2015). Further studies addressing these
issues are warranted.
The validity of these definitions may also be questioned more
M. Sadeghi et al.
directly. For example, both the EPCRC and Evans et al. frameworks use
a single cut-off point of 20 for BMI (Fearon et al., 2011; Evans et al.,
2008). However, the recent European Society of Clinical Nutrition
(ESPEN) statement advises the use of a higher cut-off point of 22 in the
elderly (Cederholm et al., 2015). Given the importance of BMI in the
risk assessment of cancer patients, this might affect analyses carried out
on patients from different age groups. Another issue may be that the
EPCRC definition groups some cachectic patients as having refractory
disease based on, among other criteria, short life expectancy (Fearon
et al., 2011). However, many studies have reported estimations of life
expectancy to be inaccurate (Wilson et al., 2005; White et al., 2016;
Mackillop and Quirt, 1997; Chow et al., 2005). This is important since
such categorization affects the treatment approach taken towards these
patients. Furthermore, one study scrutinized the diagnostic value of
including additional criteria to weight loss, the main criterion of the
second framework. No correlation was observed between overall sur-
vival and these “minor criteria” (Letilovic and Vrhovac, 2013). Another
study concluded that the differences observed in cachectic patients with
different underlying chronic diseases might make the use of the generic
definition for all types of cachexia irrelevant (Letilovic et al., 2013).
Finally, the concept of pre-cachexia has been the subject of recent
discussion. Several studies have identified an association between the
pre-cachectic status and better treatment response (Martin et al., 2015;
van der Meij et al., 2013; Wesseltoft-Rao et al., 2015). These studies,
however, are not consistent in terms of the significance of the difference
in survival between pre-cachectic and non-cachectic patients (Martin
et al., 2015; Wesseltoft-Rao et al., 2015). On the other hand, the con-
cept of a pre-cachectic stage has been discredited because of either its
very low prevalence (Blauwhoff-Buskermolen et al., 2014) or the lack of
sufficient diagnostic criteria to confidently denote a patient as pre-ca-
chectic (Blum et al., 2014). Indeed, controlled clinical trials are needed
to objectively validate the presence of any added benefit from treat-
ment in the pre-cachectic status.
In the end, the definition proposed by the SCRINIO working group
based on 1307 oncology patients in a multicenter study also merits
discussion. This cancer-specific definition identifies and classifies ca-
chectic patients based on combinations of body weight loss (< 10%,
precachexia; ≥10%, cachexia) and the presence/absence of at least 1
symptom of anorexia, fatigue, or early satiation. Unlike the three con-
sensus-based definitions, these criteria focus mainly on features avail-
able upon clinical examination without considering systemic in-
flammation and body composition and muscularity as important
diagnostic factors. As a result, this definition can be utilized by any
clinician in any clinical setting (Bozzetti and Mariani, 2009). Im-
portantly, the patient groups identified by this definition and the
EPCRC criteria were not completely concordant in one study (Bozzetti,
2013); further highlighting the need for a universally accepted and
validated definition for cancer cachexia.
3. Assessment
Cancer cachexia is a multidimensional disease, which requires a
broad range of assessments for the adequate characterization of the
condition in each patient. Furthermore, determining the overall con-
dition of the patient is important as it indicates the best possible
treatment plan; e.g., whether to pursue abortive (intended to stop the
progression of the condition) or palliative (intended to alleviate the
distress caused by the condition) therapy. Many of these evaluations are
patient reported. This is because these assessments and subsequent
treatment commonly take place in the palliative setting. Therefore, the
goal of any therapy is to provide a subjectively tangible benefit over the
patient’s current status (Wheelwright and Johnson, 2015). Here we
summarize the 4 major aspects of assessing cancer cachexia.
93
Critical Reviews in Oncology / Hematology 127 (2018) 91–104
3.1. Nutritional screening and assessment
Insufficient dietary intake is a commonly observed phenomenon in
advanced cancer patients. Both independently and in association with
cachexia, it is a main cause of morbidity and reduction of responsive-
ness towards treatment (Senesse et al., 2008). For example, pre-
operative nutritional status has been shown to affect postoperative
survival in lung cancer patients (Bo et al., 2015). Conversely, tumors,
especially of the head and neck and gastrointestinal tract, may directly
impair ingestion of food. Additionally, anti-cancer therapies including
surgery, radiotherapy, and chemotherapy could impair nutrition intake
through various unfavorable GI abnormalities (Nicolini et al., 2013). As
a result, a vicious cycle forms, with malnutrition as a result of in-
sufficient dietary intake resulting in increasing therapy toxicity and the
unmanaged tumor causing even more severe malnutrition. The effects
of malnutrition are not merely physiological; with psychosocial effects
and reduction in quality of life (QoL) commonly manifested (Isenring
et al., 2004; McGrath, 2002). Thus, it is clear that routine nutritional
screening and assessment of cancer patients could lead to the identifi-
cation of cancer patients at earlier stages of malnutrition. This could
have considerable benefits as it would lead to the earlier commence-
ment of therapy (Arends et al., 2017). Because routine assessment by
nutritionists would not be timely and cost-effective, several nutritional
screening and assessment tools have been proposed instead (Table 2).
As it is evident from the table, the available nutritional screens are
far from perfect. Notably, many more studies in cohorts of patients with
advanced malignancies are required to fully validate these tests and to
clarify the contradictory results. As for the MNA, some studies have
validated the prognostic value of the test, even suggesting MNA as a
better indicator than weight loss history (Gioulbasanis et al., 2011a;
Gioulbasanis et al., 2011b). However, other studies have questioned its
validity mainly due to its low specificity (Neelemaat et al., 2011). Si-
milarly, MUST has been validated in some studies (Velasco et al., 2011)
while discredited in others due to its low specificity and sensitivity
(Neelemaat et al., 2011; Bauer and Capra, 2003). The NRS-2002’s uti-
lity as a nutritional screening tool has also been questioned (Thoresen
et al., 2013). Furthermore, none of the nutritional screening tools are
able to detect sarcopenic obesity as they do not assess muscularity
(Blum and Strasser, 2011). It must be noted, however, that comparison
of different nutritional screening tools developed for different target
populations and different purposes (e.g., diagnostic vs prognostic) may
be flawed. This is especially true if data on disease outcomes without
nutritional intervention is used to assess the tools (Elia and Stratton,
2012). Nevertheless, the importance of screening for the identification
of patients in need of care warrants the implementation of organized
screening regardless of the screening tool used. Some tools (especially
the PG-SGA and NRS-2002 tools) have found widespread use and have
proven useful in early recognition of malnutrition in cancer patients.
Therefore, it may be argued that, currently, the implementation of
routine screening of nutritional status in our healthcare centers out-
weighs the need for a fully optimized screening tool.
3.2. Muscularity and body composition
As one of the hallmarks of cachexia, muscle depletion should be
monitored in cancer patients. This could be achieved by either ana-
lyzing muscle mass or assessment of muscle strength. In assessing
muscle mass, cross-sectional imaging techniques, including computed
tomography (CT) or magnetic resonance imaging (MRI) are preferred
over other methods (Fearon et al., 2011). In addition to determining
muscle mass, these methods are better evaluators of resting energy
expenditure (REE) (Gallagher et al., 1998) as they separate skeletal
muscle and adipose tissue more accurately (Jacquelin-Ravel and
Pichard, 2012). Other methods include dual energy x-ray imaging
(DEXA), bio-impedance analysis (BIA), and mid upper-arm muscle area
by anthropometry (Fearon et al., 2011). Type II fast-twitch muscles are
M. Sadeghi et al. Critical Reviews in Oncology / Hematology 127 (2018) 91–104

Table 3
Cancer- Methods of muscularity assessment in Caucasian cachectic patients.
specific
Assessment method Indication of muscle
Yes

No

No

No

No
depletion
Completed by patient/

Lumbar (L3) skeletal muscle index determined Men < 55 cm2/m2

by CT imaging (Prado et al., 2008) Women < 39 cm2/m2
Appendicular skeletal muscle index determined Men < 7.26 kg/m2
by DEXA (Baumgartner et al., 1998) Women < 5.45 kg/m2
Practitioner

Practitioner

Practitioner
practitioner

Whole body fat-free mass (FFM) index without Men < 14.6 kg/m2
Patient

bone determined by BIA (Janssen et al., Women < 11.4 kg/m2

Both

2002)
Mid upper-arm muscle area determined by Men < 32 cm2
anthropometry (Jetté et al., 1983) Women < 18 cm2
Assessment in addition

assessed as they are affected most commonly in cancer cachexia

to screening

(Mondello et al., 2015). Although less sensitive than cross-sectional

imaging, the DEXA and BIA have some advantages. The DEXA method
Yes

Yes

No

No

No

exposes the patient to less radiation (Mondello et al., 2015) while the
BIA method has widespread use due to its simplicity and low cost (Tuca
Yes (Neelemaat et al., 2011; Ferguson

Contradictory results (Thoresen et al.,

et al., 2011a; Neelemaat et al., 2011)
Yes (Martin et al., 2010; Kubrak and

Contradictory results (Velasco et al.,

et al., 2013). Unlike CT and MRI, however, these methods are not able
Validated in population with cancer

Contradictory results (Gioulbasanis

to assess muscle quality as determined by intra- and intermuscular fat

2011; Bauer and Capra, 2003)

(myosteatosis). This especially undermines the assessment of muscu-

2013; Velasco et al., 2011)

larity in the elderly or the obese (Barbat-Artigas et al., 2012; Erlandson

et al., 2016; Correa-de-Araujo et al., 2017).
While body composition serves as an indicator of muscularity, it
could also serve as a predictor of chemotherapy toxicity (Prado et al.,
Jensen, 2007)

et al., 1999)

2009). For the assessment of muscle strength, upper-limb hand-grip

dynamometry is the preferred method (Fearon et al., 2011). However,
this may be questioned with the observed lack of improvement in hand-
grip strength in the ROMANA trials (Temel et al., 2016). Muscle
strength is a rough manifestation of muscle mass and it might be a
Weight loss, appetite and food intake, activity

better indicator of cachexia than overall physical activity (Strasser,

Dietary and anthropometric measurement,
and function; metabolic demand, physical

2008) (Table 3).

Weight loss, appetite and food intake

Weight loss, BMI, acute disease

Weight loss, BMI, food intake

3.3. Quality of life and psychosocial assessment

Main assessment criteria

One of the much-neglected aspects of cancer cachexia is its psy-

chosocial effects on patients. These effects often present themselves as
negative emotions due to involuntary weight loss and reduced dietary
assessment

intake (Hopkinson et al., 2010). Weight loss may have different psy-
activity

chological effects on cancer patients. Most commonly, the changes in

physical appearance lead to altered self-perception and even embar-
Available nutritional assessment and screening tools for cachectic patients.

rassment (Reid et al., 2009). This leads to distress and social isolation.
Malnutrition Advisory Group of the British

However, some patients, particularly the obese, regard this weight loss
and Metabolism) (Kondrup et al., 2003)
(European Society for Clinical Nutrition
Association of Parenteral and Enteral

as beneficial (Hopkinson et al., 2006) and may even experience im-

provements in self-image. This welcoming attitude towards weight loss
might result in complacency in management of diet and physical ac-
tivity, thus accelerating the progression of the disease (Hopkinson,
(Ferguson et al., 1999)

2014).
(Guigoz et al., 1996)

Alterations in dietary intake could also lead to negative psychoso-

cial effects. Food performs many non-biological functions in our ev-
(Ottery, 1996)
Developed by

eryday lives and carries great symbolic importance (Bayer et al., 1983;
Nutrition

Chamberlain, 2004; Mathieson and Stam, 1995). Changes in eating

patterns may result in relational conflicts within both the family and
wider social contexts. Consequently, caretakers are often afflicted with
Malnutrition Universal Screening

their own psychological effects. As they try to halt the decline, they
Global Assessment (PG-SGA)

Nutritional Risk Screening-2002

attempt to increase nutritional intake through various methods

Patient-Generated Subjective

Mini-Nutritional Assessment

Malnutrition Screening Tool

(McClement et al., 2004; Hopkinson and Corner, 2006). The lack of

improvement could lead them to assume responsibility for the failure
and thus feel incompetent (McClement et al., 2004). This highlights the
Tool (MUST)

(NRS-2002)

necessity of providing psychological support for caretakers in addition

to patients in the clinic. As for the patient, the senses of failure, help-
(MNA)

(MST)

lessness, loss of independence, imminent death, and conflict with fa-

Table 2

Tool

mily members (Hopkinson, 2014) present themselves in the form of

various negative emotions (Oberholzer et al., 2013). Different factors

94
M. Sadeghi et al.
Table 4
Quality of life (QoL) assessment tools in cachectic patients.
Assessment tool Number of items for
evaluation
Cancer Rehabilitation 139-long form
Evaluation System (CARES) (Schag et al., 1991; Schag and Heinrich, 1990) 59-short form
European Organization for the 30
Treatment and Research of
Cancer-Quality of Life Questionnaire
(EORTC QLQ-C30) (Aaronson et al., 1993; Sprangers et al., 1998; Stukan et al.,
2017) **
EuroQOL (EuroQol, 1990; Park et al., 2006) 16
Functional Assessment of Anorexia/Cachexia Therapy (FAACT) –(Functional 39
Assessment of Cancer Therapy [FACT] combined with anorexia and cachexia
subscale [ACS]) (Chang et al., 2005; Ribaudo et al., 2000; Salsman et al., 2015)
Functional Living Index-Cancer (FLIC) (Bektas and Akdemir, 2008; Fong et al., 2014; 22
Laenen and Alonso, 2010)
Nottingham Health Profile (NHP) (Hunt et al., 1981; Montazeri et al., 2003) 45
Quality of Life Index: Cancer Version - III (Ferrans, 1990; Ferrans and Powers, 1992; 66
So et al., 2004)
World health Organization Quality of Life-100 item (WHOQOL-100) (The World 100
Health Organization Quality of Life Assessment, 1998; Lin et al., 2015; Paredes
et al., 2010)
** The 24-item EORTC QLQ-CAX24 has been proposed as an update on this core questionnaire with promising results in the provisional phases. Studies for full
validation are currently underway (Wheelwright et al., 2017).
influence the severity of these emotions. Young people, for example,
suffer more as they are more active in the community (Oberholzer
et al., 2013; Lovgren et al., 2008).
Assessment of psychosocial and functional properties of patients
usually takes place through quality of life (QoL) assessments. Several
subjective questionnaire-based methods are available and have been
validated, a summary of which is presented in Table 4. Even though
these methods have been shown to be competent evaluators of quality
of life in cancer cachexia patients, they have two fundamental flaws.
Firstly, only the FAACT tool is cancer-cachexia specific and yet it has
been criticized for insufficient coverage of the social domain. Secondly,
these tools require more general evaluation to be considered as fully
validated tools. Therefore, there remains the need for an internationally
validated tool, which adequately covers all psychosocial aspects of
cancer cachexia (Wheelwright et al., 2013).
3.4. Biomarkers of cachexia
Cancer cachexia has been associated with alterations in the con-
centrations of a broad array of compounds in the body fluids. These
changes are associated with the different domains of the physiological
functions affected in cancer-related anorexia and cachexia. The word
biomarker is intended to convey the broad meaning of any measurable
substance in the body which is either influential or predictive of the
incidence, outcome, or treatment response of the disease (Strimbu and
Tavel, 2010). These markers have been proposed to not only identify
cachectic patients, but also to distinguish different stages of cachexia
(Bilir et al., 2015). The most recognized serum components of cancer
cachexia are the mediators of systemic inflammation, notably the acute
phase response proteins (APRPs). In an effort to quantify the systemic
inflammation observed in cancer, the Glasgow Prognostic Score
(mGPS/GPS) was developed in 2003 and has since been validated as a
tool to objectively define cancer cachexia in numerous studies
(McMillan, 2013). Other markers are associated with anorexia, lipo-
lysis, and muscle degradation (Table 5). However, caution must be
taken in regarding these factors as validated markers of cachexia. Evi-
dence for the prognostic and predictive value of most of these markers
is contradictory. In addition, cutoff values, which could be utilized in
the clinic, are lacking for most of these markers. The contradictory
results could be attributed to the heterogeneity and small sample size of
95
Critical Reviews in Oncology / Hematology 127 (2018) 91–104
Domains of health-related QoL Condition
covered
Physical, Functional, Social, Cancer
Psychological, Sexual, Treatment
Physical, Functional, Social, Cancer
Psychological, Treatment
Physical, Functional, Social, General (Chronic Illness)
Psychological
Physical, Functional, Social, Cancer Cachexia
Emotional, Sexual
Physical, Functional, Social, Cancer
Psychological, Treatment
Physical, Functional, Social, General Illness (Chronic
Psychological, Sexual illness-cancer)
Physical, Functional, Social, Sexual Cancer
Physical, Functional, Social, General Illness
Psychological, Sexual
patients used in most of the mentioned studies. Also, many confounding
elements could blur the relationship between these markers and ca-
chexia. In one study, for example, leptin showed gender-dependent
association, decreasing in cachectic women while increasing in ca-
chectic men (Wolf et al., 2006). Moreover, these serum markers might
have intra-day variations, thus affecting research results (Fujiwara
et al., 2014). Finally, the degree of significance between the measured
amounts of these markers between cachectic and non-cachectic patients
may depend on the diagnostic criteria used (Bye et al., 2016). There-
fore, more studies with more uniform and larger study groups are
warranted in this field.
4. Treatment
To date, an international standard care guideline for cancer ca-
chexia with perfect effectivity does not exist. This hampers efforts to-
wards better treatment options as there is no universal gold standard to
which new methods could be compared with. For any treatment of
cachexia, the primary endpoints should be improvements in lean body
mass, resting energy expenditure, fatigue, anorexia, quality of life,
performance status, and a reduction in pro-inflammatory cytokines
(Donohoe et al., 2011). Patient-reported outcomes and other relevant
biomarkers also serve as endpoints. However, it should be noted that
the best treatment approach depends on the stage of the disease, as
palliative options are prioritized over curative modalities at end stages
(Maltoni et al., 2005). Currently, a consensus has formed that the
multifactorial nature of cancer cachexia requires a multimodal treat-
ment approach (Madeddu et al., 2012). For example, while some clin-
ical studies have demonstrated that provision of high amino acid loads,
either through feeding or i.v. infusion, improves muscle protein
synthesis, these effects were not enough to reverse cachexia (Dillon
et al., 2007; Deutz et al., 2011; van Dijk et al., 2015;Bozzetti and
Bozzetti, 2013; Lundholm et al., 2004). The same goes for trials with
conventional and single-drug therapies (Gramignano et al., 2006).
Thus, further trials integrating these different therapeutic modalities
seem to be the way forward. We will now consider the current treat-
ment options available in each modality.
M. Sadeghi et al. Critical Reviews in Oncology / Hematology 127 (2018) 91–104

Table 5
Biomarkers of cancer cachexia.
Domain of Cancer Cachexia Associated biomarkers Observed change

Systemic Inflammation CRP Increase (Bilir et al., 2015; Batista et al., 2013; Kerem et al., 2008; Kemik et al., 2010; Burney
et al., 2012; Scheede-Bergdahl et al., 2012; Dev et al., 2014)
IL-1α Increase (Bilir et al., 2015; Kemik et al., 2010)
IL-1β Increase (Kemik et al., 2010; Scheede-Bergdahl et al., 2012), insignificant difference (Bilir
et al., 2015)
IL-6 Increase (Batista et al., 2013; Kemik et al., 2010; Burney et al., 2012; Scheede-Bergdahl et al.,
2012; Kim et al., 2012; Krzystek-Korpacka et al., 2007)
IFN-γ Insignificant difference (Kim et al., 2012)
IL-8 Increase (Kemik et al., 2010; Scheede-Bergdahl et al., 2012; Krzystek-Korpacka et al.,
2007;Song et al., 2009)
TNF-α Increase (Bilir et al., 2015; Kemik et al., 2010), insignificant difference (Kim et al., 2012)
IL-10 Increase (Kemik et al., 2010)
Albumin Decrease (Kerem et al., 2008; Kemik et al., 2010; Burney et al., 2012; Scheede-Bergdahl et al.,
2012; Dev et al., 2014)
Hormonal dysregulation Ghrelin Increase (Wolf et al., 2006; Kerem et al., 2008; Mondello et al., 2014; Shimizu et al., 2003)
insignificant difference (Kim et al., 2012), decrease(Kemik et al., 2010)
Obestatin Decrease (Mondello et al., 2014)
Testosterone Decrease (Bilir et al., 2015; Burney et al., 2012; Dev et al., 2014)
IGF-1 Decrease (Kerem et al., 2008; Huang et al., 2005)
Adipose-derived factors Adiponectin Increase (Wolf et al., 2006; Batista et al., 2013; Kerem et al., 2008), insignificant difference
(Kim et al., 2012), decrease (Kemik et al., 2010)
Resistin Increase (Kerem et al., 2008)
Leptin Increase (Wolf et al., 2006; Kerem et al., 2008; Kemik et al., 2010), insignificant difference,
decrease (Wolf et al., 2006; Kim et al., 2012; Mondello et al., 2014)
Tumor-derived factors Zinc-α2-glycoprotein (ZAG), also known as lipid- Increase (Felix et al., 2011), observed in urine (Todorov et al., 1998)
mobilizing factor (LMF)
Proteolysis Inducing Factor (PIF) Increase (Belizario et al., 1991), observed in urine (Wigmore et al., 2000)
VEGF-A and VEGF-C Increase (Kemik et al., 2010; Krzystek-Korpacka et al., 2007)
Midkine Increase (Kemik et al., 2010; Krzystek-Korpacka et al., 2007)

Several other factors have been proposed as markers, namely: angiotensin II, neutrophil-derived proteases, TGF-1β (Penafuerte et al., 2016); fentanyl (Suno et al.,
2015); PTHrP (Hong et al., 2016); glucagon-like peptide 1 (GLP1)(Felix et al., 2011); hemoglobin, NPY, orexin, and galanin (Bilir et al., 2015); myosin and other
muscle-related proteins in urine (Skipworth et al., 2010).

4.1. Pharmacologic treatment
Many different drugs have been suggested to be effective against
cancer cachexia. The rationale is usually based on the mechanism of
action of the mediators of cachexia. Therefore, in a general classifica-
tion, these drugs perform 3 basic functions (Argiles et al., 2010):
1 Reduction of the tumor-associated inflammation
2 Capitalization on the anabolic potential of the body to counter the
wasting and hypercatabolic state
3 Appetite stimulation
Of course, the pathways involved in these phenomena are com-
pletely entangled, making the translation of laboratory results into
clinical observations difficult to interpret. One solution is to identify
convergence points where the different mediating cellular pathways are
integrated. An example is the ubiquitin-proteasome system, which ap-
pears to be the dominant system in muscle protein breakdown (Shum
and Polly, 2012). Another problematic factor is the lack of well-de-
signed randomized clinical trials on large study groups. The small size
and heterogeneity of the patient groups, in addition to the widely
varying inclusion criteria and primary endpoints, render clear conclu-
sions almost impossible to reach. In spite of all this, several drugs with
substantial promise have been identified. Currently, megestrol acetate
(MA) is the only drug in clinical use for the treatment of cachexia and
has been approved by the FDA for treating AIDS-associated cachexia. To
date, no other drug has been shown to be superior to MA in efficacy and
tolerability (Tuca et al., 2013). However, some researchers have ques-
tioned the value of MA, stating that weight gain as a result of MA may
only be the result of increased body fat and fluid retention without
significant improvement in lean body mass (Madeddu et al., 2009;
Perez De Oteyza et al., 1998). Nevertheless, extensive studies have been
conducted on a broad range of compounds in both clinical and
preclinical settings, the most important of which are listed in Tables 6.1
and 6.2 . Other notable drug categories include melanocortin-4-re-
ceptor (MC-4R) antagonists, TNF-α inhibitors, and monoclonal anti-
bodies. Activation of the MC-4R in murine models decreases food-
seeking behavior, increases basal metabolic rate, and decreases lean
body mass (Marks et al., 2001). The effectiveness of MC-4R antagonists
has been demonstrated in murine models (Dallmann et al., 2011);
however, clinical trials are yet to be initiated. TNF-α inhibitors had
been proposed as potential drugs based on the large role TNF-α plays in
the mediation of cachexia. Surprisingly, several clinical trials were
unable to achieve any attenuation of the disease using infliximab, a
monoclonal antibody against TNF-α (Jatoi et al., 2010). Other biologic
drugs, such as Clazakizumab (formerly ALD518) (Alder Biopharma-
ceuticals, Inc., Bothell, WA, USA) and OHR/AVR118 (Ohr Pharma-
ceutical, Inc., New York, NY, USA) have been studied in cancer ca-
chexia. ALD518 is a humanized anti-IL-6 antibody which has been
shown to prevent the reduction of lean body mass in phase II clinical
trials in non-small cell lung cancer patients (Rigas et al., 2010). OHR/
AVR118 targets both TNF-α and IL-6, and was observed to improve
functional status, weight stabilization, appetite stimulation, and even
weight gain (Chasen et al., 2011). Tocilizumab, an anti-IL-6 receptor
antibody sold under the trade name ACTEMRA® (Genentech, Inc.,
South San Francisco, CA, USA), has been shown to bring significant
improvements in body weight, nutritional status, inflammation, anemia
and performance status in a number of case reports (Ando et al., 2014;
Ando et al., 2013; Berti et al., 2013). Still other drugs have been pro-
posed based on the pathogenesis of cancer cachexia but have not been
validated, such as growth hormone (GH) (Tuca et al., 2013), hydrazine
sulfate (Chlebowski et al., 1990; Kosty et al., 1994), metoclopramide
(Chen et al., 1997), olanzapine (Naing et al., 2015), and bortezomib
(Jatoi et al., 2005). It should be noted that such drugs with good ra-
tionale might still prove effective since, as was mentioned before, the
heterogeneity and small size of study groups limit the confidence

96
 Table 6.1
Pharmacologic treatment options for cancer cachexia in clinical research phase.
Drug Proposed mechanism of action
Megestrol acetate Reduction and inhibition of pro-inflammatory
Medroxyprogesterone acetate (MPA) cytokines (Mantovani et al., 1995) and appetite
stimulation through increasing the release of
neuropeptide Y in the hypothalamus (McCarthy
et al., 1994)
Cannabinoids (e.g., dronabinol) Interaction with endorphin receptors, interference
with IL-1 synthesis, activation of cannabinoid
receptors involved in the neuronal circuit of leptin
and prostaglandin synthesis inhibition.
Cyproheptadine Serotonergic blockade
Non-steroidal anti-inflammatory drugs (NSAIDs), Reduction of tumor-associated inflammation
including cyclooxygenase-2 (COX-2) inhibitors
such as celecoxib, ibuprofen, and indomethacin
97
Thalidomide Immunomodulation, anti-inflammatory and TNF-α
and IL-6 inhibition properties, inhibition of NF-κB
(Jin et al., 2002; Keifer et al., 2001), and blockade of
COX-2 (Fujita et al., 2001)
Melatonin Cytokine and TNF-α inhibition (Lissoni et al., 1996)
Ghrelin (and the agonists of its receptor, anamorelin Stimulation of GH secretion (Takaya et al., 2000),
and macimorelin) suppression of pro-inflammatory cytokines and
inhibition of NF-κB (Waseem et al., 2008; Li et al.,
2004), orexigenic effects (Kamegai et al., 2001;
Cowley et al., 2003)
Selective Androgen Receptor Modulators (e.g., Act selectively on androgen receptors of the skeletal
enobosarm) muscle and bone, minimizing stimulation of other
organs such as prostate, skin, and liver.
Espindolol Non-selective β blocker with central 5-HT1a and
partial β2 receptor agonist effects
Oxymetholone, oxandrolone, nandrolone and Marked anabolic activity with minimal androgenic
fluoxymesterone effects (Lesser et al., 2006)
Observed improvements
Appetite, food intake, weight gain,
quality of life (Lesniak et al., 2008;
Pascual Lopez et al., 2004; Garcia et al.,
2013)
Appetite, food
intake, homeostatic mechanisms of
energy storage (Gamage and Lichtman,
2012)
Mild stimulation of appetite (Kardinal
et al., 1990)
Lean body mass, TNF-α levels, grip
strength, quality of life, Glasgow
prognostic score (Mantovani et al.,
2010; McMillan et al., 1999; Lai et al.,
2008)
Appetite, lean body mass, weight
(Gordon et al., 2005), quality of life
(Davis et al., 2012)
Contradicting results (Lissoni et al.,
1996; Del Fabbro et al., 2013)
Body weight, appetite, lean body mass
(Neary et al., 2004; Garcia et al., 2007;
Garcia et al., 2015)
Physical performance and lean body
mass (Dalton et al., 2011; Dobs et al.,
2013)
Lean body mass, weight, hand grip
strength (Stewart Coats et al., 2016)
Lean body mass, subjective anorexia
score (Lesser et al., 2006)
Drug category
Progestogens
Cannabinoids
Antiserotonergic drugs
Cytokine inhibitors
Cytokine inhibitors
Cytokine inhibitors
Selective androgen receptor
modulators (SARMs)
Non-selective β blocker with
central 5-HT1a and partial β2
receptor agonist effects
Synthetic anabolic steroids
Shortcomings
Confirmed efficacy
M. Sadeghi et al.
Increased risk of thromboembolic events (most
important), peripheral
edema, breakthrough bleeding, hyperglycemia,
hypertension,
and Cushing’s syndrome (Maccio et al., 2012a;
Marshall, 2003)
Severe adverse effects, especially on the central
nervous system, e.g., hallucinations, vertigo,
psychosis (Bagshaw and Hagen, 2002; Tafelski
et al., 2016)
.
Based on the current literature, evidence for the
use of cannabinoids for the treatment of cancer-
related cachexia-anorexia syndrome remains
equivocal (Reuter and Martin, 2016; Cannabis In
Cachexia Study, Group et al., 2006; Jatoi et al.,
2002).
Sedating effects (Mantovani et al., 2001)
Further clinical trials are needed following
inconsistent results (Kardinal et al., 1990; Couluris
et al., 2008).
Risk of renal and hepatic impairment and gastro-
intestinal bleeding (NSAIDs) (Reid et al., 2013)
The initial results are positive (Maccio et al.,
2012b); however, they are not sufficient to
recommend widespread use outside of clinical
trials (Reid et al., 2013; Solheim et al., 2013).
Poor tolerability in esophageal cancer (Wilkes
et al., 2011)
Larger clinical trials are needed based on
promising initial results (Mantovani, 2010;
Yennurajalingam et al., 2012; Wen et al., 2012).
More clinical trials specifically designed for the
study of the effect of this hormone are needed.
Phase 3 clinical trials on melatonin have been
conducted without observation of any
improvement (NCT0051337).
Ghrelin might stimulate tumor growth (Murphy
and Lynch, 2012).
Confirmation requires further clinical research.
Phase 3 clinical trials
have been conducted (NCT01395914,
NCT01387282).
Phase 3 clinical trials have been conducted
(NCT01355484, NCT01355497).
More efficacy and safety data needed but the
initial data have been promising (Stewart Coats
et al., 2016).
(continued on next page)
Critical Reviews in Oncology / Hematology 127 (2018) 91–104
 Table 6.1 (continued)

Drug Proposed mechanism of action Observed improvements Drug category Shortcomings

Confirmed efficacy
M. Sadeghi et al.

High hepatotoxicity (García-Cortés et al., 2016)

Pentoxifylline (a methylxanthine derivative) Anti-inflammatory and TNF-α inhibition properties
(immunomodulation through inhibition of
phosphodiesterase)
Dexamethasone Suppression of pro-inflammatory cytokines such as
Prednisone TNF-α (Han et al., 1990) and IL-1 (Uehara et al.,
Methylprednisone 1989)
Not significant (Goldberg et al., 1995;
Mehrzad et al., 2016)
Appetite, calorie intake, sensation of
wellbeing, and nausea (Bruera et al.,
1985; Della Cuna et al., 1989; Willox
et al., 1984)
Confirmatory data are still lacking and have
sometimes been shown to be inferior compared to
other treatments (Loprinzi et al., 1999). Most
studies have been conducted in patients with
cachexia of a non-oncological origin (Storer et al.,
2005).
Cytokine inhibitors Its efficacy in cancer-associated cachexia has not
been demonstrated (Goldberg et al., 1995;
Mehrzad et al., 2016).
Corticosteroids The effect is short lived (less than 4 weeks).
Furthermore, long-term side effects (insulin
resistance, fluid retention, steroidal myopathy,
skin fragility, adrenal insufficiency, sleep and
cognitive disorders) have been observed (Tuca
et al., 2013).
Clinical trials have been conducted
(Yennurajalingam et al., 2012; Goldberg et al.,
1995).

98
Table 6.2
Pharmacologic treatment options for cancer cachexia in preclinical research phase.
Drug Proposed mechanism of action Observed improvements Drug category Shortcomings
Confirmed efficacy

Clenbuterol, salbutamol, salmeterol, and Increase muscle mass through inhibition of protein degradation
formoterol (Benson et al., 1991) and activation of muscle protein synthesis
(Choo et al., 1992); activation of the AKT/mTOR pathway (Kline
et al., 2007)
Insulin and insulin sensitizers Counter the peripheral insulin resistance that is frequently
(Thiazolidinediones such as associated with cancer cachexia. Thiazolidinediones decrease
rosiglitazone) pro-inflammatory cytokines and increase adiponectin and also
stimulate peroxisome proliferator-activated receptor (PPAR γ)
(Hauner, 2002).
Metformin Increases the activity of AMP-activated protein kinase (AMPK),
and the PI3K pathway, in muscle cells, 2 mechanisms involved in
muscle wasting (Mondello et al., 2015).
Muscle mass and function (Busquets et al.,
2004; Greig et al., 2014; Toledo et al.,
2016)
Calorie intake, body fat (Lundholm et al.,
2007), and lean body mass (Yki-Jarvinen,
2004; Chen and Xiao, 2014)
Body composition, protein degradation
(Oliveira and Gomes-Marcondes, 2016)
Beta-2-agonists They might have cardiovascular side effects (Toledo et al.,
2014; Jeppsson et al., 1986).
Based on the initial promising results in animal models (Pinto
et al., 2004), randomized trials are warranted.
Insulin and TZDs have proven to be promising agents against cancer-
insulin sensitizers associated cachexia in animal models (Chen and Xiao, 2014;
Asp et al., 2011). Clinical trials in human cancer patients
present an interesting area for future research.
Insulin and Clinical studies are yet to be conducted.
insulin sensitizers
Critical Reviews in Oncology / Hematology 127 (2018) 91–104
M. Sadeghi et al.
associated with the conclusion of each trial. Therefore, it is best to in-
tegrate these drugs into multimodal approaches in order to better de-
termine their effectiveness (Solheim and Laird, 2012). Recently
emerged drug categories such as ruxolitinib, a JAK/STAT3 inhibitor,
and BYM338, a myostatin/activin inhibitor (Novartis Pharmaceuticals,
East Hanover, NJ, USA), should also be considered.
4.2. Nutritional treatment
Cancer patients often have reduced calorie intakes (Bosaeus et al.,
2001; Hutton et al., 2006; Bovio et al., 2008). This could be the direct
result of the presence of the tumor (e.g., obstruction of the gastro-
intestinal tract) or the host’s response to the tumor and treatment.
Systemic inflammation due to the tumor may lead to anorexia while
nausea, mucositis, and vomiting as a result of anticancer therapy could
severely decrease food intake (Nicolini et al., 2013). Therefore, it is of
utmost importance to reverse these symptoms when possible. In addi-
tion, the deficiency in calorie intake should be compensated assuming
total energy expenditure in cancer patients to be equal to healthy
controls (Arends et al., 2017). Other aspects of nutritional intervention
include dietary counseling, nutritional supplementation, and artificial
nutrition. Nutritional counseling must be done, preferably by a pro-
fessional dietician, through calculation of energy and nutritional re-
quirements (Arends et al., 2017). It should be noted, however, that the
value of dietary counseling as an intervention has been assessed in
several studies with heterogeneous results. Therefore, further evidence
is needed to prove this intervention as a means of improving weight
gain (Balstad et al., 2014). At this stage, recommendations include
dietary changes, such as intake of an energy- and protein-rich diet, and
lifestyle changes, such as increasing meal frequency and decreasing
meal size. If these changes could not satisfy the patient’s energy re-
quirement, oral supplementations may be offered. Several compounds,
notably, β-hydroxy-β-methylbutyrate (HMB) (Aversa et al., 2011;
Fitschen et al., 2013), eicosapentaenoic acid (Murphy et al., 2011;
Fearon et al., 2006b; Sanchez-Lara et al., 2014), and L-carnitine
(Gramignano et al., 2006; Kraft et al., 2012) have been shown in some
trials to positively affect cachectic patients; however, insufficient data
exist for recommending HMB and L-carnitine for medical use (Arends
et al., 2017). The therapeutic potential of omega-3 fatty acids for cancer
cachexia has been widely studied. The results have been inconclusive
thus far (Dewey et al., 2007; Mazzotta and Jeney, 2009; Ries et al.,
2012; Bruera et al., 2003); however, recent studies with better study
design have been in favor of their use (Ryan et al., 2009; Weed et al.,
2011; van der Meij et al., 2010). These results, in addition to mild side
effects and sound biological rationale, support the use of these fatty
acids as nutritional supplements (Arends et al., 2017). If patients be-
come unable to eat adequately for a long time, artificial nutrition will
become necessary (Arends et al., 2017). Even though numerous studies
have attempted to compare enteral and parenteral nutrition with no
conclusive result, it is now generally accepted that each mode of de-
livery has its unique indications and contraindications, thus rendering
comparisons between them superfluous. It is widely accepted that the
enteral route should have priority, while parenteral nutrition could be
applied when the enteral route is not sufficient or feasible (Arends
et al., 2017; Cotogni, 2016).
4.3. Exercise treatment
One of the main goals of cancer cachexia therapy is preservation of
muscle mass and physical performance. A very good rationale supports
exercise as a therapeutic approach to cachexia (Maddocks et al., 2013;
Stene et al., 2013). Exercise has an anti-inflammatory effect (Petersen
and Pedersen, 2005) and could counter the inflammation-induced
muscle degradation and insulin resistance (Gould et al., 2013). Fur-
thermore, experiments with animal models have shown the effect of
exercise on decreasing skeletal muscle degradation and body weight
99
Critical Reviews in Oncology / Hematology 127 (2018) 91–104
loss (Alves et al., 2015). In human cancer patients and survivors, ex-
ercise leads to a wide range of improvements, including decreased in-
flammation and oxidative stress, reduced depressive symptoms, and
increased anabolic hormones such as IGF-1 (Lira et al., 2015). In ad-
dition, in a randomized controlled trial, Oldervoll et al. found that
exercise could maintain physical performance as measured by the
shuttle walk and hand grip tests (Oldervoll et al., 2011). Nevertheless,
several considerations must be made before accepting physical activity
as a feasible therapeutic approach. Cancer patients regularly suffer from
chronic fatigue and thus have a diminished capacity for full time ex-
ercise regiments (Argiles et al., 2012). This is further demonstrated by
the high drop-out rates from clinical trials including exercise
(Maddocks et al., 2011). In addition, patient condition should be con-
sidered before prescription of exercise. For example, acute physical
activity must be avoided in anemic cancer patients (Argiles et al.,
2012). Another consideration in the prescription of exercise is the re-
lative efficacies of aerobic and resistance training. Although some stu-
dies have favored resistance training (Courneya et al., 2007; Schwartz
and Winters-Stone, 2009), the general data is inconclusive. This must
not prevent, however, the assignment of training programs containing
both types of physical activity. Overall, exercise has shown positive
effects mostly in early stages of cancer and sufficient data on patients in
advanced stages of disease is lacking (Stene et al., 2013; Navigante and
Morgado, 2016). Since cancer patients usually experience cachexia at
such advanced stages, it is difficult to interpret these data in the context
of cancer cachexia. Clearly, as is common with other aspects of cancer
cachexia, there have been too few robust randomized controlled trials
to determine the best therapeutic approach using physical activity and,
therefore, this presents a possible area for future research.
4.4. Psychosocial treatment
As was true for the assessment of the psychosocial aspect of ca-
chexia, management of these symptoms has been much neglected in
many healthcare settings. A unique feature of this therapeutic modality
is that the patient’s caregivers should also be included in the inter-
ventions (Hudson and Payne, 2011). With the growing importance of
home care, fiscal and psychosocial support of family caregivers would
lead to better quality of care (Reid, 2014). The negativity of the emo-
tions experienced by the patient and caregivers is inversely propor-
tional to acceptance of the situation and the effectiveness of their
coping strategies (Oberholzer et al., 2013). As a result, it has been
proposed to base psychosocial interventions on Lazarus and Folkman’s
Coping and Adaptation Theory (Reid, 2014; Lazarus and Folkman,
1984). Currently, Reid et al. are conducting a clinical trial to test a new
psychoeducation intervention which focuses on practicality as well as
the aforementioned concepts (Reid et al., 2014).
5. Conclusion
With the growing understanding of cancer cachexia, it has become a
more important focus of research. Numerous trials have been conducted
towards the development of better treatment options and various
treatment guidelines have been proposed (Arends et al., 2017).
Nevertheless, several elements have frequently limited the applicability
of their results. Individually, many studies suffer from the small size
and heterogeneity of their patient samples. These factors contribute to
the contradictory results observed in different trials. In addition, dif-
ferences in inclusion criteria used for generating patient samples have
made comparing study results even more difficult. Consequently, pro-
posing an international standard guideline treatment has proven to be
impossible so far. It is clear that constructing a standard study protocol
for cancer cachexia, which would unify inclusion criteria and endpoints
in all trials, would bear immense benefits. Conduction of better de-
signed trials using these criteria would enable the data to be better
compared and integrated, thus paving the way towards a universally
M. Sadeghi et al. Critical Reviews in Oncology / Hematology 127 (2018) 91–104

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