Cancer-associated cachexia

Vickie E. Baracos1, Lisa Martin2, Murray Korc3, Denis C. Guttridge4 and Kenneth C.H. Fearon5†

1
Division of Palliative Care Medicine, Department of Oncology, University of Alberta, Cross Cancer
Institute 11560 University Avenue, Edmonton, T6G1Z2 Alberta, Canada
2
Department of Agricultural, Food & Nutritional Science, University of Alberta, Edmonton, Alberta, Canada
3
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis,
Indiana, USA
4
Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio, USA
5
Clinical and Surgical Sciences, School of Clinical Sciences and Community Health, Royal Infirmary,
University of Edinburgh, Edinburgh, UK.

Correspondence to: V.E.B.

vbaracos@ualberta.ca

†It is with sadness we learned of the passing of Professor Kenneth Fearon on 3 September 2016. Ken’s
research spanned every aspect of cancer cachexia, from experimental models to clinical trials. His
landmark paper (Definition and classification of cancer cachexia, an international consensus, Lancet
Oncol. 12, 489–495 (2011)) will continue to serve as a roadmap for the field, and as legacy for
researchers seeking to mitigate cachexia-related suffering.

Competing interests
V.E.B. receives financial support from the Canadian Institutes of Health Research and The Alberta
Cancer Foundation. L.M. is funded by Alberta Innovates, the Izaak Walton Killam Foundation and the
American Society of Parenteral & Enteral Nutrition. M.K. is partially funded by National Cancer Institute
grant CA-075059 and by the consortium for the study of Chronic Pancreatitis, Diabetes and Pancreatic
Cancer (U01 DK108323). D.C.G. receives funding support from the National Institutes of Health and from
the Ohio State University Comprehensive Cancer Center.

Author contributions
Introduction (V.E.B.); Epidemiology (L.M.); Mechanisms/pathophysiology (M.K. and D.C.G.); Diagnosis,
screening and prevention (V.E.B.); Management (K.C.H.F.); Quality of life (V.E.B.); Outlook (V.E.B.);
overview of the Primer (V.E.B.).
Abstract | Cancer-associated cachexia is a disorder characterized by loss of body weight with specific
losses of skeletal muscle as well as adipose tissue. Cachexia is driven by a variable combination of
reduced food intake and metabolic changes, including elevated energy expenditure, excess catabolism
and inflammation. Cachexia is most highly associated with cancers of the pancreas, oesophagus,
stomach, lung, liver and bowel; this group of malignancies is responsible for half of all cancer deaths
worldwide. Cachexia involves diverse mediators derived from the cancer cells and cells within the tumour
microenvironment, including inflammatory and immune cells. In addition, endocrine, metabolic and central
nervous system perturbations combine with these mediators to elicit catabolic changes in skeletal and
cardiac muscle and adipose tissue. At the tissue level, mechanisms include activation of inflammation,
proteolysis, autophagy and lipolysis. Cachexia associates with a multitude of morbidities encompassing
functional, metabolic, and immune disorders as well as aggravated toxicity and complications of cancer
therapy. Patients experience impaired quality of life, reduced physical, emotional and social well-being,
and increased use of health-care resources. To date, no effective medical intervention completely
reverses cachexia and there are no approved drug therapies. Adequate nutritional support remains a
mainstay of cachexia therapy, whereas drugs that target overactivation of catabolic processes, cell injury
and inflammation are currently under investigation.

[H1] Introduction

Cachexia is a disorder characterized by the involuntary loss of body weight, with loss of homeostatic
control of both energy and protein balance1; it has been acknowledged since the earliest written medical
treatises. Cachexia occurs in association with multiple chronic non-malignant diseases, including heart
failure, kidney disease, chronic obstructive pulmonary disease, neurological diseases, AIDS and
rheumatoid arthritis. Cancer-associated cachexia — the focus of this Primer — has distinctive tumour-
driven components and leads to progressive functional impairment, cancer-related mortality, treatment-
related complications and poor quality of life2. The disorder is driven by a variable combination of reduced
food intake and metabolic changes, including elevated energy expenditure, excess catabolism and
inflammation. Cachexia is distinct from malnutrition, which is readily reversible by the provision of
adequate nutrients.

Consensus is needed regarding the definition of and the specific criteria to adequately describe cancer-
associated cachexia, as multiple discordant definitions for cachexia are used in the literature. A single
definition widely accepted by clinicians and researchers will aid in the identification and treatment of
patients with cachexia as well as the development and approval of potential therapeutic agents2.
Accordingly, an international Delphi consensus process in 2011 provided a definition and conceptual
framework specific to cancer-associated cachexia2, stating that it is a multifactorial syndrome defined by
an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that can be partially but not
entirely reversed by conventional nutritional support.

Half of all cancer deaths worldwide (~8.2 million people per year)3 are attributed to the cancers most
frequently associated with cachexia, namely, pancreatic (0.33 million deaths), oesophageal (0.40 million),
gastric (0.72 million), pulmonary (1.59 million), hepatic (0.75 million) and colorectal (0.69 million).
Available data from palliative care settings suggest that rates of cachexia are uniformly very high at the
end of life, regardless of cancer site4. However, in spite of its clear association with advanced-stage
disease, cachexia is not an inevitable consequence of cancer. Notable inter-individual variation has been
noted with regards to the prevalence and severity of cachexia among patients with the same cancer
diagnosis and stage. Indeed, some patients with advanced-stage disease maintain or gain weight,
skeletal muscle and fat mass5,6. As the nutritional deficits that form an important part of cachexia are
preventable and are at least partially reversible, patients with cancer can demonstrate protein anabolic
response to feeding7,8. Furthermore, some individuals might be resistant to the development of cachexia.
For example, patients with a loss of function mutation in the gene encoding the cell adhesion molecule P-
selectin (SELP), have a low likelihood of developing cachexia9. Experimental studies in rodent models
also show that even in advanced-stage malignancies, cachexia can be substantially mitigated,
independent of tumour progression10,11.

In this Primer, we describe the unfolding mechanistic insights into cancer-associated cachexia, including
imbalances of proteolysis and protein synthesis; imbalances of lipolysis and lipogenesis; and the roles of
stem cells, inflammation and the central nervous system (CNS). Individual genetic and tumour-specific
factors as well as variations in treatment type might explain the considerable inter-individual variation in
cachexia prevalence, phenotype, severity and progression. Each of the patient-specific and tumour-
specific elements might be clinically relevant for a small number of individuals, but relevant at the
population level when considered all together. An improved understanding of the specific perturbations
that occur in a given patient could guide novel, patient-directed therapeutic approaches.

[H2] Prevalence
Cancer is a leading cause of morbidity and mortality worldwide, with ~14 million new cases and ~8.2
million deaths in 2012 (Ref.3). Cancer-associated cachexia is not included in national cancer statistics in
any country; however, it is mainly associated with incurable disease and is highly prevalent at the end of
life. Thus, the rate of cancer death is a plausible upper limit for the number of people affected by
cachexia; cachexia seldom if ever appears on certificates of death. Cachexia can also occur in curable
cancers, and may be reversed by successful treatment of the underlying cancer.
The diagnosis of cancer cachexia is based on the rate of weight loss as well as attainment of low body
mass index (BMI)2. Most prevalence data are derived from national point prevalence studies or from
systematic screening programs in cancer centres12–15. Exact criteria used to define cachexia are not
consistent across studies, making it difficult to aggregate data. Regardless of the criteria applied, certain
cancers are more prominently associated with cachexia (Fig. 1)12–15. Additional factors that contribute to
the variable prevalence of cachexia include more-advanced cancer stage, sex (men are more susceptible
than women), age, genetic risk factors, comorbidities and treatment-related catabolic effects. For
example, ~30% of patients with cancer have concurrent cardiac disorders with risk for cardiac cachexia;
concurrent cancer-cachexia and cardiac-cachexia are speculated to progressively exacerbate each
other16. Similarly, several drugs used in cancer therapy (such as sorafenib, a tyrosine protein kinase
inhibitor)17 or in palliation of cancer symptoms (such as glucocorticoids), have specific catabolic effects on
skeletal muscle.

Variation in the prevalence of cachexia might also partly be due to genotype. A candidate gene approach
has been used to explore inherited genetic variations that could explain inter-individual variations in
susceptibility to cachexia9. However, this area of research is in its early stages and genome-wide
approaches are needed to fully appreciate heritable risk.

[H3] Cachexia in the context of obesity

Current WHO statistics indicate >600 million adults worldwide are obese (BMI of >30 kg/m2)18, with
national rates as high as 50% in some countries19. Accordingly, given that cachexia is partly defined by
low BMI, contemporary patients with cancer are increasingly less likely to reach traditionally accepted
clinically underweight BMI levels (BMI<18.5 kg/m2). One-third of cancer diagnoses are attributed to
behavioural and dietary risks, including being overweight or obesity, which increases the likelihood of
obesity in patients with a cancer diagnosis. By contrast, rates of underweight adults are generally <10% in
western countries but 30–40% in developing countries. This upward shift in BMI renders the diagnosis of
cachexia increasingly unclear.

For patients who are of normal or low BMI before their cancer diagnosis, the effect of weight loss is
magnified. Underweight and severely underweight (BMI <16 kg/m2) patients are at elevated risk of
morbidity and mortality20. Additionally, large magnitude weight losses can occur in obese individuals
without achieving a low absolute BMI20. Importantly, severe depletion of skeletal muscle (sarcopenia) may
go undetected in patients with obesity21 (Fig. 2). Importantly, muscle loss can occur in the absence of fat
loss, and hence can escape detection in obese individuals. For example, patients with breast cancer may
gain weight following diagnosis, sometimes in association with loss of muscle mass, leading to
development of sarcopenic obesity22.
[H4] Mechanisms/pathophysiology

Cancer profoundly alters the normal homeostatic control of energy balance (Box 1), of which reduced
food intake is an important and in some cases predominant component23,24. Decreased muscle protein
synthesis has also been documented in weight-losing patients with cancer, and the fact that protein
synthesis can be reactivated by the provision of nutrients7,8,25–27 implies the importance of reduced dietary
intake in the aetiology of cancer-associated cachexia.

Additionally, tumour metabolism and a rich tumour secretome are important factors unique to cancer-
associated cachexia. Tumours possess an intrinsic metabolic rate, which is related to their mass and
degree of oxidative versus anaerobic energy metabolism28. Tumours compete with other organs and
tissues for energy fuels and biosynthetic substrates, and secrete molecules that directly elicit catabolism
in target tissues, including a long list of pro-inflammatory cytokines, eicosanoids and factors with tissue-
specific effects such as activin (skeletal muscle) or adrenomedullin (adipose tissue). The enhanced
inflammation elicited by the tumour also participates in the generation of catabolic pro-inflammatory
factors. These effectors modulate homeostatic controls in the CNS, prompting catabolic neural outputs
via the sympathetic nervous system, as well as neuroendocrine outputs (such as the release of adrenal
corticosteroids) and sickness behaviour (such as anorexia and fatigue). These humoral, neural and
behavioural outputs directly activate proteolysis and lipolysis in target organs, primarily skeletal muscle,
adipose tissue and cardiac muscle29. It has also been suggested that futile cycling — whereby oxidative
phosphorylation is uncoupled from ATP synthesis, resulting in only the production of heat — in brown or
browned adipose tissue elicits enhanced and inefficient energy expenditure30, contributing to cachexia
(Fig. 3). Moreover, futile metabolism cycles occur not only in the adipose tissue, but as a consequence of
the inflammation, insulin-resistance and so on also in other cells, such as the immune cells. Abnormalities
of mitochondrial dysfunction have also been noted in skeletal muscles, but these mechanisms have not
yet been verified in humans with cancer cachexia [Barreto et al., 2016, PMID:27259276; Brown et al.,
2017, PMID:28845591; VanderVeen et al., 2017, PMID:28785374)]

Sarcopenia is a key feature of cancer-associated cachexia2 and its consequences include increased
chemotherapy toxicity, complications from cancer surgery and mortality68. Increased mortality in cachexia
is suggested to include cardiac arrhythmias, electrolyte abnormalities that enhance the risk of developing
arrhythmias, thrombo-embolic events, respiratory difficulties due to diaphragm muscle weakness,
aspiration pneumonias due to the bedridden state and swallowing difficulties, gastrointestinal mucosal
atrophy leading to endotoxin absorption, poor wound healing and sepsis69. The prevailing hypothesis for
the association between sarcopenia and toxicity of systemic cancer therapy is that patients with low
muscle mass have a reduced volume of distribution in relation to the dose of chemotherapy that they
receive70,71. For example, when body surface area is used as the basis for dosing cytotoxic
chemotherapy, in sarcopenic patients the dose may distribute, be metabolized and be cleared within a
grossly depleted lean compartment. Although few pharmacokinetic data show that sarcopenic patients
experience greater drug exposure during cancer treatment, an association of dose-limiting toxicity with
sarcopenia in different treatment settings has repeatedly been shown16.

As data are limited on the longitudinal changes of whole-body and tissue-specific mechanisms in patients
with progressive cancer cachexia, information must be pieced together from separate studies. Collecting
data in patients is often difficult because cachexia occurs at a stage in which patient vulnerability limits
use of invasive metabolic tests and biopsies, and disease progression limits the number of patients
available for follow-up. Accordingly, additional mechanistic insights must be derived from animal models.
However, disparities between clinical and animal findings remain difficult to reconcile. In spite of these
limitations, measurements of whole-body energy expenditure and metabolic fluxes, lipolysis,
gluconeogenesis, protein synthesis and degradation and substrate utilization have been made in
patients27. Here, we outline the key mechanisms occurring in cancer-associated cachexia, relying on
animal data and pointing out where findings have been recapitulated in patient-derived samples.

[H5] Pro-cachexia cytokines and factors

Catabolic pro-inflammatory factors have attracted the most attention as mediators of cachexia, including
several interleukins, tumour necrosis factor (TNF), IFNg, leukemia inhibitory factor (LIF),
growth/differentiation factor 15 (GDF15) and TNF ligand superfamily member 12 (TWEAK) (Fig. 3).
Identified primarily through cell culture conditions and tumour xenograft models, these factors signal
through their respective cell surface receptors and activate selective transcription factors, which in turn
promote the transcription of ubiquitin proteasome and autophagy components (Fig. 4). Synthesized by
tumour or immune cells, the activities of these signalling molecules are sufficient to promote catabolism in
target organs such as skeletal muscle, but confirmatory patient data have lagged behind31.

In addition to inflammatory cytokines, other circulating factors have been described that exhibit pro-
cachectic activity towards skeletal muscle (Fig. 4). Activin A is a member of the TGFb superfamily of
growth factors that is produced by both tumour and immune cells32. In cultured myotubes, activin A
promotes atrophy and when over expressed in mice promotes weight and skeletal muscle loss with
higher potency than IL-6 (Refs33–35). Another pro-cachexia cytokine is TWEAK, which belongs to the TNF
family. TWEAK acts through the TNFRSF12A receptor (also known as FN14), which when overexpressed
in tumours correlates with cachexia; its role was shown via neutralization of TNFRSF12A, which inhibited
weight loss and increased the lifespan in a mouse model 36. Similar to TNF and IL-6, activin A and
TWEAK can promote muscle atrophy in non-malignant conditions, making these factors and their
respective receptors through which they signal potentially interesting therapeutic targets37,38. Clinical trials
for intervention studies targeting activin A and TWEAK have been initiated in both cancer and non-cancer
indications (NCT00771329 and NCT01604642). Information gained from these human studies might
determine whether single-line therapy against activin A, TWEAK or TNFRSF12A is sufficient to rescue
muscle atrophy in patients with cancer or whether, similar to therapies against TNF and IL-6, a
combinatorial approach will be needed to ablate the activities of multiple circulating pro-cachexia factors.

In rodent models of cancer cachexia, expression of E3 ubiquitin-protein ligases TRIM63 (also known as
MuRF1) and F-box only protein 32 (commonly known as atrogin-1 or MAFbx)39,40, which are part of the
ATP dependent ubiquitin proteasome pathway, are strongly upregulated. Expression of these proteasome
components is largely under the control of the transcription factors FoxO1 and FoxO3, whose activities
are post-translationally regulated41,42 and seem to function as a regulatory node between anabolic and
catabolic processes. Under physiological conditions, AKT phosphorylates the FoxO proteins, causing
their cytoplasmic localization. However, in cachexia, AKT activity is often suppressed, either under the
influence of inflammatory cytokines or owing to the decline in insulin-like growth factor-1 (IGF1) levels
(which stimulates muscle anabolism). Decreased AKT activity leads to the dephosphorylation and
subsequent nuclear translocation of the FoxO proteins, which in turn, enables their nuclear translocation
and the transcription of MuRF1 and atrogin-1, the induction of which correlates with the degradation of
myofibrillar proteins, in particular thick filament proteins such as myosin heavy chain43,44. Inhibition of
mechanistic target of rapamycin (mTOR), which also leads to the concomitant decline in protein
synthesis. Thus, in cancer, as in other chronic illnesses associated with cachexia, muscle atrophy is likely
regulated by an imbalance of anabolic and catabolic processes. However, muscle AKT activity is not
always reduced in cancer cachexia models45 or in patients with cancer46.

Additionally, inflammatory factors such as cytokines and angiotensin II reduce AKT activity, thereby
causing FoxO nuclear shuttling and induction of muscle protein catabolism47–50. In addition to the muscle
E3 ubiquitin ligases genes, FoxO transcription factors have a vital role in transcribing genes involved in
the autophagy system51. Under physiological conditions, skeletal muscle homeostasis requires autophagy
to eliminate damaged proteins and organelles. However, in cachexia, the upregulation of autophagy
genes leads to excessive activation of autophagy pathways that contribute to enhanced breakdown of
skeletal muscle. Other transcription factors such as NF-kB, STAT3, and C/EBPb also contribute to the
regulation of the E3 ubiquitin ligases and autophagy genes52–61 (Fig. 4). Given that animal models do not
always recapitulate complex events that occur in cancer cachexia in humans62, it will be important moving
forward to validate the significance of these transcription factors by measuring their activities in skeletal
muscle in patients with cancer-associated cachexia.

Indeed, when targeted RNA and protein analysis was performed, components of the ubiquitin proteasome
pathway and markers of systemic inflammation were associated with weight loss in patients with cancer63.
Decreases in the AKT pathway as well as myofibrillar proteins were separately described in patients with
cancer-associated cachexia64,65, which collectively are consistent with findings from animal models of
cancer cachexia. By contrast, global gene expression analysis studies to this point have not been able to
recapitulate findings in the protein turnover pathways, which have been widely described in animal
models66,67. Tissue biopsy from patients, usually collected intraoperatively during cancer surgery to
minimize invasiveness, has added mechanistic data.

[H6] Homeostatic control in the CNS

Sickness behaviours, which include anorexia and catabolism of lean body tissues, in addition to fever and
lethargy, are classic responses in multiple forms of acute and chronic illness, including malignant disease.
An increasing body of evidence suggests the CNS exerts overarching control of the pathogenesis of
cachexia72 through the recognition of cytokines as molecular signals of sickness. Existing data support a
model wherein peripheral inflammation is amplified and modified within the mediobasal hypothalamus,
creating a paracrine inflammatory milieu that in turn initiates and sustains alterations in the activity of
neuronal populations that regulate appetite and metabolic processes, including proteolysis and
lipolysis73,74. Hypothalamic exposure to any of numerous inflammatory stimuli (such as IL-1β and TNF)
triggers an acute illness response, leading to anorexia, weight loss and skeletal muscle atrophy. These
molecules act acutely by binding to receptors on hypothalamic neuronal populations, such as pro-
opiomelanocortin and Agouti-related protein neurons, which trigger a feed-forward loop that involves
skeletal muscle protein catabolism and lipolysis75. CNS-delimited IL-1β signalling alone can evoke a
catabolic program in muscle, rapidly inducing atrophy. This effect is dependent on hypothalamic-pituitary-
adrenal axis activation, as CNS IL-1β-induced atrophy is blocked by adrenalectomy or by muscle-specific
knockout of glucocorticoid receptors.

Animal studies are particularly germane to the development of understanding of CNS function in cancer
cachexia, and these are starting to be complemented by functional MRI brain imaging studies in patients.
For example, Molfino et al.76 showed that patients with cancer who have anorexia had low hypothalamic
activity on blood-oxygen-level dependent contrast functional MRI; this activity was also poorly responsive
to stimulation by oral feeding compared with patients with cancer who did not have anorexia.

[H7] Adipose tissue depletion

In addition to skeletal muscle, a substantial portion of weight loss in patients with cancer derives from the
depletion of adipose tissue5,77. Studies have shown that this depletion results from a reduction in fat mass
due to lipolysis rather than the irreversible degeneration of fat cells due to apoptosis78,79. In mouse
models of cancer-associated cachexia, fat loss precedes skeletal and cardiac muscle loss43, potentially
reflecting the early phases of the anorexia-cachexia syndrome. Fat and muscle atrophy in cachexia have
been considered independent events owing to the fact that cytokines such as TNF can induce catabolism
in both skeletal muscle and adipose cells. However, this concept was challenged by genetic studies
performed in mice in which Atgl, encoding adipose triglyceride lipase, was ablated; mice bearing Lewis
lung carcinoma xenografts were resistant to the lipolysis of white adipose tissue, but surprisingly retained
hind limb muscle mass80. This finding suggested that fat loss predisposes muscle loss in cancer-
associated cachexia. Similar conclusions were reached in a study in which secretion of parathyroid-
hormone related protein (PTHrP) from Lewis lung tumours in mice was shown to alter the thermogenesis
of adipose tissue via the ‘browning’ of white adipose cells81. Use of an anti-PTHrP antibody inhibited
adipose browning, as well as the loss of skeletal muscle mass, suggesting that altered fat metabolism
might be a prerequisite for skeletal muscle atrophy. Thermogenesis is regulated by the uncoupling protein
1 (UCP1), the expression of which increases in various mouse models of cancer cachexia, as well as in
white adipose tissue from patients with cancer-associated cachexia82.

How fat loss predisposes skeletal muscle atrophy is not known. Although several mechanisms have been
proposed to account for tumour-induced lipolysis — including the presence of inflammatory cytokines
associated from infiltrating tissue macrophages83,84, induction of adipose triglyceride lipase85 and loss of
AMP-activated protein kinase (AMPK)86 —whether one or more paracrine factors are capable of cross-
talk between fat and skeletal muscle to mediate the catabolism of myofibrillar proteins in unclear.

In patients with cancer, isotopic tracer methodologies have been used to show that cachexia results in an
increase of whole-body lipolysis (mean increase of 50%) and whole-body proteolysis rate (mean increase
of 40%). Steady-state amino acid flux measurements — across the leg in patients with cancer suggest
that muscle loss is not driven by increased protein degradation, but arises due to decreased protein
synthesis rate87. Muscle fractional protein synthesis rate has also been specifically measured in an
isotopic tracer approach combined with biopsy88. Another primary metabolic defect of cancer-associated
cachexia is the increased rate of whole-body glycolysis and the concomitantly augmented rate of
gluconeogenesis from the lactic acid cycle (mean increase of 300%). Adipose tissue biopsy from patients
has added mechanistic data.

[H8] Cardiac muscle atrophy

Little research is available concerning the effects of cachexia on vital organs in those with cancer.
Cardiac muscle performs an essential physiological role and was assumed to be spared in cachexia, as it
cannot simply be exploited as a repository of amino acids as skeletal muscle can. Although cardiac
atrophy remains to be evaluated in human cancer-associated cachexia, research in animal models has
shown significant cardiac atrophy in multiple cachexia-inducing tumour models, along with
echocardiography-defined evidence of cardiac functional impairment16. The mechanisms of cardiac
muscle atrophy are also described in animal models and are highly similar to those proposed for skeletal
muscle, involving inflammation, proteolysis, apoptosis and autophagy.
[H9] Diagnosis, screening and prevention
Although our understanding of cancer-associated cachexia has progressed, a single unified international
set of diagnostic criteria are not available. Indeed, a host of disparate diagnostic criteria, which are a
detriment to the identification and treatment of cachexia in clinical practice, have been reported2,89.
Regardless of which criteria used, weight loss is always included, either weight loss alone or in
combination with one or several additional features (such as anorexia, reduced food intake, muscle loss,
decreased strength, fatigue and biochemical markers89). In addition to the use of different combinations of
diagnostic criteria, heterogeneity in data collection and reporting of each individual criterion makes
defining cachexia for clinical use difficult.

International consensus groups have begun to address these disparities and have provided a conceptual
framework for the classification of cancer-associated cachexia2. Any useful classification criteria will
define definitive cutoff values for each diagnostic criterion that are determined from large contemporary
datasets by determining the values that relate optimally to meaningful patient-centered outcomes.
Datasets that include information collected in a standardized fashion are necessary and should be large
enough to capture representative distributions of candidate diagnostic criteria, relevant covariates and
outcomes for adequately powered statistical analyses, including subset analyses. Inclusion of
contemporary patients ensures representation from a variety of populations, body weight demographics
and treatment plans.

[H10] Diagnosis
The presence of weight loss is an important clinical sign that can even be the first detectable
manifestation of the presence of cancer. After the possibility of intentional weight loss (for example, by
dieting) has been excluded, alternative causes of weight loss of unknown origin are investigated. Weight
loss is typically the first element of a cachexia diagnosis, and has a distinctive course in each patient. For
example, weight loss can occur prior to or after the cancer diagnosis and can be slow, intense,
continuous or episodic; it should be monitored over time and referenced to the patient’s pre-cancer body
weight.

Weight also loss varies in its severity: 5% loss is considered the threshold of significant risk of poor
clinical outcome2, with increasing risk as weight loss cumulatively reaches 10%, 15%, 20% or higher.
Cancer-associated cachexia contributes to poor prognosis through progressive depletion of the body's
energy and protein reserves; thus, it is relevant to determine the impact of weight loss as a function of
initial body reserves2. The prognostic significance of weight loss in patients who initially have a low,
intermediate or high BMI was determined within an international cancer cachexia data repository
including >11,000 patients20. This multivariate analysis of the association between BMI, weight loss and
mortality was controlled for age, sex, cancer site, cancer stage and performance status20. A grading
system based on combinations of BMI and weight loss was developed to differentiate groups with distinct
median survival durations (Fig. 5)20. This grading system has been validated90 and included in current
European clinical practice guidelines91.

[H11] Other criteria

The diagnosis of cancer cachexia will inevitably include additional information beyond weight loss.
Although no consensus is available on the definitions of and methodologies for measuring skeletal
muscle depletion, reduced food intake and biological indicators of altered metabolism and catabolism,
measurement of these elements is becoming increasingly specific, precise and clinically available.

A key driving mechanism of cachexia is reduced food intake2. The gap between energy expenditure and
energy intake can be estimated from direct measures of resting energy expenditure (indirect calorimetry;
Box 1) and records of dietary intake92. A variety of validated questionnaires are also available to assess
quantity and type of dietary intake (Box 2)93.

No standard clinical assessment of skeletal muscle mass is available; however, most published data have
been collected from axial lumbar CT images (Fig. 2). Standard oncological CT images, collected for
cancer diagnostic purposes, offer a new opportunity to precisely quantify skeletal muscle and fat, and to
evaluate their changes over time21. Indeed, low levels of muscle mass, associated with treatment
complications and mortality, have been characterized21,68. CT-defined skeletal muscle mass
measurements have been increasingly reported in the literature (including >20,000 cancer patients to
date since 2008), with calls for this approach to be used more widely94. Data are available in different
diseases, cancer sites, cancer stages and regions; some provisional sex-specific cutoff values are
available as benchmarks to identify patients with muscle depletion21,95. These cutoff values have been
determined using statistical methods to identify risks (such as mortality, toxicity and quality of life) that
emerge at specific threshold levels of skeletal muscle. As CT data continue to accumulate, these can be
aggregated to develop sex-specific and age-specific reference values for skeletal muscle depletion68,
enabling the identification of cachexia in patients with high fat mass.

The specific abnormalities of metabolism that define cachexia in a given individual are not routinely
assessed, with the possible exception laboratory measures of the acute phase response (the proteins of
which are part of the innate immune system response to neoplasia)2,92,. The acute phase response is
characterized by leukocytosis, fever and changes in the plasma concentrations of positive acute-phase
proteins (namely, fibrinogen, α1-acid glycoprotein serum amyloid A, and C-reactive protein (CRP)) and
negative acute-phase proteins (namely, albumin and transferrin)96. Typical laboratory values are: albumin
(<35 g/L), transthyretin (prealbumin) (<110 mg/L) and CRP (>10 mg/L). The Glasgow Prognostic Score,
which provides scores for patients with cancer based on albumin, CRP or both, is established as a
powerful prognostic tool in multiple cancers for tumour progression, survival and symptom burden97,98.
CRP testing is not routine everywhere, but neutrophil to lymphocyte ratios offer similar prognostic
information99.

Although the production of pro-inflammatory cytokines is understood to be central to the inflammatory

response to malignant disease, serum cytokine levels have proven too inconsistent to be useful biological
criteria. Various different pro-cachectic mediators suggested by preclinical investigations, are being
evaluated in patient populations at risk for cachexia. For example, PTHrP was shown to be independently
prognostic of weight loss100 whereas increased levels of GDF15, IL-6 and IL-8 are correlated with weight
loss101. In the future, changes of inflammatory markers over time might also be useful as markers of the
efficacy of cachexia therapy102.

[H12] Screening
Cachexia screening is performed with the aim of increasing awareness and enabling early recognition
and treatment. To detect cachexia at an early stage and to detect its acceleration, regular evaluation of
weight change and BMI is needed, beginning at the cancer diagnosis and repeated depending on the
stability of the clinical situation. Cancer sites, stages and treatment plans with higher prevalence of
cachexia (pancreatic, oesophageal, gastric, pulmonary, hepatic and colorectal) are a priority for
screening.

Height and weight are routine, if not mundane, clinical measures, but the continuity of these measures
over time is essential to avoid large cumulative weight loss to go unnoticed. Screening for weight loss is
performed as a part of evaluation of nutritional risk within clinical nutrition services of cancer centres,
linked with nutrition therapy and monitoring of outcomes. Mandatory screening for weight loss in patients
with cancer has been established in some countries91 under the auspices of screening for malnutrition.
Screening can be efficient, brief and inexpensive. Patient-reported outcomes are of value in the
assessment of various facets of cachexia; evidence support the reliability of patient self-reported height,
weight and weight history91. Weight loss history and an index of food intake may be obtained directly, or
via validated nutrition screening tools (Box 2)91,103.

Abnormal screening results by themselves do not provide enough information to design individualized
cachexia care pathways. Patients with a history of substantial weight loss, therefore, need to be followed-
up with specific assessments to determine the origin and severity of food intake impairment and
metabolic derangements. Within the conventional organization of cancer care, clinical services might exist
that have aspects of the management of cachexia in their charge, but there is no set standard. Only a few
institutions possess a dedicated cachexia clinic104–107. Otherwise, cachexia can fall in the purview of
symptom control or palliative care, but may equally well be attended to by clinical nutrition services insofar
as access to dietitians and medical nutritionists is often available in cancer centres and hospitals.
Because of the important role of reduced dietary intake in development of cachexia, presence of this
issue can be part of the primary screen, and used to direct further assessments towards identifying needs
for nutritional support.

[H13] Prevention
Prevention has not been the standard in the clinical approach to cancer-associated cachexia. Although
weight loss can occur early, active treatment of cachexia has often been left to the end stages of the
disease and the refractory stage of the cachexia. However, a shift towards considering preventative
cachexia therapy (see below) is apparent. Notably, recent trials of cachexia therapeutics108,109 have been
shifted to an earlier time in the disease trajectory and are delivered concurrently with first-line
chemotherapy rather than in the end of life phase110–112. The earliest possible approach would be
contingent on developing a clear understanding of the predictors of cachexia, including the pre-cachexia
biomarkers.

[H14] Management
Cancer-associated cachexia evolves over time, and goals of care should be established at each stage of
the evolution. The majority of patients with advanced-stage cancers of the lung, pancreas, oesophagus,
stomach, colon and liver will experience cachexia1,12–15, and this foreknowledge should be a basis for
early and systematic attention to cachexia management. Although exact diagnostic criteria for
‘precachexia’ remain undetermined, this is a useful concept that enables preventative intervention at the
onset of low-grade weight loss. Recent phase III trials have adopted a strategy of early intervention,
moving away from using 5% weight loss as an inclusion criteria and instead including patients with either
minimal weight loss (≥2%; see, for example, NCT00467844)108 or removing a requirement for prior weight
loss altogether (see, for example, NCT01355484)109. This approach is based on a high and imminent
probability of patients in the trial developing cachexia.

The catabolic sequelae of cancer treatments can add substantially to overall weight loss. For example,
mean weight losses in patients receiving neoadjuvant chemotherapy for oesophago-gastric cancer (~4.2
kg)113 or receiving chemoradiotherapy for head and neck cancer (~11.4 kg)23 are substantial, and these
losses are composed of lean tissue in the majority of patients24,113. Preventive measures can also be
deployed in anticipation of these losses. A multimodal approach targeting the multiple facets of cachexia
is likely to be the optimal approach.

[H15] Nutritional and metabolic treatment

Provision of adequate nutrition is a mainstay of cachexia treatment, and up-to-date guidelines for clinical
nutrition in oncology are available91. First-line approaches include oral nutritional supplements and
consultation with a nutritional health care professional to increase the quantity and quality of the patient’s
food. In patients in whom the dominant cause of weight loss is deficit of dietary intake (for example, those
receiving high-dose chemotherapy ahead of bone marrow transplantation, in whom daily deficits of oral
intake can exceed 1,200 kcal/day), active nutritional management leads to better treatment tolerance and
better quality of life95. For the majority of patients, and particularly for those with advanced-stage cancer,
the presence of insufficient dietary intake is not always identified and active nutritional management is not
always implemented15. Furthermore, compliance to oral nutritional supplements is generally low and in
some cases nutritional supplements merely displace food intake at mealtime114.

If volitional food intake remains insufficient after dietary consultation and oral nutritional supplements
have been deployed, escalation to artificial (enteral or parenteral) nutritional support is an option (Box 3).
Orexigenic drugs (appetite stimulants) have been developed to counteract low appetite in patients with
cachexia. Cannabinoids, corticosteroids and progestagens have these actions, but adverse effects
constrain their use115. For example, corticosteroids increase appetite but result in skeletal muscle atrophy;
progestogens have the same effect as well as increasing the risk of thromboembolism115. New therapies
to enhance food intake under investigation include ghrelin receptor agonists108,116 and melanocortin
receptor 4 antagonists117; these agents act on the hypothalamus, which regulates appetite and satiety,
but also have systemic effects to promote protein anabolism and energy storage.

Anabolic deficit may be partly addressed by maintenance of physical activity, a notion that is endorsed
within European oncology nutrition clinical practice guidelines91 as well as in the design of clinical trials of
multimodal intervention (see, for example, NCT02330926). Patients should be given support to enable
them to exercise within their safe capacity91,118. Cachexia in chronic non-malignant illnesses such as
chronic obstructive pulmonary disease has long been managed by a multimodal approach (including
nutrition and exercise)119. Indeed, a systematic review of 16 trials in patients with cancer in active
oncology treatment, showed that aerobic exercise, resistance exercise and a combination of two improve
upper and lower body muscle strength compared to usual care120. However, it has been noted that
patients with established cachexia might lack the motivation and self-efficacy to undertake regular
structured exercise121. Others have proposed interventions designed to provide exercise intervention
optimized for individual patient activity tolerance122.

Altered metabolism remains the most challenging aspect of cancer-associated cachexia for therapeutic
intervention. Specific therapeutic targets have been proposed for testing in clinical trials (Table 1) based
on preclinical investigation and covering a broad range of mechanisms. These targets reflect the
complexity of cachexia and are drawn from every point of our understanding of cachexia physiology,
including tumour-specific factors, pro-inflammatory cytokines and eicosanoids, and mediators of organ-
specific or tissue-specific control systems (Fig. 6). However, none of these suggested targets has as yet
led to approval of a drug for the indication of cancer-associated cachexia. Our understanding of the
underlying mechanisms of cachexia in individual patients is crude at best; accordingly, further
characterization of the clinical aetiologies is needed. One approach might be to assess and ‘rank’
different pro-cachectic mechanisms to guide drug development; however, routine management has not
achieved such a level of sophistication and aetiology-based diagnostic criteria has not been standardized
in clinical care or in clinical trials.

[H16] Symptom control

Cachexia does not occur in isolation; it occurs within a variable terrain of comorbid conditions, cancer
treatment response and toxicity, and alongside pain and other symptoms. Symptoms are a considerable
source of clinical heterogeneity in weight-losing patients, can change rapidly over the course of the
disease trajectory and treatment plan123 and are most common among patients receiving treatment for
advanced-stage cancers124 — but remain undetected by clinicians in up to half of patients125. Symptoms
present at any point in time are only a ‘snapshot’ of a longer story that can last several years, with
multiple treatments and complications contributing to progressive wasting. Cachexia cannot be divorced
from these circumstances and good medical management of pain and symptoms is another major
principle of cachexia management. Often, multiple causes of potentially reversible weight loss must be
assessed and appropriately managed; this is a point for action and immediate benefit to the patient118.

Causes of weight loss that are amenable to effective management include, but are not limited to, pain,
nausea, vomiting, dental problems, dysphagia, early satiety, oesophageal obstruction, malabsorption,
endocrine and metabolic disorders, anxiety, depression, distress and inability to sleep. Clinical trials of
cachexia therapy have been conducted in the past without a common standard of supportive care
elements across centers, which has been suggested to be a source of heterogeneity in individual patient
response. A multidisciplinary team approach to supportive care is needed91, the benefits of which have
been reported from prospectively conducted non-randomized studies126,127. Clinical services are emerging
that operate in partnership between palliative care physicians and the oncology community, as endorsed
currently by many cancer agencies including the American Society for Clinical Oncology128; these
services will be an asset for efficient management of symptoms contributing to cachexia.

[H17] Multimodal care

The inherent complexity of cancer cachexia calls for a multifaceted assessment strategy that focuses on
food intake, pain and symptoms, specific losses of muscle and fat, catabolic factors, tumour burden,
systemic inflammation and altered endocrine status, as well as the clinical, functional and psychosocial
consequences of the condition129–132. The rationale is that addressing food intake alone (for example)
would be insufficient because this would not necessarily be expected to mitigate excess catabolism (and
vice versa). In cancer surgery, a multimodal approach is embraced by multi-component enhanced
recovery after surgery protocols133. In current clinical practice, multimodal therapy is achieved by a
collaborative approach that engages a multidisciplinary team of health professionals as well as patients
and their families. Expertise included in multimodal therapy include clinical oncology, clinical nutrition and
palliative care teams as well as the possibility of specialist referral (for example, gastroenterologists).
Guidelines and protocols exist, and descriptions of dedicated cachexia services have been reported104–
106
. In ongoing clinical trials (see, for example, NCT02330926), multimodal intervention is formalized and
the study design can include nutritional therapy, anti-inflammatory interventions and/or exercise therapy.
However, such multimodal interventions remain a minority of available studies (Fig. 6 and Table 1).

A critically important underlying concept is that the driving forces advancing tumour growth and
metastases are the same driving forces that underlie cachexia. Accordingly, a combined and collaborative
approach to cancer and cachexia therapy, rather than sequential (or parallel) approaches would seem
most logical. The potential for a downward spiral, in which cachexia exacerbates treatment toxicity134,135,
which then further exacerbates cachexia, should be acknowledged. This spiral can be interrupted by
careful management of cachexia throughout treatment and attention to providing chemotherapy at doses
that are within the limits of tolerability for patients already affected by cachexia at the time treatment is
initiated. In day-to-day practice, patients who are older or who seem to have a reduced level of fitness are
routinely given lower chemotherapy doses or provided a regimen with reduced toxicity, at the treating
oncologist’s discretion. These approaches may be relevant for patients with manifestations of cachexia.

[H18] Cachexia at the end of life

At the distal end of the cachexia spectrum, the disorder can become refractory to therapeutic intervention;
when catabolism intensifies at an exponential pace5,136, cachexia is driven by progressive disease that no
longer responds to antineoplastic therapy, patients frequently become emaciated and death becomes
imminent. These blatant manifestations heighten the sense of anguish related to cachexia for patients
and their families. Psychological support is key at this point, with lesser emphasis on dietary intake as a
therapeutic objective.

Cachexia therapies are associated with risks, burdens and costs that need to be weighed against the
expected benefits, with the knowledge and consent of the patient. In refractory cachexia, medical
interventions may be futile or inappropriately invasive91,137. Artificial nutritional support in the form of
parenteral nutrition is a well-known example; clinical practice guidelines in nutrition, oncology and
palliative medicine consistently agree that in patients expected to survive <2 months, initiation of
parenteral feeding is not recommended91,137. Robust predictors of a patient’s entry into the end of life
phase are needed to limit the potential harm of aggressive anti-cancer therapy and anti-cachexia therapy.
Prognostic models for survival have been developed to assist decision-making concerning the use of
parenteral nutrition in patients with advanced cancer138.
A particular weakness of many previous clinical trials of cancer cachexia interventions was to include
patients with refractory cachexia or a mixture of these with individuals at earlier stages. Not surprisingly, a
substantial proportion of patients died within just a few weeks of random assignment110–112. Clinical trials
of cachexia therapy often have had inclusion criteria such as ‘expected survival’ of >6 months. However,
in the absence of adequate prognostic algorithms, such criteria have not prevented inclusion of
imminently dying patients in trials. High rates of attrition and missing data have created great difficulty in
interpreting the results of many investigations.

[H19] Quality of life

Cachexia-related quality of life is not currently evaluated by a single agreed instrument. The European
Organization for Research and Treatment of Cancer QLQ-C30 (EORTC-QLQC30) and Functional
Assessment of Anorexia Cachexia Therapy (FAACT) questionnaires are the most commonly used
instruments in the literature, whereby the former is not specific to cachexia and the latter has been used
but has been criticized as not fully representing all of the relevant domains139,140. A new cachexia quality
of life instrument is in development within the EORTC paradigm: the QLQ-CAX24 is a cancer cachexia-
specific questionnaire comprising 24 items for health-related quality of life assessment in clinical trials and
practice141. It contains five multi-item scales (food aversion, eating and weight-loss worry, eating
difficulties, loss of control and physical decline).

Psychological dimensions of the experience of cancer-associated cachexia from the perspective of

patients and their family members is less well explored than the biomedical aspects of the condition120-128.
Negative interactions with food and eating are described at every stage of cachexia; because of
alterations in the taste, smell and texture of food, usual foods and even favourite foods can become
unpleasant or even repulsive123,142,143. Chewing and swallowing can be painful, and an unpleasant
sensation of early satiety makes patients feel too full to continue eating or repelled by the quantity of food
served. Furthermore, patients express distress about weight loss and not eating enough and are highly
aware of death as the ultimate result of the weight loss123. Patients describe laborious efforts to maintain
and increase food intake and are often frustrated by emergent pain and symptoms. The wasted
appearance of the cachectic patient with cancer is a major source of concern for both patients and
families144,145. This experience occurs within unique personal, social, historical and cultural contexts.

Loss of control is another major theme in patient narratives about the experience of cancer-associated
cachexia. Even the most successful cachexia therapies only slow the rate of weight loss and weight is
lost regardless of the level of food intake. Fatigue, weakness and loss of independence compound the
sense of helplessness in patients, as does feeling pressured by others with respect to food and
eating123,145,146. If the patient and his or her family members do not have an equal degree of
understanding of disruption in food connections, conflict with family members over food and social
isolation can ensue144. For patients, the inability to share food in the manner hoped for by family members
can contribute to a larger concern about being a burden.

Psychosocial support to patients and families is recommended as part of cachexia management,

especially in the refractory stage129,130. The components of such support are in development147 and
include a reduces emphasis on preparing and serving food, enabling family to provide aid without
applying pressure and providing information about cachexia and how it will affect the patient and their
families.

[H20] Outlook
Cachexia represents a constellation of various phenotypes that require further study from many angles as
illustrated in this Primer. Encouragingly, cachexia now has wider recognition as an unmet medical
need148: its research is supported by an international society — the Society on Sarcopenia, Cachexia and
Wasting Disorders (http://society-scwd.org/) — and it has a dedicated research publication (namely, the
Journal of Cachexia, Sarcopenia and Muscle149) as well as a series of international conferences. Cancer
research has for many decades been advanced through a system of cooperative research groups that
conduct national or international multi-disciplinary research for cancer control; a timely addition to cancer
cachexia research would be a cooperative group of researchers, cancer centres and community-based
physicians to mount studies that test new ways to screen, prevent, diagnose and treat cancer cachexia.

[H21] Mechanisms/pathophysiology
Emerging mechanistic insights continue to emerge from studies in animal models. For example, new data
have surfaced that places attention on skeletal muscle stem cells150. Specifically, a resident stem cell
population called satellite cells151, which is marked by the transcription factor Pax7 (Ref.152), provides
regenerative capacity to this tissue. However, in experimental cancer-associated cachexia, this program
lacks key myogenic factors MyoD and myogenin that are needed to repair damaged myofibres150. Other
muscle progenitor cell populations (such as those expressing non-satellite cell markers, namely NG2 and
PDGFRa) also have been shown to be expanded in association with tumour-induced muscle damage.
Collectively, these Pax7+ progenitor cells demonstrate activation of NF-kB, which serves to retain a stem
cell fate rather than proceed through a differentiating regeneration program. This block in regeneration
that contributed to myofiber atrophy, occurred independently from the activation of the ubiquitin
proteasome and autophagy pathways that drive muscle loss from within the myofiber.

Another recent report suggested link between muscle weakness and bone metastasis arising from solid
tumours such as breast cancer or lytic bone lesions due to multiple myeloma153. Lytic metastatic lesions
release TGFb from bone matrix; circulating TGFb was shown to signal to skeletal muscle through SMAD2
and SMAD3 transcription factors to induce the transcription of NOX4 (which encodes NADPH oxidase).
NADPH oxidase stabilizes ryanodine receptor l (RyR1) via oxidation, causing aberrant Ca2+ ‘leakage’
from the sarcoplasmic reticulum, resulting in muscle weakness. Muscles from patients with lung and
prostate cancer with metastases to bone also exhibited oxidized RyR1. Many solid tumours, including
cancers of the stomach, pancreas, breast, colon and rectum154–157, release TGFb into the systemic
circulation. Using data from The Cancer Genome Atlas (TCGA), a recent study documented the presence
of a strong inflammatory gene signature in pancreatic cancer that includes IL-6 and IL-11, occurring in
conjunction with a strong TGFb gene signature158. Thus, inflammatory cytokines such as IL-6 and IL-11
possibly cause muscle loss that combines with TGFb-induced muscle weakness to accelerate cachexia-
associated muscle dysfunction.

Despite these advances, a translational gap between human and animal studies of cancer cachexia
remains. A large proportion of prior research in rodent models has been conducted on a rather limited
repertoire, including models harbouring colon-26 adenocarcinoma, Lewis lung carcinoma, Yoshida
hepatoma and Walker 256 carcinosarcoma159–162. The original cell lines have become unavailable, cells
have been passed between different laboratories and currently available subclones might have deviated
no longer provide consistent results81. The generation of genetically engineered models of cancer,
aligned with the clinical cachexia phenotypes, should offer new avenues for preclinical investigations. For
example, a murine model of pancreatic cancer, KRASG12D/+ P53-/- Pdx-Cre (KPC) congenic allografts in
C57Bl/6 mice163 as well as patient-derived orthotopic pancreatic cancer xenografts164 recapitulate the
cachexia features specifically associated with pancreatic ductal adenocarcinoma. Finally, cachexia
models do not reflect the clinical complexity of oncology patients, who are generally older and often
present with significant concomitant comorbidities and prior, as well as concurrent, treatment with
systemic therapies. Solutions to these issues are urgently needed.

[H22] Diagnosis
Aetiology-based diagnostic criteria for cancer-associated cachexia would represent a significant advance.
Weight loss ‘not otherwise specified’ is traditionally used as the basis for a diagnosis of cachexia and the
indication for treatment, regardless of aetiology. In past clinical trials, unspecified weight loss was treated
with a number of highly specific agents (including the monoclonal antibody infliximab, which targets
TNFa165) without testing whether the patients expressed the target. As the field continues to advance and
patients can be better classified and sub-classified using biomarkers, genomics or metabolomics, we will
be able to offer a more-personalized, mechanistically derived treatment approach to each patient. Some
emerging areas of human biology of cancer-associated cachexia include genetic risk variants9,166,167,
transcriptional variants168,169 and biological profiling using high dimensional omics approaches170–172.

[H23] Management
Because cachexia can be divorced mechanistically from the underlying disease10,11, and anabolic
processes can be activated under appropriate conditions in patients, the targeting of anabolic processes
should be possible. For example, patients with locally advanced or metastatic disease demonstrate
activation of muscle protein synthesis after intake of high-quality proteins8,25,26. Furthermore, drugs that
inhibit catabolic processes have been shown to increase both lean and fat mass in kilogram quantities
has been achieved in patients with some of the most catabolic diseases, including advanced-stage lung
cancer and cholangiocarcinoma6,7,108. Optimal conditions for exploiting this anabolic potential are currently
under study, with the overall aim of net improvements in muscle mass, functionality, performance status
and treatment tolerance.

Another area of growing interest is to use mechanistic insights to develop biomarkers and targeted
therapies for cachexia. To achieve this, more information on origins of heterogeneity in the patient-
specific aetiology of cachexia is needed. For example, tumour over-production of specific individual
mediators that are potently catabolic towards muscle or adipose tissue, such as PTHrP30,81,82 and
adrenomedullin173 (both of which elicit lipolysis in white adipose tissue), are potential targets. PTHrP is
normally absent in the peripheral blood of healthy individuals but mutations that amplify its expression in
tumours174 can promote high systemic concentrations in patients with cancer; this expression is
associated with poor prognosis175. Adrenomedullin has been shown to be encapsulated in tumour-derived
exosomes in pancreatic cancer173. It was also demonstrated that microvesicles (which include exosomes)
derived from pancreatic cancer cell lines can induce myoblast apoptosis by activating c-Jun N-terminal
kinase, and that this effect is mediated through the Toll-like receptor TLR7 (Ref.176). These effectors may
prove to be actionable targets of cancer cachexia in patients whose tumours overexpress them. However,
where complex inflammatory cascades are activated, redundancy between individual mediators is
common. Accordingly, the targeting a single mediator will unlikely ‘cure’ the majority of patients with
cancer-associated cachexia. Points of targeted intervention must be chosen to maximize impact on the
overall syndrome.

Intriguing relationships between cachexia therapy and cancer therapy are also emerging. For example,
studies suggest that tumour cell proliferation and the excess muscle protein catabolism characteristic of
cachexia might have a common mechanism. Specifically, the mitogen-activated protein kinase kinases
MEK1 and MEK2 act downstream of RAS and RAF to induce ERK activation, thereby communicating
input from growth factors to promote proliferation of tumour cells. This signalling pathway also seems to
be involved in the activation of excess muscle protein catabolism in the tumour-bearing organism6,177.
MEK inhibitors might, therefore, simultaneously have anti-cachexic and anti-tumour activity. Further
exploration of these types of interactions is warranted.

Finally, clinical trials of cancer-associated cachexia continue to evolve in their design and end points.
Until recently, the landscape of clinical trials for cachexia was somewhat limited and the overall quality of
the evidence was low91,115. However, now trials are no longer conducted in the refractory stage, avoiding
issues of confounding by death, dropout and missing data. Additionally, patient populations and
concurrent anti-cancer treatments in current cachexia clinical trials are more homogeneous than in the
past. However, regulatory authorities are being challenged with issues in study design and the specific
nature of approvable end points148. For example, although the consensus is that cachexia therapies
should be expected to produce stabilization or gain of radiologically-defined lean mass, skeletal muscle
and fat mass, an independent form of clinical benefit associated with these tissue gains is mandated by
regulatory authorities. The definition of this clinical benefit is contentious, and several recent randomized
phase III studies failed to meet criteria for approval based on the clinical benefit end points of handgrip
strength108 and stair climb test109. Alternatives to these end points are under discussion and might include
patient-reported outcomes, health care utilization, costs and/or survival. Although these developments are
ongoing, creating opportunities for patient participation in clinical trials of emerging drug therapies and
nutritional interventions for the indication of cancer-associated cachexia provides a way to access front-
line treatments. These investigations are essential to advance the testing and approval of new cachexia
therapies.

Display items

Box 1. Energy intake and energy expenditure imbalance in cancer-associated cachexia

Body weight remains stable when there is balance between energy intake (that is, calories provided via
oral, enteral or parenteral routes) and the total energy expenditure (TEE) by the body (see illustration).
Body weight loss occurs when there is a negative energy balance; a state where TEE exceeds energy
intake. TEE is the sum of resting energy expenditure (REE), activity-related energy expenditure (AEE)
and the thermic effect of food (TEF). REE is the amount of energy expended by the body at rest, and is
the largest contributor to TEE. Accordingly, as TEE is difficult to measure clinically in free-living
individuals, REE is typically assumed to represent energy metabolism. REE can be accurately measured
using indirect calorimetry or estimated using various widely used equations, which have many limitations.
Tumour metabolism and inflammation might increase REE and simultaneously decrease energy intake
(through, for example, loss of appetite), shifting the scale toward negative energy balance178,179.
Additionally, cancer treatments also influence energy balance; for example, energy intake may fall by
>50% (~1,200 kcal per day) during chemoradiotherapy in cancers of the head and neck23. These factors
contribute to the negative energy balance in cancer-associated cachexia.

Box 2. Assessment of dietary intake in clinical practice

Food intake — assessed as a component of clinical questionnaires — is used to screen or assess

nutritional status.
 • Example tools include the Patient Generated-Subjective Global Assessment (PGSGA), Mini
Nutrition Assessment (MNA), Malnutrition Screening Tool (MST), Malnutrition Universal
Screening Tool (MUST), Short Nutrition Assessment Questionnaire (SNAQ), Nutrition Risk
Screen (NRS2002).
• Questionnaires are completed by a healthcare provider or the patient, with reponses being
categorical in nature. Reductions to food intake are assessed as a ‘yes’ or ‘no’ response, or from
a categorical list describing the severity of the reduction (for example, ‘no decrease in food
intake’, ‘moderate decrease in food intake’ or ‘severe decrease in food intake’).
• The time frames for assessing reductions in food intake tend to be retrospective and are variable
(for example, current intake, recent intake, intake in the past week, past month or past 3 months)
• These tools are clinically practical and expedient, and are obtained from patient reporting.
• The information obtained identifies patients with reduced food intake who might benefit from
further dietary assessment and intervention.

Food intake can also be assessed from patient food records.

• Example tools include 24-hour recall (food consumed the previous day) and prospectively
collected 1–7-day food diaries.
• Current food and fluid intakes are recorded, entered into a country-specific nutrient database,
and macronutrient and micronutrient estimates are calculated.
• Diet records are burdensome to the patient and to healthcare provider who must process the
collected information, but are useful for determining food preferences and patterns of
consumption, which can aide in the development of a nutrition intervention.
Box 3. Options for nutrition support in patients with cancer

[H1] Volitional nutrition

Volitional nutrition refers to the oral ingestion of nutrients as normal food and/or oral nutritional
supplements (ONS). Dietary modification (such as increased calorie or protein density, or texture
modifications) and ONS are typical first-line interventions to improve intake in patients with cancer.
Management of pain and symptoms is essential to optimize volitional food intake.

[H2] Artificial nutrition

Artificial nutrition is non-volitional feeding and is initiated when an individual cannot meet their nutritional
requirements via oral intake. The indications to implement artificial nutrition are either total inability to eat
for >1 week or an energy intake <60% of requirement for >2 weeks91. Artificial nutrition is provided by the
enteral route, unless the gastrointestinal tract is not functional and includes:

• Enteral nutrition (tube feeding), which is any mode of feeding that uses the gastrointestinal tract
to deliver all or part of a patient’s nutritional requirement. A tube is used to access either the
stomach or jejunum. This might be used, for example, owing to tumour obstruction of the
oesophagus or dysphagia in pharyngeal cancer).
• Parenteral nutrition (intravenous feeding), which is a mode of feeding that delivers all or part of a
patient’s nutritional requirements intravenously via a central or peripheral vein, thereby
completely bypassing the gastrointestinal tract. This might be used, for example, in patients with
gastrointestinal tumours following surgical resection.

Associated risks of artificial nutrition include infections, gastrointestinal adverse effects (such as nausea,
vomiting, diarrhoea and hepatic abnormalities), metabolic dysregularities (such as hyperglycaemia) and
mechanical complications. High-quality evidence is lacking for the use of artificial nutrition to treat cancer-
associated cachexia; however, in settings in which intake is severely impaired primarily owing to tumour
location or symptoms of treatment, artificial nutrition can be partially effective and improve outcomes91.

Figure 1. Cancer cachexia by tumour site. The prevalence of cachexia (defined as >5% weight loss in
previous 6 months) by cancer site (panel a) and the average weight loss (%) and its variation (error bars)
by cancer site (panel b). Data from Refs12,15 .

Figure 2. Severe muscle depletion can occur in patients with cachexia or obesity. CT images from
two female patients with sarcopenia are shown; the images on the left correspond to a woman with a BMI
of 47 kg/m2, the images on the right correspond to a woman with a BMI of 17 kg/m2. Sarcopenia is occult
in the woman on the left but obvious in the woman on the right. For both women, the lumbar skeletal
muscle index (SMI, a standardized unit of measure of muscle area normalized for stature), is 36.8
cm2/m2. Although both women are 60 years of age, this SMI value is typical for a patient with cancer who
is >80 years of age68. Axial plane with tissue annotations (panels a and b). Sagittal plane (panels c and
d). Coronal plane (panels e and f). g | Distribution of SMI in female patients with advanced-stage
cancer68.

Figure 3. Inter-organ relationships in cancer-associated cachexia. On the basis of clinical and

experimental findings, tumour-derived catabolic factors have been shown to act on target tissues to elicit
excess catabolism. Numerous pro-inflammatory cytokines are generated through tumour cross-talk with
the immune system, which act directly on target tissues as well as through alteration of central nervous
system (CNS) controls of energy intake and expenditure. Mobilization of adipose tissue results from
specific tumour-derived lipolytic molecules (such as adrenomedulin), tumour factors which induce
uncoupling and futile cycling in this tissue (such as parathyroid hormone-related protein) and/or by
activation of sympathetic neural output. Skeletal and cardiac muscle mobilization is induced by multiple
pro-inflammatory cytokines, eicosanoids, and transforming growth factor-b (TGFb) family effectors (such
as activin and myostatin). These effectors might also be responsible for the failure of muscle stem cells to
appropriately proliferate and differentiate. Inflammation in the CNS evokes a catabolic programme in
muscle, rapidly inducing atrophy. This effect is dependent on hypothalamic–pituitary–adrenal axis
activation. GDF15, growth/differentiation factor 15; LIF, leukaemia inhibitory factor; miR; microRNA;
PGE2, prostaglandin E2; TNF, tumour necrosis factor; TNFRSF12A, TNF receptor superfamily member
12A (also known as FN14); TRAF6, TNF receptor-associated factor 6; TWEAK, TNF ligand superfamily
member 12.

Figure 4. Signalling pathways involved in tumour-induced skeletal muscle atrophy. Skeletal muscle
atrophy in cancer cachexia is regulated by signaling pathways that are activated by cytokines produced
by the immune system or the tumour itself. These factors signal through their respective cell-surface
receptors that activate selective transcription factors, which in turn bind to promoters of genes coding for
components of the ubiquitin proteasome and autophagy systems. In general, activation of these systems
leads to the destruction of selective myofibrillar proteins that form the sarcomere and provide contractile
function to skeletal muscles. Loss of these myofibrillar proteins presumably results in muscle atrophy and
weakness. Alternatively, growth factors such as and transforming growth factor-b (TGFb) can signal to
alter calcium (Ca2+) handling, leading to the dysfunction of the sarcomere without decaying sarcomeric
proteins. In addition to cytokines, growth factors such as insulin-like growth factor-1 (IGF1) signal through
AKT to mediate functional repression of the forkhead box proteins (Fox) O1 and FoxO3 transcription
factors to inhibit the expression of ubiquitin ligase and autophagy selective genes; in cachexia this activity
is often suppressed (indicated by dashed lines), leading to the transcription of genes that encode E3
ubiquitin ligase components. ActRII, activin receptor type-2A; C/EBPb, CCAAT/enhancer-binding protein-
b; GP130R; LIF, leukaemia inhibitory factor; NF-kB, nuclear factor-kB; P, phosphate; R, receptor; SMAD,
mothers against decapentaplegic homolog; STAT3, signal transducer and activator of transcription 3;
TNF, tumour necrosis factor; TNFRSF12A, TNF receptor superfamily member 12A (also known as FN14);
TWEAK, TNF ligand superfamily member 12.

Figure 5. Grading scheme for weight loss based on risk of mortality in patients with advanced-
stage cancer. The grading scheme was developed based on groupings of body mass index (BMI) and
weight loss (WL) showing distinct median survival durations. The analysis was laid out in a 5 × 5 matrix
representing five different weight loss categories within each of the five different BMI categories and
producing 25 possible combinations of weight loss and BMI. Grade 0 was assigned to the subgroups in
the matrix with the lowest risk (longest survival), and grades 1–4 were assigned to the subgroups
according to decreasing survival rates. Grades were developed based on 8,160 patients and adjusted for
age, sex, cancer site, cancer stage and performance status. Adapted from Ref.20

Figure 6. Proportional distribution of therapeutic approaches in clinical trials of cancer cachexia therapy.
Although not exhaustive, this summary of 134 trials (including published works and ongoing
investigations) of the major classes of cachexia therapies includes treatments at phase II–IV clinical trial.
The trials are reported in www.clinicaltrials.gov.
Table 1. Example phase III clinical trials for cancer-associated cachexia, anorexia and muscle wasting

Study n Therapy (mechanism) Therapeutic Results

approach

Temel et al.108 979 Anamorelin (ghrelin Appetite- • Increased lean body mass
receptor agonist) modifying • No effect handgrip strength
(NCT01395914 and anabolic
and

NCT01387269)

Crawford et al.109 651 Enobosarm (selective Anabolic Increased lean body mass, stair climb power
androgen receptor and stair climb speed in those receiving taxane
(NCT01355484 agonist) chemotherapy versus non-taxane
and chemotherapy

NCT01355497)

Bourdel- 341 Dietary advice Nutritional • No change in survival at 1 year and 2

Marchasson et years
al.180 • No change in chemotherapy toxicity
• No change body weight
(NCT00459589)

Sánchez-Lara et 96 w-3 fatty acids (oral Nutritional • Increased weight

al.181 nutritional supplement) • Increased lean body mass
• No change in chemotherapy response
(NCT01048970)

Madeddu et al.182 60 L-Carnitine, celecoxib Multimodal Non-inferiority of two-agent versus three-agent

and megestrol acetate combination with respect to lean body mass
versus L-carnitine and and total daily physical activity
celecoxib (nutritional
supplement and COX2
inhibitor with or without
appetite stimulant)
NCT02330926 240 Ibuprofen, physical Multimodal In progress; assessing body weight, muscle
activity, dietary advice mass and physical activity
and w-3 fatty acids
NCT02138422 276 Xilonix™ (anti-IL-1a) Anti- In progress; assessing disease response rate,
inflammatory muscle mass and appetite

NCT02553187 160 Kanglaite (coicis oil) Herbal or In progress; assessing body weight and lean
alternative body mass

NCT02802540 78 Nabilone (synthetic Other In progress; assessing anorexia, weight loss and
cannabinoid) caloric intake
Highlighted references

Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, Jatoi A, Loprinzi C, MacDonald N,
Mantovani G, Davis M, Muscaritoli M, Ottery F, Radbruch L, Ravasco P, Walsh D, Wilcock A, Kaasa S,
Baracos VE. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol.
2011;12(5):489-95. A Delphi consensus process provides a definition, provisional diagnostic
criteria and a roadmap for future development of clinical cachexia research.

Zhou X, Wang JL, Lu J, Song Y, Kwak KS, Jiao Q, Rosenfeld R, Chen Q, Boone T, Simonet WS, Lacey
DL, Goldberg AL, Han HQ. Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism
leads to prolonged survival. Cell. 2010;142(4):531-43. An experimental study showing survival benefit
in tumour bearing mice by an agent of which essentially the sole action is to prevent loss of
skeletal muscle mass.

Martin L, Senesse P, Gioulbasanis I, Antoun S, Bozzetti F, Deans C, et al. Diagnostic criteria for the
classification of cancer-associated weight loss. J Clin Oncol. 2015;33(1):90-9. Risk of mortality in an
international cachexia data set, stratified by BMI and weight loss, providing a prognostic grading
scheme for cancer-associated weight loss.

Martin L, Birdsell L, MacDonald N, Reiman T, Clandinin MT, McCargar LJ, et al. Cancer cachexia in the
age of obesity: skeletal muscle depletion is a powerful prognostic factor, independent of body mass index.
J Clin Oncol. 2013;31(12):1539-47. Risk of mortality in patients with solid tumours, associated with
reduced skeletal muscle mass.

Martin L, Birdsell L, MacDonald N, Reiman T, Clandinin MT, McCargar LJ, et al. Cancer cachexia in the
age of obesity: skeletal muscle depletion is a powerful prognostic factor, independent of body mass index.
J Clin Oncol. 2013;31(12):1539-47. Risk of mortality in patients with solid tumours, associated with
reduced skeletal muscle mass.

Fujiwara N, Nakagawa H, Kudo Y, Tateishi R, Taguri M, Watadani T, et al. Sarcopenia, intramuscular fat
deposition, and visceral adiposity independently predict the outcomes of hepatocellular carcinoma. J
Hepatol. 2015;63(1):131-40. Association of muscle depletion and mortality in an Asian population

Fujiwara N, Nakagawa H, Kudo Y, Tateishi R, Taguri M, Watadani T, et al. Sarcopenia, intramuscular fat
deposition, and visceral adiposity independently predict the outcomes of hepatocellular carcinoma. J
Hepatol. 2015;63(1):131-40. Association of muscle depletion and mortality in an Asian population

Mittal, A., et al., The TWEAK-Fn14 system is a critical regulator of denervation-induced skeletal muscle
atrophy in mice, J. Cell Biol., 2010, 188(6): 833-849.An early study demonstrating the requirement of
the TWEAK ligand and Fn14 receptor in regulating muscle wasting due to disuse atrophy
Lecker, S.H., et al., Multiple types of skeletal muscle atrophy involve a common program of changes in
gene expression. FASEB J, 2004. 18(1): p. 39-51. A gene expression profile analysis demonstrating
that the ubiquitin proteasome system is activated in multiple rodent models of skeletal muscle
atrophy

Sandri, M., et al., Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and
cause skeletal muscle atrophy, Cell, 2004, 117(3):399-412. Both the Stitt et al.[38] and Sandri et al.,
identified Foxo transcription factors as regulators of the ubiquitin proteasome system

Guttridge DC, Mayo MW, Madrid LV, Wang CY, & Baldwin AS, Jr. (2000) NF-kappaB-induced loss of
MyoD messenger RNA: possible role in muscle decay and cachexia. Science 289(5488):2363-2366. In a
C2C12 myotube system NF- B was identified as a regulator of muscle breakdown in response to
inflammatory cytokines

Cai D, et al. (2004) IKKbeta/NF-kappaB activation causes severe muscle wasting in mice. Cell
119(2):285-298. In vivo proof of concept that the NF- B signaling pathway is a regulator of skeletal
muscle atrophy

He, W.A., et al., NF-kappaB-mediated Pax7 dysregulation in the muscle microenvironment promotes
cancer cachexia. J Clin Invest, 2013, 123(11): 4821–4835. Evidence that dysfunctional regeneration
is a causal event in cancer-induced muscle wasting

Waning, D.L. et al., Excess TGF-b mediates muscle weakness associated with bone metastases in mice,
Nat. Med., 2015, 12(11):1262-1271. Provided evidence that bone-derived TGF mediates skeletal
muscle weakness by the misregulation of intracellular calcium

Craven, K.E., Gore, J., Wilson, J.L., & Korc M. Angiogenic gene signature in human pancreatic cancer
correlates with TGF-beta and inflammatory transcriptomes. Oncotarget 7, 323-41 (2016). Establishes an
association between enhanced TGF-β signaling in PDAC, enhanced expression of pro-
inflammatory genes, and increased JAK signaling, which may combine to worsen muscle loss.

Das, S.K., Eder, S., Schauer, S., Diwoky, C., Temmel, H., Guertl, B., Gorkiewicz, G., Tamilarasan, K.P.,
Kumari, P., Trauner, M. et al., Adipose triglyceride lipase contributes to cancer-associated cachexia,
Science, 2011; 333: 233–238. Provided evidence that lipolysis in cancer predisposes skeletal
muscle to undergo wasting.

Arends J, Bachmann P, Baracos V, Barthelemy N, Bertz H, Bozzetti F, Fearon K, Hütterer E, Isenring E,

Kaasa S, Krznaric Z, Laird B, Larsson M, Laviano A, Mühlebach S, Muscaritoli M, Oldervoll L, Ravasco P,
Solheim T, Strasser F, de van der Schueren M, Preiser JC. ESPEN guidelines on nutrition in cancer
patients. Clin Nutr. 2017;36(1):11-48. Evidence-based guidelines for nutrition screening and
intervention in patients with cancer

Dev R, Hui D, Chisholm G, Delgado-Guay M, Dalal S, Del Fabbro E, Bruera E. Hypermetabolism and
symptom burden in advanced cancer patients evaluated in a cachexia clinic. J Cachexia Sarcopenia
Muscle. 2015;6(1):95-8. One of several recent reports on a dedicated clinic for the treatment of
cancer cachexia

Temel JS, Abernethy AP, Currow DC, Friend J, Duus EM, Yan Y, Fearon KC. Anamorelin in patients with
non-small-cell lung cancer and cachexia (ROMANA 1 and ROMANA 2): results from two randomised,
double-blind, phase 3 trials. Lancet Oncol. 2016;17(4):519-31. Phase III clinical studies of a small
molecular weight ghrelin receptor agonist, demonstrating lean tissue gain in patients with non-
small cell lung cancer

Engelen MP, Safar AM, Bartter T, Koeman F, Deutz NE. High anabolic potential of essential amino acid
mixtures in advanced nonsmall cell lung cancer. Ann Oncol. 2015;26(9):1960-6. One of a series of
recent publications including Engelen et al. [129] and vanDijk et al. [130], demonstrating robust
protein synthetic responses to amino acid feeding in patients with advanced cancer

Sagar G, Sah RP, Javeed N, Dutta SK, Smyrk TC, Lau JS, Giorgadze N, Tchkonia T, Kirkland JL, Chari
ST, Mukhopadhyay D. Pathogenesis of pancreatic cancer exosome-induced lipolysis in adipose tissue.
Gut. 2016;65(7):1165-74. Clinical study of a novel mechanism of tumour-induced lipolysis

Fearon K, Argiles JM, Baracos VE, Bernabei R, Coats A, Crawford J, Deutz NE, Doehner W, Evans WJ,
Ferrucci L, Garcia JM, Gralla RJ, Jatoi A, Kalantar-Zadeh K, Lainscak M, Morley JE, Muscaritoli M,
Polkey MI, Rosano G, Rossi-Fanelli F, Schols AM, Strasser F, Vellas B, von Haehling S, Anker SD.
Request for regulatory guidance for cancer cachexia intervention trials. J Cachexia Sarcopenia Muscle.
2015;6(4):272-4. Commentary on regulatory issues for clinical cachexia research and drug
approval
1. DeWys, W. D. Pathophysiology of cancer cachexia: current understanding and areas for future
research. Cancer Res. 42, 721s–726s (1982).
2. Fearon, K. et al. Definition and classification of cancer cachexia: an international consensus.
Lancet. Oncol. 12, 489–95 (2011).
3. WHO. Cancer Fact sheet [online], http://www.who.int/mediacentre/factsheets/fs297/en/ (2017).
4. Amano, K. et al. C-reactive protein, symptoms and activity of daily living in patients with advanced
cancer receiving palliative care. J. Cachexia. Sarcopenia Muscle 8, 457–465 (2017).
5. Prado, C. M. et al. Central tenet of cancer cachexia therapy: do patients with advanced cancer
have exploitable anabolic potential? Am. J. Clin. Nutr. 98, 1012–1019 (2013).
6. Prado, C. M. M. et al. Skeletal muscle anabolism is a side effect of therapy with the MEK inhibitor:
selumetinib in patients with cholangiocarcinoma. Br. J. Cancer 106, 1583–6 (2012).
7. Baracos, V. E. Skeletal muscle anabolism in patients with advanced cancer. Lancet. Oncol. 16,
13–4 (2015).
8. van Dijk, D. P. et al. Effects of oral meal feeding on whole body protein breakdown and protein
synthesis in cachectic pancreatic cancer patients. J. Cachexia. Sarcopenia Muscle 6, 212–21
(2015).
9. Johns, N. et al. New genetic signatures associated with cancer cachexia as defined by low
skeletal muscle index and weight loss. J. Cachexia. Sarcopenia Muscle 8, 122–130 (2017).
10. Zhou, X. et al. Reversal of Cancer Cachexia and Muscle Wasting by ActRIIB Antagonism Leads to
Prolonged Survival. Cell 142, 531–543 (2010).
11. Tseng, Y.-C. et al. Preclinical Investigation of the Novel Histone Deacetylase Inhibitor AR-42 in the
Treatment of Cancer-Induced Cachexia. J. Natl. Cancer Inst. 107, djv274 (2015).
12. Pressoir, M. et al. Prevalence, risk factors and clinical implications of malnutrition in French
Comprehensive Cancer Centres. Br. J. Cancer 102, 966–971 (2010).
13. Bozzetti, F. & SCRINIO Working Group. Screening the nutritional status in oncology: a preliminary
report on 1,000 outpatients. Support. Care Cancer 17, 279–84 (2009).
14. Segura, A. et al. An epidemiological evaluation of the prevalence of malnutrition in Spanish
patients with locally advanced or metastatic cancer. Clin. Nutr. 24, 801–14 (2005).
15. Hébuterne, X. et al. Prevalence of malnutrition and current use of nutrition support in patients with
cancer. JPEN. J. Parenter. Enteral Nutr. 38, 196–204 (2014).
16. Kazemi-Bajestani, S. M. R., Becher, H., Fassbender, K., Chu, Q. & Baracos, V. E. Concurrent
evolution of cancer cachexia and heart failure: bilateral effects exist. J. Cachexia. Sarcopenia
Muscle 5, 95–104 (2014).
17. Antoun, S. et al. Association of skeletal muscle wasting with treatment with sorafenib in patients
with advanced renal cell carcinoma: results from a placebo-controlled study. J. Clin. Oncol. 28,
1054–60 (2010).
18. WHO. BMI classification [online], http://apps.who.int/bmi/index.jsp?introPage=intro_3.html (2017).
19. WHO. Obesity and overweight fact sheet [online],
http://www.who.int/mediacentre/factsheets/fs311/en/ (2016).
20. Martin, L. et al. Diagnostic criteria for the classification of cancer-associated weight loss. J. Clin.
Oncol. 33, 90–9 (2015).
21. Martin, L. et al. Cancer cachexia in the age of obesity: skeletal muscle depletion is a powerful
prognostic factor, independent of body mass index. J. Clin. Oncol. 31, 1539–47 (2013).
22. Demark-Wahnefried, W., Campbell, K. L. & Hayes, S. C. Weight management and its role in
breast cancer rehabilitation. Cancer 118, 2277–87 (2012).
23. Kubrak, C. et al. Clinical determinants of weight loss in patients receiving radiation and
chemoirradiation for head and neck cancer: A prospective longitudinal view. Head Neck 35, 695–
703 (2012).
24. Silver, H. J., Dietrich, M. S. & Murphy, B. A. Changes in body mass, energy balance, physical
function, and inflammatory state in patients with locally advanced head and neck cancer treated
with concurrent chemoradiation after low-dose induction chemotherapy. Head Neck 29, 893–900
(2007).
25. Engelen, M. P. K. J., Klimberg, V. S., Allasia, A. & Deutz, N. E. P. Presence of early stage cancer
does not impair the early protein metabolic response to major surgery. J. Cachexia. Sarcopenia
Muscle 8, 447–456 (2017).
26. Engelen, M. P. K. J., Safar, A. M., Bartter, T., Koeman, F. & Deutz, N. E. P. High anabolic
potential of essential amino acid mixtures in advanced nonsmall cell lung cancer. Ann. Oncol. 26,
1960–1966 (2015).
27. Hall, K. D. & Baracos, V. E. Computational modeling of cancer cachexia. Curr. Opin. Clin. Nutr.
Metab. Care 11, 214–221 (2008).
28. Friesen, D. E., Baracos, V. E. & Tuszynski, J. A. Modeling the energetic cost of cancer as a result
of altered energy metabolism: implications for cachexia. Theor. Biol. Med. Model. 12, 17 (2015).
29. Murphy, K. T. The pathogenesis and treatment of cardiac atrophy in cancer cachexia. Am. J.
Physiol. Heart Circ. Physiol. 310, H466-77 (2016).
30. Kir, S. & Spiegelman, B. M. CACHEXIA &amp; BROWN FAT: A BURNING ISSUE IN CANCER.
Trends in cancer 2, 461–463 (2016).
31. Fearon, K. C. H., Glass, D. J. & Guttridge, D. C. Cancer cachexia: mediators, signaling, and
metabolic pathways. Cell Metab. 16, 153–66 (2012).
32. Loomans, H. A. & Andl, C. D. Intertwining of Activin A and TGFβ Signaling: Dual Roles in Cancer
Progression and Cancer Cell Invasion. Cancers (Basel). 7, 70–91 (2014).
33. Loumaye, A. et al. Role of Activin A and myostatin in human cancer cachexia. J. Clin. Endocrinol.
Metab. 100, 2030–8 (2015).
34. Togashi, Y. et al. Activin signal promotes cancer progression and is involved in cachexia in a
subset of pancreatic cancer. Cancer Lett. 356, 819–27 (2015).
35. Chen, J. L. et al. Differential Effects of IL6 and Activin A in the Development of Cancer-Associated
Cachexia. Cancer Res. 76, 5372–82 (2016).
36. Johnston, A. J. et al. Targeting of Fn14 Prevents Cancer-Induced Cachexia and Prolongs Survival.
Cell 162, 1365–78 (2015).
37. Mittal, A. et al. The TWEAK-Fn14 system is a critical regulator of denervation-induced skeletal
muscle atrophy in mice. J. Cell Biol. 188, 833–49 (2010).
38. Sato, S., Ogura, Y., Tajrishi, M. M. & Kumar, A. Elevated levels of TWEAK in skeletal muscle
promote visceral obesity, insulin resistance, and metabolic dysfunction. FASEB J. 29, 988–1002
(2015).
39. Bodine, S. C. et al. Identification of ubiquitin ligases required for skeletal muscle atrophy. Science
294, 1704–8 (2001).
40. Gomes, M. D., Lecker, S. H., Jagoe, R. T., Navon, A. & Goldberg, A. L. Atrogin-1, a muscle-
specific F-box protein highly expressed during muscle atrophy. Proc. Natl. Acad. Sci. U. S. A. 98,
14440–5 (2001).
41. Stitt, T. N. et al. The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced
ubiquitin ligases by inhibiting FOXO transcription factors. Mol. Cell 14, 395–403 (2004).
42. Sandri, M. et al. Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and
cause skeletal muscle atrophy. Cell 117, 399–412 (2004).
43. Acharyya, S. et al. Cancer cachexia is regulated by selective targeting of skeletal muscle gene
products. J. Clin. Invest. 114, 370–8 (2004).
44. Clarke, B. A. et al. The E3 Ligase MuRF1 degrades myosin heavy chain protein in
dexamethasone-treated skeletal muscle. Cell Metab. 6, 376–85 (2007).
45. Penna, F. et al. Muscle atrophy in experimental cancer cachexia: is the IGF-1 signaling pathway
involved? Int. J. cancer 127, 1706–17 (2010).
46. Stephens, N. A. et al. Evaluating potential biomarkers of cachexia and survival in skeletal muscle
of upper gastrointestinal cancer patients. J. Cachexia. Sarcopenia Muscle 6, 53–61 (2015).
47. Sandri, M. Protein breakdown in muscle wasting: role of autophagy-lysosome and ubiquitin-
proteasome. Int. J. Biochem. Cell Biol. 45, 2121–9 (2013).
48. Sandri, M. Protein breakdown in cancer cachexia. Semin. Cell Dev. Biol. 54, 11–9 (2016).
49. Milan, G. et al. Regulation of autophagy and the ubiquitin-proteasome system by the FoxO
transcriptional network during muscle atrophy. Nat. Commun. 6, 6670 (2015).
50. Song, Y.-H. et al. Muscle-specific expression of IGF-1 blocks angiotensin II-induced skeletal
muscle wasting. J. Clin. Invest. 115, 451–8 (2005).
51. Sartori, R. et al. BMP signaling controls muscle mass. Nat. Genet. 45, 1309–18 (2013).
52. Guttridge, D. C., Mayo, M. W., Madrid, L. V, Wang, C. Y. & Baldwin, A. S. NF-kappaB-induced
loss of MyoD messenger RNA: possible role in muscle decay and cachexia. Science 289, 2363–6
(2000).
53. Cai, D. et al. IKKbeta/NF-kappaB activation causes severe muscle wasting in mice. Cell 119, 285–
98 (2004).
54. Mourkioti, F. et al. Targeted ablation of IKK2 improves skeletal muscle strength, maintains mass,
and promotes regeneration. J. Clin. Invest. 116, 2945–54 (2006).
55. Silva, K. A. S. et al. Inhibition of Stat3 activation suppresses caspase-3 and the ubiquitin-
proteasome system, leading to preservation of muscle mass in cancer cachexia. J. Biol. Chem.
290, 11177–87 (2015).
56. Zimmers, T. A., Fishel, M. L. & Bonetto, A. STAT3 in the systemic inflammation of cancer
cachexia. Semin. Cell Dev. Biol. 54, 28–41 (2016).
57. Ma, J. F. et al. STAT3 promotes IFNγ/TNFα-induced muscle wasting in an NF-κB-dependent and
IL-6-independent manner. EMBO Mol. Med. 9, 622–637 (2017).
58. Guo, D., Wang, C., Wang, Q., Qiao, Z. & Tang, H. Pantoprazole blocks the JAK2/STAT3 pathway
to alleviate skeletal muscle wasting in cancer cachexia by inhibiting inflammatory response.
Oncotarget 8, 39640–39648 (2017).
59. Zhang, G., Lin, R.-K., Kwon, Y. T. & Li, Y.-P. Signaling mechanism of tumor cell-induced up-
regulation of E3 ubiquitin ligase UBR2. FASEB J. 27, 2893–2901 (2013).
60. Marchildon, F., Lamarche, É., Lala-Tabbert, N., St-Louis, C. & Wiper-Bergeron, N. Expression of
CCAAT/Enhancer Binding Protein Beta in Muscle Satellite Cells Inhibits Myogenesis in Cancer
Cachexia. PLoS One 10, e0145583 (2015).
61. Sun, R. et al. Valproic acid attenuates skeletal muscle wasting by inhibiting C/EBPβ-regulated
atrogin1 expression in cancer cachexia. Am. J. Physiol. - Cell Physiol. 311, C101–C115 (2016).
62. Mueller, T. C., Bachmann, J., Prokopchuk, O., Friess, H. & Martignoni, M. E. Molecular pathways
leading to loss of skeletal muscle mass in cancer cachexia – can findings from animal models be
translated to humans? BMC Cancer 16, 75 (2016).
63. DeJong, C. H. C. et al. Systemic inflammation correlates with increased expression of skeletal
muscle ubiquitin but not uncoupling proteins in cancer cachexia. Oncol. Rep. 14, 257–63 (2005).
64. Schmitt, T. L. et al. Activity of the Akt-dependent anabolic and catabolic pathways in muscle and
liver samples in cancer-related cachexia. J. Mol. Med. (Berl). 85, 647–54 (2007).
65. Acharyya, S. et al. Dystrophin glycoprotein complex dysfunction: a regulatory link between
muscular dystrophy and cancer cachexia. Cancer Cell 8, 421–32 (2005).
66. Johns, N. et al. New genetic signatures associated with cancer cachexia as defined by low
skeletal muscle index and weight loss. J. Cachexia. Sarcopenia Muscle 8, 122–130 (2017).
67. Gallagher, I. J. et al. Suppression of skeletal muscle turnover in cancer cachexia: evidence from
the transcriptome in sequential human muscle biopsies. Clin. Cancer Res. 18, 2817–27 (2012).
68. Kazemi-Bajestani, S. M. R., Mazurak, V. C. & Baracos, V. Computed tomography-defined muscle
and fat wasting are associated with cancer clinical outcomes. Semin. Cell Dev. Biol. 54, 2–10
(2016).
69. Kalantar-Zadeh, K. et al. Why cachexia kills: examining the causality of poor outcomes in wasting
conditions. J. Cachexia. Sarcopenia Muscle 4, 89–94 (2013).
70. Prado, C. M. M. et al. Prevalence and clinical implications of sarcopenic obesity in patients with
solid tumours of the respiratory and gastrointestinal tracts: a population-based study. Lancet.
Oncol. 9, 629–35 (2008).
71. Sjøblom, B. et al. Drug Dose Per Kilogram Lean Body Mass Predicts Hematologic Toxicity From
Carboplatin-Doublet Chemotherapy in Advanced Non–Small-Cell Lung Cancer. Clin. Lung Cancer
18, e129–e136 (2017).
72. Burfeind, K. G., Michaelis, K. A. & Marks, D. L. The central role of hypothalamic inflammation in
the acute illness response and cachexia. Semin. Cell Dev. Biol. 54, 42–52 (2016).
73. Grossberg, A. J. et al. Arcuate nucleus proopiomelanocortin neurons mediate the acute anorectic
actions of leukemia inhibitory factor via gp130. Endocrinology 151, 606–16 (2010).
74. Bodnar, R. J. et al. Mediation of anorexia by human recombinant tumor necrosis factor through a
peripheral action in the rat. Cancer Res. 49, 6280–4 (1989).
75. Braun, T. P. et al. Central nervous system inflammation induces muscle atrophy via activation of
the hypothalamic-pituitary-adrenal axis. J. Exp. Med. 208, 2449–63 (2011).
76. Molfino, A. et al. Cancer anorexia: hypothalamic activity and its association with inflammation and
appetite-regulating peptides in lung cancer. J. Cachexia. Sarcopenia Muscle 8, 40–47 (2017).
77. Fouladiun, M. et al. Body composition and time course changes in regional distribution of fat and
lean tissue in unselected cancer patients on palliative care—Correlations with food intake,
metabolism, exercise capacity, and hormones. Cancer 103, 2189–2198 (2005).
78. Zuijdgeest-van Leeuwen, S. D. et al. Lipolysis and lipid oxidation in weight-losing cancer patients
and healthy subjects. Metabolism 49, 931–936 (2000).
79. Rydén, M. & Arner, P. Fat loss in cachexia—is there a role for adipocyte lipolysis? Clin. Nutr. 26,
1–6 (2007).
80. Das, S. K. et al. Adipose Triglyceride Lipase Contributes to Cancer-Associated Cachexia. Science
(80-. ). 333, 233–238 (2011).
81. Kir, S. et al. Tumour-derived PTH-related protein triggers adipose tissue browning and cancer
cachexia. Nature 513, 100–104 (2014).
82. Petruzzelli, M. et al. A Switch from White to Brown Fat Increases Energy Expenditure in Cancer-
Associated Cachexia. Cell Metab. 20, 433–447 (2014).
83. Neves, R. X. et al. White adipose tissue cells and the progression of cachexia: inflammatory
pathways. J. Cachexia. Sarcopenia Muscle 7, 193–203 (2015).
84. Camargo, R. et al. NF-κBp65 and Expression of Its Pro-Inflammatory Target Genes Are
Upregulated in the Subcutaneous Adipose Tissue of Cachectic Cancer Patients. Nutrients 7,
4465–4479 (2015).
85. Zimmermann, R. Fat Mobilization in Adipose Tissue Is Promoted by Adipose Triglyceride Lipase.
 Science (80-. ). 306, 1383–1386 (2004).
86. Rohm, M. et al. An AMP-activated protein kinase–stabilizing peptide ameliorates adipose tissue
wasting in cancer cachexia in mice. Nat. Med. 22, 1120–1130 (2016).
87. Tisdale, M. J. Cachexia in cancer patients. Nat. Rev. Cancer 2, 862–71 (2002).
88. MacDonald, A. J. et al. Habitual Myofibrillar Protein Synthesis Is Normal in Patients with Upper GI
Cancer Cachexia. Clin. Cancer Res. 21, 1734–40 (2015).
89. Martin, L. Diagnostic criteria for cancer cachexia: data versus dogma. Curr. Opin. Clin. Nutr.
Metab. Care 19, 188–98 (2016).
90. Vagnildhaug, O. M. et al. The applicability of a weight loss grading system in cancer cachexia: a
longitudinal analysis. J. Cachexia. Sarcopenia Muscle (2017). doi:10.1002/jcsm.12220
91. Arends, J. et al. ESPEN guidelines on nutrition in cancer patients. Clin. Nutr. 36, 11–48 (2017).
92. Vazeille, C. et al. Relation between hypermetabolism, cachexia, and survival in cancer patients: a
prospective study in 390 cancer patients before initiation of anticancer therapy. Am. J. Clin. Nutr.
105, 1139–1147 (2017).
93. Read, J. A. et al. Nutritional Assessment in Cancer: Comparing the Mini-Nutritional Assessment
(MNA) With the Scored Patient-Generated Subjective Global Assessment (PGSGA). Nutr. Cancer
53, 51–56 (2005).
94. Hubbard, J. M., Cohen, H. J. & Muss, H. B. Incorporating biomarkers into cancer and aging
research. J. Clin. Oncol. 32, 2611–6 (2014).
95. Fujiwara, N. et al. Sarcopenia, intramuscular fat deposition, and visceral adiposity independently
predict the outcomes of hepatocellular carcinoma. J. Hepatol. 63, 131–140 (2015).
96. Epstein, F. H., Gabay, C. & Kushner, I. Acute-Phase Proteins and Other Systemic Responses to
Inflammation. N. Engl. J. Med. 340, 448–454 (1999).
97. Douglas, E. & McMillan, D. C. Towards a simple objective framework for the investigation and
treatment of cancer cachexia: The Glasgow Prognostic Score. Cancer Treat. Rev. 40, 685–691
(2014).
98. Laird, B. J. A. et al. Quality of Life in Patients With Advanced Cancer: Differential Association With
Performance Status and Systemic Inflammatory Response. J. Clin. Oncol. 34, 2769–2775 (2016).
99. Wei, B. et al. The neutrophil lymphocyte ratio is associated with breast cancer prognosis: an
updated systematic review and meta-analysis. Onco. Targets. Ther. Volume 9, 5567–5575
(2016).
100. Hong, N. et al. Serum PTHrP Predicts Weight Loss in Cancer Patients Independent of
Hypercalcemia, Inflammation, and Tumor Burden. J. Clin. Endocrinol. Metab. 101, 1207–1214
(2016).
101. Lerner, L. et al. Plasma growth differentiation factor 15 is associated with weight loss and mortality
in cancer patients. J. Cachexia. Sarcopenia Muscle 6, 317–324 (2015).
102. Macciò, A. et al. A randomized phase III clinical trial of a combined treatment for cachexia in
 patients with gynecological cancers: evaluating the impact on metabolic and inflammatory profiles
and quality of life. Gynecol. Oncol. 124, 417–25 (2012).
103. Isenring, E. & Elia, M. Which screening method is appropriate for older cancer patients at risk for
malnutrition? Nutrition 31, 594–597 (2015).
104. Scott, D., Reid, J., Hudson, P., Martin, P. & Porter, S. Health care professionals’ experience,
understanding and perception of need of advanced cancer patients with cachexia and their
families: The benefits of a dedicated clinic. BMC Palliat. Care 15, (2016).
105. Dev, R. et al. Hypermetabolism and symptom burden in advanced cancer patients evaluated in a
cachexia clinic. J. Cachexia. Sarcopenia Muscle 6, 95–98 (2015).
106. Vigano, A., Del Fabbro, E., Bruera, E. & Borod, M. The Cachexia Clinic: From Staging to
Managing Nutritional and Functional Problems in Advanced Cancer Patients. Crit. Rev. Oncog. 17,
293–304 (2012).
107. Blum, D., Hess, J., Omlin, A., Jurt, G. & Strasser ABHPM, F. Comprehensive cancer cachexia
staging and its impact in the outpatient oncology setting: A phase II study. J. Clin. Oncol. 27,
e20530–e20530 (2009).
108. Temel, J. S. et al. Anamorelin in patients with non-small-cell lung cancer and cachexia (ROMANA
1 and ROMANA 2): results from two randomised, double-blind, phase 3 trials. Lancet Oncol. 17,
519–531 (2016).
109. Crawford, J. et al. Study Design and Rationale for the Phase 3 Clinical Development Program of
Enobosarm, a Selective Androgen Receptor Modulator, for the Prevention and Treatment of
Muscle Wasting in Cancer Patients (POWER Trials). Curr. Oncol. Rep. 18, (2016).
110. Fearon, K. C. H. et al. Double-Blind, Placebo-Controlled, Randomized Study of Eicosapentaenoic
Acid Diester in Patients With Cancer Cachexia. J. Clin. Oncol. 24, 3401–3407 (2006).
111. Bruera, E. et al. Effect of Fish Oil on Appetite and Other Symptoms in Patients With Advanced
Cancer and Anorexia/Cachexia: A Double-Blind, Placebo-Controlled Study. J. Clin. Oncol. 21,
129–134 (2003).
112. Strasser, F. et al. Comparison of Orally Administered Cannabis Extract and Delta-9-
Tetrahydrocannabinol in Treating Patients With Cancer-Related Anorexia-Cachexia Syndrome: A
Multicenter, Phase III, Randomized, Double-Blind, Placebo-Controlled Clinical Trial From the
Cannabi. J. Clin. Oncol. 24, 3394–3400 (2006).
113. Awad, S. et al. Marked changes in body composition following neoadjuvant chemotherapy for
oesophagogastric cancer. Clin. Nutr. 31, 74–77 (2012).
114. Fearon, K. C. H. Effect of a protein and energy dense n-3 fatty acid enriched oral supplement on
loss of weight and lean tissue in cancer cachexia: a randomised double blind trial. Gut 52, 1479–
1486 (2003).
115. Baracos, V. E., Watanbe, S. & Fearon, K. in The Oxford Textbook of Palliative Medicine 5th Edn
702–712 (2015).
116. DeBoer, M. D. Ghrelin and cachexia: Will treatment with GHSR-1a agonists make a difference for
patients suffering from chronic wasting syndromes? Mol. Cell. Endocrinol. 340, 97–105 (2011).
117. Dallmann, R. et al. The orally active melanocortin-4 receptor antagonist BL-6020/979: a promising
candidate for the treatment of cancer cachexia. J. Cachexia. Sarcopenia Muscle 2, 163–174
(2011).
118. MacDonald, N., Easson, A. M., Mazurak, V. C., Dunn, G. P. & Baracos, V. E. Understanding and
managing cancer cachexia. J. Am. Coll. Surg. 197, 143–161 (2003).
119. Garvey, C. et al. Pulmonary Rehabilitation Exercise Prescription in Chronic Obstructive Pulmonary
Disease. J. Cardiopulm. Rehabil. Prev. 36, 75–83 (2016).
120. Stene, G. B. et al. Effect of physical exercise on muscle mass and strength in cancer patients
during treatment--a systematic review. Crit. Rev. Oncol. Hematol. 88, 573–93 (2013).
121. Wasley, D. et al. Patients with established cancer cachexia lack the motivation and self-efficacy to
undertake regular structured exercise. Psychooncology. (2017). doi:10.1002/pon.4512
122. Mayo, N. E. et al. Pedometer-facilitated walking intervention shows promising effectiveness for
reducing cancer fatigue: a pilot randomized trial. Clin. Rehabil. 28, 1198–209 (2014).
123. Shragge, J. E., Wismer, W. V, Olson, K. L. & Baracos, V. E. Shifting to conscious control:
psychosocial and dietary management of anorexia by patients with advanced cancer. Palliat. Med.
21, 227–233 (2007).
124. Reilly, C. M. et al. A literature synthesis of symptom prevalence and severity in persons receiving
active cancer treatment. Support. Care Cancer 21, 1525–1550 (2013).
125. Pakhomov, S. V, Jacobsen, S. J., Chute, C. G. & Roger, V. L. Agreement between patient-
reported symptoms and their documentation in the medical record. Am. J. Manag. Care 14, 530–9
(2008).
126. Gagnon, B. et al. A prospective evaluation of an interdisciplinary nutrition–rehabilitation program
for patients with advanced cancer. Curr. Oncol. 20, 310 (2013).
127. Chasen, M. R., Feldstain, A., Gravelle, D., MacDonald, N. & Pereira, J. An interprofessional
palliative care oncology rehabilitation program: effects on function and predictors of program
completion. Curr. Oncol. 20, 301 (2013).
128. Smith, T. J. et al. American Society of Clinical Oncology Provisional Clinical Opinion: The
Integration of Palliative Care Into Standard Oncology Care. J. Clin. Oncol. 30, 880–887 (2012).
129. Fearon, K. C. H. Cancer cachexia: Developing multimodal therapy for a multidimensional problem.
Eur. J. Cancer 44, 1124–1132 (2008).
130. Maddocks, M. et al. Practical multimodal care for cancer cachexia. Curr. Opin. Support. Palliat.
Care 10, 298–305 (2016).
131. Fearon, K., Arends, J. & Baracos, V. Understanding the mechanisms and treatment options in
cancer cachexia. Nat. Rev. Clin. Oncol. 10, 90–99 (2012).
132. Aapro, M. et al. Early recognition of malnutrition and cachexia in the cancer patient: a position
 paper of a European School of Oncology Task Force. Ann. Oncol. 25, 1492–1499 (2014).
133. Lassen, K. et al. Pancreaticoduodenectomy: ERAS recommendations. Clin. Nutr. 32, 870–871
(2013).
134. Palmela, C. et al. Body Composition as a Prognostic Factor of Neoadjuvant Chemotherapy
Toxicity and Outcome in Patients with Locally Advanced Gastric Cancer. J. Gastric Cancer 17, 74
(2017).
135. Daly, L. E. et al. The impact of body composition parameters on ipilimumab toxicity and survival in
patients with metastatic melanoma. Br. J. Cancer 116, 310–317 (2017).
136. Lieffers, J. R. et al. A viscerally driven cachexia syndrome in patients with advanced colorectal
cancer: contributions of organ and tumor mass to whole-body energy demands. Am. J. Clin. Nutr.
89, 1173–1179 (2009).
137. Bozzetti, F. ESPEN guideline on ethical aspects of artificial nutrition and hydration. Clin. Nutr. 35,
1577 (2016).
138. Bozzetti, F. et al. Development and validation of a nomogram to predict survival in incurable
cachectic cancer patients on home parenteral nutrition. Ann. Oncol. 26, 2335–2340 (2015).
139. Tarricone, R., Ricca, G., Nyanzi-Wakholi, B. & Medina-Lara, A. Impact of cancer anorexia-
cachexia syndrome on health-related quality of life and resource utilisation: A systematic review.
Crit. Rev. Oncol. Hematol. 99, 49–62 (2016).
140. Wheelwright, S. et al. A systematic review of health-related quality of life instruments in patients
with cancer cachexia. Support. Care Cancer 21, 2625–2636 (2013).
141. Wheelwright, S. J. et al. Development of the EORTC QLQ-CAX24, A Questionnaire for Cancer
Patients With Cachexia. J. Pain Symptom Manage. 53, 232–242 (2017).
142. Oberholzer, R. et al. Psychosocial Effects of Cancer Cachexia: A Systematic Literature Search
and Qualitative Analysis. J. Pain Symptom Manage. 46, 77–95 (2013).
143. Maschke, J. et al. Nutritional care of cancer patients: a survey on patients’ needs and medical care
in reality. Int. J. Clin. Oncol. 22, 200–206 (2016).
144. Hopkinson, J. B. Psychosocial impact of cancer cachexia. J. Cachexia. Sarcopenia Muscle 5, 89–
94 (2014).
145. Wheelwright, S., Darlington, A.-S., Hopkinson, J. B., Fitzsimmons, D. & Johnson, C. A systematic
review and thematic synthesis of quality of life in the informal carers of cancer patients with
cachexia. Palliat. Med. 30, 149–160 (2016).
146. Hopkinson, J. B. Food connections: A qualitative exploratory study of weight- and eating-related
distress in families affected by advanced cancer. Eur. J. Oncol. Nurs. 20, 87–96 (2016).
147. Hopkinson, J. B. & Richardson, A. A mixed-methods qualitative research study to develop a
complex intervention for weight loss and anorexia in advanced cancer: The Family Approach to
Weight and Eating. Palliat. Med. 29, 164–176 (2014).
148. von Haehling, S. & Anker, S. D. Cachexia as major underestimated unmet medical need: Facts
 and numbers. Int. J. Cardiol. 161, 121–123 (2012).
149. Journal of Cachexia, Sarcopenia and Muscle [online],
http://onlinelibrary.wiley.com/journal/10.1007/13539.2190-6009 (2017).
150. He, W. A. et al. NF-kB mediated Pax7 dysregulation in the muscle microenvironment promotes
cancer cachexia. J. Clin. Invest. 123, 4821–4835 (2013).
151. Viguie, C. A., Lu, D.-X., Huang, S.-K., Rengen, H. & Carlson, B. M. Quantitative study of the
effects of long-term denervation on the extensor digitorum longus muscle of the rat. Anat. Rec.
248, 346–354 (1997).
152. Seale, P. et al. Pax7 Is Required for the Specification of Myogenic Satellite Cells. Cell 102, 777–
786 (2000).
153. Waning, D. L. et al. Excess TGF-β mediates muscle weakness associated with bone metastases
in mice. Nat. Med. 21, 1262–1271 (2015).
154. Sheen-Chen, S.-M. Serum Levels of Transforming Growth Factor β1 in Patients With Breast
Cancer. Arch. Surg. 136, 937 (2001).
155. HUANG, A. et al. Increased serum transforming growth factor-beta1 in human colorectal cancer
correlates with reduced circulating dendritic cells and increased colonic Langerhans cell infiltration.
Clin. Exp. Immunol. 134, 270–278 (2003).
156. Li, X. et al. Elevated serum level and gene polymorphisms of TGF-β1 in gastric cancer. J. Clin.
Lab. Anal. 22, 164–171 (2008).
157. Poch, B. et al. Systemic immune dysfunction in pancreatic cancer patients. Langenbeck’s Arch.
Surg. 392, 353–358 (2007).
158. Craven, K. E., Gore, J., Wilson, J. L. & Korc, M. Angiogenic gene signature in human pancreatic
cancer correlates with TGF-beta and inflammatory transcriptomes. Oncotarget 1, 323–341 (2010).
159. Morrison, S. D. Feeding response to change in absorbable food fraction during growth of Walker
256 carcinosarcoma. Cancer Res. 32, 968–72 (1972).
160. Baccino, F. M., Tessitore, L., Bonelli, G. & Isidoro, C. Protein turnover states of tumour cells and
host tissues in an experimental model. Biomed. Biochim. Acta 45, 1585–90 (1986).
161. Ohe, Y. et al. Interleukin-6 cDNA transfected Lewis lung carcinoma cells show unaltered net
tumour growth rate but cause weight loss and shortened survival in syngeneic mice. Br. J. Cancer
67, 939–944 (1993).
162. Tanaka, Y. et al. Experimental cancer cachexia induced by transplantable colon 26
adenocarcinoma in mice. Cancer Res. 50, 2290–5 (1990).
163. Michaelis, K. A. et al. Establishment and characterization of a novel murine model of pancreatic
cancer cachexia. J. Cachexia. Sarcopenia Muscle (2017). doi:10.1002/jcsm.12225
164. Go, K. L. et al. Orthotopic Patient-Derived Pancreatic Cancer Xenografts Engraft Into the
Pancreatic Parenchyma, Metastasize, and Induce Muscle Wasting to Recapitulate the Human
Disease. Pancreas 1 (2017). doi:10.1097/mpa.0000000000000843
165. Wiedenmann, B. et al. A multicenter, phase II study of infliximab plus gemcitabine in pancreatic
cancer cachexia. J. Support. Oncol. 6, 18–25 (2008).
166. Tan, B. H. L. et al. P-selectin genotype is associated with the development of cancer cachexia.
EMBO Mol. Med. 4, 462–71 (2012).
167. Johns, N. et al. Genetic basis of interindividual susceptibility to cancer cachexia: selection of
potential candidate gene polymorphisms for association studies. J. Genet. 93, 893–916 (2014).
168. Narasimhan, A. et al. Small RNAome profiling from human skeletal muscle: novel miRNAs and
their targets associated with cancer cachexia. J. Cachexia. Sarcopenia Muscle 8, 405–416 (2017).
169. Gallagher, I. J. et al. Suppression of Skeletal Muscle Turnover in Cancer Cachexia: Evidence from
the Transcriptome in Sequential Human Muscle Biopsies. Clin. Cancer Res. 18, 2817–2827
(2012).
170. Twelkmeyer, B., Tardif, N. & Rooyackers, O. Omics and cachexia. Curr. Opin. Clin. Nutr. Metab.
Care 20, 181–185 (2017).
171. Gallagher, I. J., Jacobi, C., Tardif, N., Rooyackers, O. & Fearon, K. Omics/systems biology and
cancer cachexia. Semin. Cell Dev. Biol. 54, 92–103 (2016).
172. Ebhardt, H. A. et al. Comprehensive proteome analysis of human skeletal muscle in cachexia and
sarcopenia: A pilot study. J. Cachexia. Sarcopenia Muscle (2017). doi:10.1002/jcsm.12188
173. Sagar, G. et al. Pathogenesis of pancreatic cancer exosome-induced lipolysis in adipose tissue.
Gut 65, 1165–1174 (2015).
174. Sidler, B. et al. Amplification of the parathyroid hormone-related peptide gene in a colonic
carcinoma. J. Clin. Endocrinol. Metab. 81, 2841–2847 (1996).
175. Washam, C. L. et al. Identification of PTHrP(12-48) as a Plasma Biomarker Associated with Breast
Cancer Bone Metastasis. Cancer Epidemiol. Biomarkers Prev. 22, 972–983 (2013).
176. He, W. A. et al. Microvesicles containing miRNAs promote muscle cell death in cancer cachexia
via TLR7. Proc. Natl. Acad. Sci. U. S. A. 111, 4525–9 (2014).
177. Baracos, V. E. Mitogen-Activated Protein Kinases Inhibitors: Potential Therapeutic Agents for
Cancer Cachexia. Mol. Cancer Ther. 16, 263–264 (2017).
178. Hall, K. D. et al. Energy balance and its components: implications for body weight regulation. Am.
J. Clin. Nutr. 95, 989–994 (2012).
179. Purcell, S. A., Elliott, S. A., Baracos, V. E., Chu, Q. S. C. & Prado, C. M. Key determinants of
energy expenditure in cancer and implications for clinical practice. Eur. J. Clin. Nutr. 70, 1230–
1238 (2016).
180. Bourdel-Marchasson, I. et al. Nutritional advice in older patients at risk of malnutrition during
treatment for chemotherapy: a two-year randomized controlled trial. PLoS One 9, e108687 (2014).
181. Sánchez-Lara, K. et al. Effects of an oral nutritional supplement containing eicosapentaenoic acid
on nutritional and clinical outcomes in patients with advanced non-small cell lung cancer:
randomised trial. Clin. Nutr. 33, 1017–23 (2014).
182. Madeddu, C. et al. Randomized phase III clinical trial of a combined treatment with carnitine +
celecoxib ± megestrol acetate for patients with cancer-related anorexia/cachexia syndrome. Clin.
Nutr. 31, 176–82 (2012).
Figure 1

B
 A B
G
Figure 2

Patients (%)
D
C
Lumbar skeletal muscle index (cm2/m2)

Yellow: visceral adipose tissue

Red : skeletal muscle
Blue: subcutaneous adipose tissue
Green: intermuscular adipose tissue

F
E
Figure 3
Tumour-derived catabolic factors
• Activin

immune infiltration
Crosstalk •
•
Myostatin
TGFb
• Serotonin
• PTHrP

Tumour with
• Adrenomedullin and miR-21 (exported in exosomes)

Pro-inflammatory mediators arising from tumour-immune system

crosstalk
• IL-1a • LIF
• IL-1b • GDF-15
• IL-6 • TWEAK
• IFNg • TRAF6
• TNF • Oncostatin M
• IL-11 • FN14
• IL-17 • PGE2

White adipose tissue

‘Browned’
adipose Brown adipose tissue
tissue

Satellite cells
Figure 4

TGFb
IL-6 LIF
TNF TWEAK Activin Myostatin

IGF

TNFR FN14 GP130R

ActRII/TbRII
IGFR STAT3
NF-kB SMAD2 /
Myonucleus Ca2+ mishandling
SMAD3
C/EBPb

PI3K
Contractile
P dysfunction
FoxO1/ Inhibition of
AKT nuclear import
­ Transcription
FoxO3
Myofibrillar
E3 ubiquitin ligase genes
Autophagy genes protein
breakdown

Sarcomere
Myonucleus
Figure 5