REVIEW
Managing Cachexia in Head and Neck Cancer:
a Systematic Scoping Review
Antti A. Ma¨kitie . Rasheed Omobolaji Alabi . Helena Orell .
Omar Youssef . Alhadi Almangush . Akihiro Homma .
Robert P. Takes . Fernando Lo´pez . Remco de Bree . Juan P. Rodrigo .
Alfio Ferlito
Received: January 11, 2022 / Accepted: February 3, 2022 / Published online: February 27, 2022
 The Author(s) 2022
ABSTRACT
Introduction: Patients with head and neck
cancer (HNC) are usually confronted with
functional changes due to the malignancy itself
or its treatment. These factors typically affect
important structures involved in speech,
breathing, chewing, swallowing, and saliva
production. Consequently, the intake of food
will be limited, which further contributes to loss
of body weight and muscle mass, anorexia,
malnutrition, fatigue, and anemia. This multi-
factorial condition can ultimately lead to cancer
cachexia syndrome. This study aims to examine
the treatment of cachexia in HNC patients.
Methods: We systematically searched
OvidMedline, PubMed, Scopus, and Web of
Science for articles examining the treatment of
cachexia in HNC.
Results: A total of nine studies were found, and
these suggested interventions including nutri-
tional, pharmacologic, therapeutic exercise, and
This article was written by members and invitees of the
International Head and Neck Scientific Group
(www.IHNSG.com).
A. A. Ma¨kitie (&)
Department of Otorhinolaryngology-Head and Neck
Surgery, University of Helsinki and Helsinki
University Hospital, P.O. Box 263, 00029 HUS
Helsinki, Finland
e-mail: antti.makitie@helsinki.fi
A. A. Ma¨kitie  R. O. Alabi  O. Youssef 
A. Almangush
Faculty of Medicine, Research Program in Systems
Oncology, University of Helsinki, Helsinki, Finland
A. A. Ma¨kitie
Division of Ear, Nose and Throat Diseases,
Department of Clinical Sciences, Intervention and
Technology, Karolinska Institute and Karolinska
University Hospital, Stockholm, Sweden
R. O. Alabi
Department of Industrial Digitalization, School of
Technology and Innovations, University of Vaasa,
Vaasa, Finland
H. Orell
Clinical Nutrition Unit, Internal Medicine and
Rehabilitation, University of Helsinki and Helsinki
University Hospital, Helsinki, Finland
O. Youssef  A. Almangush
Department of Pathology, University of Helsinki,
Helsinki, Finland
A. Almangush
Institute of Biomedicine, Pathology, University of
Turku, Turku, Finland
A. Homma
Department of Otolaryngology-Head and Neck
Surgery, Faculty of Medicine and Graduate School of
Medicine, Hokkaido University, Sapporo, Japan
R. P. Takes
Department of Otolaryngology-Head and Neck
Surgery, Radboud University Medical Center,
Nijmegen, The Netherlands
Adv Ther (2022) 39:1502–1523
https://doi.org/10.1007/s12325-022-02074-9
multimodal approaches. The nutritional inter-
vention includes essential components such as
dietary counseling, oral nutritional supple-
ments, and medical nutritional support. Indi-
vidualized nutritional interventions include
oral, enteral (feeding tubes i.e., percutaneous
endoscopic gastrostomy [PEG], nasogastric tube
[NGT]) and parenteral nutrition. The pharma-
cologic interventions aim at increasing the
appetite and weight of cachectic patients.
Therapeutic exercise and increased physical
activity can help to enhance the synthesis of
muscle protein, reducing inflammation and the
catabolic effects of cachexia syndrome.
Conclusion: Owing to the multifactorial nature
of this syndrome, it is expected that the manage-
ment approach should be multi-interventional.
Early implementation of these interventions may
help to improve survival and quality of health and
life of cachectic HNC patients.
Keywords: Anorexia; Cachexia; Head and neck
cancer; Systematic review; Sarcopenia
Key Summary Points
Head and neck cancer (HNC) patients
frequently suffer from cachexia, which is a
multifactorial condition that can affect
the treatment outcome and quality of life
of these patients.
The management approach of HNC-
related cachexia should be multi-
interventional because of the
multifactorial nature of the syndrome.
The optimal approach would include
preventive measures and early diagnosis
of this condition. Additionally, novel
technology carries the potential to aid in
recognizing and monitoring early signs of
cachexia.
Awareness of this entity (cachexia) needs
to be raised among both surgical and
oncologic caregivers. To perform the
required clinical research, the standard for
clinically applicable score for cachexia
classification and assessment should be
defined.
In the future, individualized treatment
options that can be offered for this patient
population should be explored.
INTRODUCTION
Cancer may be associated with pain, psycho-
logic distress, disfiguration, dysfunction, mal-
nutrition, metabolic changes, and ultimately
death [1]. It is the second leading cause of death
worldwide and can affect any part of the body
including the head and neck region [2]. In the
USA, head and neck cancer (HNC) accounts for
3% of new cases for all cancers and 1.5% of all
cancer deaths [3, 4]. Furthermore, HNC was
ranked as one of the most common cancers
globally in 2018 [1].
Several recent advancements in the treat-
ment planning and management of HNC
include minimally invasive procedures, transo-
ral robotic surgery, organ-sparing surgical pro-
cedures, advancements in radiotherapy, and
curative multimodal treatment including
immune-checkpoint inhibitors [1]. All of these
are targeted at reducing morbidity, mortality,
and physical and psychologic changes while
preserving the daily function that can enhance
improved quality of life of HNC patients. HNC
patients frequently suffer from dysphagia and
anorexia because of the tumor growth itself
and/or treatment-related side effects or anxiety
as to the possible outcome of treatment [5].
Consequently, malnourishment and weight loss
F. Lo´pez  J. P. Rodrigo
Department of Otolaryngology-Head and Neck
Surgery, Hospital Universitario Central de Asturias,
University of Oviedo, ISPA, IUOPA, CIBERONC,
Oviedo, Spain
R. de Bree
Department of Head and Neck Surgical Oncology,
University Medical Center Utrecht, Utrecht, The
Netherlands
A. Ferlito
Coordinator of the International Head and Neck
Scientific Group, Padua, Italy
Adv Ther (2022) 39:1502–1523 1503
T
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1504 Adv Ther (2022) 39:1502–1523
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ad
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[2
6]
/
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nd
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co
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Adv Ther (2022) 39:1502–1523 1505
T
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eh
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[2
7]
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or
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fa
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(3
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pa
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th
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7
pa
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Is
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in
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—
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fa
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cr
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w
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m
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m
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E
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G
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.
[2
8]
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co
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Pr
og
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ni
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in
ca
ch
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ca
nc
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pa
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un
de
rg
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ra
di
ot
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ra
py
:a
ra
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co
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d
pi
lo
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as
ib
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tr
ai
l
20
ca
ch
ec
ti
c
pa
ti
en
ts
(n
=
10
re
ce
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ed
m
ac
hi
ne
-s
up
po
rt
ed
pr
og
re
ss
iv
e
re
si
st
an
ce
tr
ai
ni
ng
,n
=
10
re
ce
iv
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us
ua
l
ca
re
)
Pr
og
re
ss
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re
si
st
an
ce
tr
ai
ni
ng
is
an
ex
er
ci
se
-
or
ie
nt
ed
tr
ai
ni
ng
T
he
tr
ai
ni
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to
ok
pl
ac
e
3
9
in
a
w
ee
k
fo
r
30
m
in
Pr
og
re
ss
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e
re
si
st
an
ce
tr
ai
ni
ng
in
ca
ch
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ti
c
H
N
C
pa
ti
en
ts
se
em
s
to
be
sa
fe
an
d
po
si
te
d
to
be
be
ne
fic
ia
l
fo
r
ge
ne
ra
l
fa
ti
gu
e
an
d
qu
al
it
y
of
lif
e
B
ar
-S
el
a
et
al
.
[2
9]
/
or
ig
in
al
st
ud
ya
Is
ra
el
T
he
ef
fe
ct
s
of
do
sa
ge
-c
on
tr
ol
le
d
ca
nn
ab
is
ca
ps
ul
es
on
ca
nc
er
-r
el
at
ed
ca
ch
ex
ia
an
d
an
or
ex
ia
sy
nd
ro
m
e
in
ad
va
nc
ed
ca
nc
er
pa
ti
en
ts
:
pi
lo
t
st
ud
y
24
pa
ti
en
ts
(1
7
st
ar
te
d
bu
t
11
re
ce
iv
ed
ca
ps
ul
es
fo
r
m
or
e
th
an
2
w
ee
ks
)
Ph
ar
m
ac
ol
og
ic
in
te
rv
en
ti
on
T
he
ca
nn
ab
is
ca
ps
ul
e
tr
ea
tm
en
t
le
d
to
in
cr
ea
se
in
w
ei
gh
t
of
th
e
pa
ti
en
ts
1506 Adv Ther (2022) 39:1502–1523
T
a
b
le
1
co
n
ti
n
u
ed
St
ud
y/
ty
pe
of
st
ud
y
L
oc
at
io
n
T
it
le
of
th
e
st
ud
y
Si
ze
of
th
e
se
ri
es
(m
et
ho
do
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gy
)
In
te
rv
en
ti
on
C
on
cl
us
io
n
O
sm
ol
ak
et
al
.
[3
0]
/
ra
nd
om
iz
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co
nt
ro
lle
d
tr
ia
l
U
SA
D
oe
s
pe
ri
op
er
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Adv Ther (2022) 39:1502–1523 1507
are typically observed. Among HNC patients
receiving radiotherapy (RT), severe weight loss
was seen prior to RT in 3% and at the end of RT
in 44% of patients, while the frequency of
malnutrition increased from 3% up to 88%
[6, 7].
Cachexia (or anorexia-cachexia syndrome) is
a complex metabolic syndrome in which sys-
temic inflammation is the key feature and
weight loss (e.g., C 5% of body weight during
the past 6 months) is the key diagnostic crite-
rion. Cachexia can be an underlying condition
in patients with sarcopenia. Anorexia is char-
acterized by decreased food intake because of
treatment side effects and depression, and it
manifests as reduced energy intake and invol-
untary weight loss in these patients [5].
Cachexia can be defined as a multifactorial
syndrome characterized by an ongoing loss of
skeletal muscle mass (with or without loss of fat
mass) that cannot be fully reversed by conven-
tional nutritional support and leads to progres-
sive functional impairment. Cachexia is
primarily associated with a particular underly-
ing condition such as uncontrollable tumor
growth that leads to extreme loss of appetite
and weight and systemic signs of inflammations
[5, 8–11]. When it affects oncologic patients, it
is known as cancer cachexia (cancer-induced
cachexia) [12]. In this case, there is a loss of
appetite due to metabolic alterations associated
with cancer. Thus, the quality of life and health
of these patients are affected due to the cancer
itself and increased by treatment-related toxic-
ity [13] causing poor survival [14]. Weight loss
can be associated with loss of muscle mass and
function (e.g., strength), and this is referred to
as sarcopenia. Sarcopenia was first thought to be
a physiologic state in the elderly; however, sci-
entific research has changed the perception of
the condition and uncovered myriad causes.
Sarcopenia can be the result of cancer cachexia,
and it has been associated with adverse treat-
ment outcome in HNC patients [15].
Among HNC patients, cachexia is more pro-
nounced as this cancer affects the functional
structures of the human body that are directly
involved in nutritional intake. As a result, deg-
lutitive and masticatory functions are affected
resulting in a deterioration of nutritional status.
*Search hits:
PubMed: 514
Scopus: 923
OvidMedline: 143
Web of Science: 398
Total of 1978 potentially relevant articles
To Science: 593
Records removed before 
screening:
Exact match duplicate 
records removed (n = 251)
Close match duplicate 
records removed (n = 329)
Records screened
(n = 1335)
Records excluded
(n = 1167)
Reports sought for retrieval
(n = 168)
Reports not retrieved
(n = 128)
Reports assessed for eligibility
(n = 40)
Reports excluded:
Not addressing management of 
cachexia (n = 24)
Conference (n = 1)
Not available (n = 3)
Reviews (4)
Records identified from:
Google Scholar (n = 1)
Google search (n = 1)
Citation searching (n = 1)
MedRxiv, Preprints.org (n = 0)
Reports assessed for eligibility
(n = 1)
Reports excluded (n = 0)
Studies included in review
(n = 8)
Reports of included studies
(n = 1)
Identification of studies via databases and registers Identification of studies via other methods
noitacifitnedI
Sc
re
en
in
g
In
cl
ud
ed
Reports sought for retrieval
(n = 3)
Reports not retrieved
(n = 2)
Fig. 1 PRISMA flow chart
1508 Adv Ther (2022) 39:1502–1523
In addition, patients may become vulnerable to
infection, fatigue, pain, and dyspnea. All these
may contribute further to weight loss and have
a negative effect on functional and survival
prognoses [16]. As sarcopenia is primarily a
functional condition, the patients with
cachexia experience negative changes in meta-
bolic functioning, loss of appetite, loss of adi-
pose tissue, wasting of tissues, and loss of
skeletal muscle mass.
We systematically reviewed the published
studies on the treatment of cachexia in HNC. It
was our primary aim to explore the scientific
evidence on the preventive approaches and
management of cachexia in this patient
population.
METHODS
Search of Databases and Study Period
We systematically searched OvidMedline,
PubMed, Scopus, and Web of Science databases
from inception until 15 October 2021 to
retrieve all studies addressing cachexia in HNC.
Search Terms
The potentially relevant articles were retrieved
by combining search keywords: [(‘cachexia OR
sarcopenia’) AND (‘head and neck cancer’)].
Search Analysis
The search analysis was done using RefWorks
web-based bibliography and database manager.
All the retrieved potentially relevant articles
were exported to RefWorks for further analyses.
The hits were further analyzed for possible
duplicates and irrelevant studies. The inclusion
and exclusion criteria were defined based on the
study-specific research questions.
Inclusion and Exclusion Criteria
All studies that had examined the treatment
interventions of cachexia or sarcopenia in HNC
were included. Considering the need to gather
important information and to reduce research
waste regarding cachexia and its management
in head and neck cancer, systematic reviews on
cachexia in HNC were included in this study.
Furthermore, studies with no specific mention
of a cancer site were considered in this review to
check if they included general treatment inter-
ventions for cachexia. As the number of rele-
vant studies appeared limited, a scoping review
approach was applied. To minimize the omis-
sion of any potential study, the reference lists of
all the potentially eligible articles were manu-
ally searched to ensure that all the relevant
studies were adequately included. Comments,
opinions, perspectives, guidelines, editorials,
and articles in languages other than English
were excluded. All articles about the
Table 2 Summary of quality assessment using the Oxford
quality scoring system (Jadad scale)
Study Oxford quality
scoring system
Quality
interpretation
Mantovani
et al. [23]
3 High
Lai et al. [24] 5 High
Mantovani
et al. [25]
4 High
Madeddu et al.
[26]
5 High
Yeh et al. [27] 5 High
Grote et al.
[28]
4 High
Bar-Sela et al.
[29]
2 Low
Osmolak et al.
[30]
3 High
Blum et al.
[31]
3 High
Adv Ther (2022) 39:1502–1523 1509
Table 3 Tool for assessing the risk of bias ( adapted from Higgins et al. 2011)
Bias domain Source of bias Support for judgment
Selection bias Random sequence
generation
State how the cachectic patients were selected in sufficient detail to allow an
assessment of whether it should produce comparable groups
Allocation
concealment
Describe the control group (groups that did not receive cachectic intervention) or
compare between interventions in sufficient detail to determine whether
intervention allocations were effective during enrollment
Performance
bias
Blinding of
participantsa
State all measures used, if any, to prevent trial participants from having the
knowledge of which intervention they received
Detection
bias
Blinding of outcome
assessmenta
State all measures used, if any, to prevent influence of the knowledge of
intervention received on the outcome assessment
Attrition bias Incomplete outcome
dataa
Describe the completeness of outcome data for each endpoint, including
incomplete and excluded participants from the analysis
Reporting
bias
Selective reporting State how the endpoint reporting was done and what was the conclusion
Other biases Anything else, ideally
prespecified
Other biases not covered elsewhere in the examined domains. For example, the
inclusion of other tumors besides head and neck cancer in the analysis
aAssessments made for each main outcome (endpoint)
Table 4 Presentation of risk of bias assessments for the included studies
Study Ra
nd
om
 se
qu
en
ce
 g
en
er
a
on
Al
lo
ca
o
n 
co
nc
ea
lm
ee
nt
Bl
in
di
ng
 o
f p
ar
c
ip
an
ts
Bl
in
di
ng
 o
f o
ut
co
m
e 
as
se
ss
m
en
t
In
co
m
pl
et
e 
ou
tc
om
e 
da
ta
Se
le
c
ve
 re
po
r
ng
O
th
er
 b
ia
se
s
Mantovani et al., 2006
Lai et al., 2008
Mantovani et al., 2010
Madeddu et al., 2012
Yeh et al., 2013
Grote et al., 2018
Bar-Sela et al., 2019
Osmolak et al., 2019
Blum et al., 2021
Low risk Unclear risk High risk
1510 Adv Ther (2022) 39:1502–1523
Table 5 Included studies and the examined endpoints
S/
N
Studies Examined
endpoints
Intervention Duration of
intervention
Results
1 Mantovani
et al. [23]/
original
studya
Body weight
Lean body
mass
Pharmacologic intervention 12 weeks 500 mg/day
medroxyprogesterone
acetate; 200 mg/day
celecoxib; 2.2 g/day
eicosapentaenoic acid or
0.9 g/day docosa hexaenoic
acid; antioxidant
These improved the following
endpoints:
Improved quality of life
Increased appetite
2 Lai et al. [24]/
original
study
Body weight
Body mass
index
Quality of life
Pharmacologic intervention—
celecoxib
21 days Patients that received celecoxib
showed:
Increase in body weight
Increase in body mass index
Increased quality of life score
3 Mantovani
et al. [25]/
original
studya
Primary
endpoints:
Lean body
mass
Decrease in
resting
energy
expenditure
Decrease in
fatigue
Secondary
endpoints:
Appetite
Quality of
life
Grip
strength
Pharmacologic intervention—
Nutritional intervention
Hybrid regimen: combination
of pharmacologic and
nutritional interventions
4 months A combination of 500 mg/day
of medroxyprogesterone or
320 mg/day ? oral
supplement with
eicosapentaenoic
acid ? 4 g/day of L-
carnitine ? 200 mg/day of
thalidomide improved the
following endpoints:
Improved lean body mass
Increased appetite
Interleukin (IL)—6 decreased
significantly
Toxicity reduced
Adv Ther (2022) 39:1502–1523 1511
Table 5 continued
S/
N
Studies Examined
endpoints
Intervention Duration of
intervention
Results
4 Madeddu et al.
[26]/
original
studya
Primary
endpoints:
Lean body
mass
Physical
activity
Secondary
endpoints:
Physical
performance
Grip
strength
Walk test
Pharmacologic intervention 4 months 4 g/day
L-carnitine ? 300 mg/day
celecoxib ± 320 mg/day
megestrol acetate
Improved physical function
Fatigue
Improved performance
Appetite
5 Yeh et al.
[27]/
original
study
Body weight
Serum
albumin
level
Albumin level
Nutritional intervention—
ethanwell/ethanzyme (EE)
regimen enriched with
Omega-3 fatty acid,
micronutrient, and
probiotic-enriched nutrition
or control (Isocal) for
3 months period
3 months Patients with body mass index
\ 19 showed improved
body weight
Higher serum albumin levels
Higher prealbumin level
The increase in body weight
was associated with increased
serum albumin and
prealbumin level
6 Grote et al.
[28]/
randomized
controlled
trial
Fatigue (body
weight)
Quality of life
Exercise (progressive resistance
training)
15 weeks (7 weeks
of radiotherapy
and 8 weeks
after
radiotherapy)
Less fatigue was observed
Improved quality of life
1512 Adv Ther (2022) 39:1502–1523
pathophysiology, pathogenesis, assessments,
overview, effects, definitions, and diagnostic
features of cachexia or sarcopenia were exclu-
ded. Similarly, studies that focused on anorexia,
dysphagia, or mucositis, or mainly on nutri-
tional support in cancer patients, were exclu-
ded. All studies that examined cachexia in
animals were excluded.
Search Reporting and Screening
Two independent researchers (R.A. and O.Y)
performed the screening of potentially relevant
articles and used a data extraction sheet to
minimize the omission of possible eligible
studies. Possible discrepancies were resolved by
discussion until a consensus was reached. Thus,
the interobserver reliability between the two
independent researchers was measured using
Cohen’s kappa coefficient (k ¼ 0:94). All eligible
studies to be included are summarized in
Table 1. The reporting of the search protocols
(searching and screening processes) is given
using the Preferred Reporting Items for Sys-
tematic Review and Meta-Analysis (PRISMA)
(Fig. 1). This study was conducted in accordance
with the ethical principles of the Declaration of
Helsinki and followed the PRISMA guidelines in
the review process. As this study is a systematic
Table 5 continued
S/
N
Studies Examined
endpoints
Intervention Duration of
intervention
Results
7 Bar-Sela et al.
[29]/
original
studya
Primary
endpoints:
Body weight
Secondary
endpoints:
Appetite
Reduction in
pain and
fatigue
Grip
strength
Pharmacologic intervention—
(tetrahydrocannabinol and
cannabidiol)
6 months Weight increase of 10% in
patients that received 5 mg
9 1 or 5 mg 9 2 capsules
daily
Improvement in appetite and
mood
Reduction in pain and fatigue
8 Osmolak et al.
[30]/
randomized
controlled
trial
Prealbumin
levels
Surgical
wounds
Nutritional intervention—
oxandrolone
10 days 10 mg twice a day:
Improvement in prealbumin
levels
Improvement in surgical
wounds
9 Blum et al.
[31]/a case
seriesa
Muscle mass
Appetite
Nutritional intervention—
ghrelin
4 days (twice/day).
Then, 6 weeks
of maintenance
period (10
doses/week)
32 lg/kg of body weight:
improved appetite and eating-
related symptoms
Stable muscle mass and
strength
aAdvanced stage solid cancers including head and neck cancer
Adv Ther (2022) 39:1502–1523 1513
scoping review, ethical review and informed
consent were not required.
Quality Appraisal
As this study considered original studies and
randomized controlled trials as eligible studies,
two different quality appraisal paradigms were
used. The quality of the included studies was
initially appraised using the quality guideline
for systematic review as recommended by the
National Institute of Health Quality Assessment
tools [17]. These studies were subjected to four
quality criteria informed by the same quality
assessment tool [18]. These criteria were modi-
fied to include design, methodology, interven-
tions, and statistical analysis. The studies that
showed reasonable quality (C 50%) from this
initial quality assessment were further subjected
to the Oxford quality scoring system, also
known as the Jadad scale. The Jadad quality
assessment scale is a representative quality
assessment tool that is suitable for systematic
review that includes randomized controlled
trails. It is an easy-to-use scale with known
reliability and external validity and important
elements that have empirically been shown to
correlate with bias [19]. Based on this scale, the
maximum attainable score was 5 points; two in
relation to randomization, two in relation to
blinding, and one in relation to the dropout
rate [20, 21]. An overall score C 3 indicated
‘high’ quality. Conversely, a Jadad scale score
of B 2 was defined as ‘low’ quality (Table 2)
[20]. The quality assessment was followed by
the risk of bias analysis of the included studies
Fig. 2 Management interventions of cachexia
Fig. 3 Understanding precachexia, cachexia, and refractory cachexia
1514 Adv Ther (2022) 39:1502–1523
using the Cochrane collaboration risk of bias
tool (‘‘Risk of Bias Analysis’’).
Risk of Bias Analysis
We used the Cochrane Collaboration’s tool for
assessing the risk of bias of the included studies.
This tool was modified from Higgins et al.
(2011) to properly examine the risk of bias in
this study [22]. The modified bias domains
appear summarized in Table 3. The details of the
bias analysis and the corresponding results from
each examined bias are presented in Table 4.
Data Extraction
In each eligible study, the first author’s name,
year of publication, country, title of the study,
number of the participants in the study or
number of studies reviewed, site of cancer con-
sidered, suggested interventions or cachexia
management, and summary of the study were
extracted (summarized in Table 1). The detailed
explanation of the strategic interventions to
manage cancer cachexia in HNC patients is
discussed collectively in the Discussion sec-
tion. Based on the summary of the included
studies (Table 1), the endpoints examined
through randomized control trials, case series,
and original studies included in this systematic
scoping review are specifically discussed in this
study and summarized in Table 5.
RESULTS
Results of the Database Search
A total of 1978 hits were retrieved. After delet-
ing duplicates (N = 580), irrelevant papers
(N = 1357), and exclusions (N = 32), we found
nine studies eligible to be included in this
scoping review as shown in Fig. 1 [23–31].
Characteristics of Relevant Studies
All the articles included were published in the
English language. The quality assessment of the
included studies showed that eight (88.9%)
showed high-quality assessment scores
[23–28, 30, 31]. Likewise, only a single study
(14.3%) of the included studies had a low-
quality score (Table 2) [29]. In terms of the risk
of bias, all the included studies showed low risk
of bias in the selection of cachectic patients,
analysis of the cachectic intervention and end-
point evaluation, and reporting of outcome of
these interventions (Table 4). Similarly, six out
of the nine studies showed a low risk of unreli-
ability of the examined interventions by com-
paring the outcome of the various intervention
groups and those that received either placebo or
no intervention at all [24–28, 30] (Table 4).
However, only one study had a high risk of bias
regarding the evaluated cachexia intervention
because a reasonable number of the participants
did not complete the study [29]. Additionally,
four studies included other advanced stage solid
cancers alongside head and neck cancer, which
may include other biases in terms of the actual
efficacy of the intervention [23, 25, 26, 29].
Of the nine included studies, five (55.6%)
had been carried out in Europe
[23, 25, 26, 28, 31] and two (22.2%) studies each
in the US [24, 30] and Asia [27, 29]. From the
included studies, two (22.2%) recommended
both nutritional and pharmacologic interven-
tions for the management of cachexia in HNC
patients [23, 25]. Three (33.3%) studies each
suggested only either nutritional intervention
[27, 30, 31] or pharmacologic intervention
[24, 26, 29]. Similarly, only one study (14.3%)
suggested other emerging interventions in
addition to the nutritional and pharmacologic
interventions such as exercise or resistance
training [28]. Of note, it was suggested that a
multi-modal/multi-interventional approach
that consists of pharmacologic, nutritional, and
other targeted interventions is poised to be the
most effective treatment in terms of the tar-
geted endpoints of lean body mass, resting
energy expenditure, fatigue, appetite, quality of
life, and grip strength [25] (Fig. 2).
Adv Ther (2022) 39:1502–1523 1515
Summary of the Findings
from the Relevant Studies
The findings of these studies (summarized in
Table 1) indicate that cancer cachexia is asso-
ciated with weight loss, poor nutritional status,
and systemic inflammation. Cancer cachexia
can thus predict a poor treatment outcome in
patients with HNC. The primary endpoints
examined for cachexia intervention in some of
the included studies in this systematic scoping
review were lean body mass, body weight, rest-
ing energy expenditure, fatigue, serum albumin
level, prealbumin level, and body mass index
[23–31] (Table 5). Likewise, the highlighted
secondary endpoints for cachexia interventions
were appetite, quality of life, reduction in pain,
grip strength, physical performance, walk test,
and surgical wounds [24–26, 28, 29, 31]
(Table 5).
Hybrid regimens that include a combination
of pharmacologic and nutritional interventions
led to increase in lean body mass and decrease
in resting energy expenditure and fatigue [25].
Similarly, hybrid regimens were also found to be
potent interventions for cachectic endpoints of
improved appetite, grip strength, and quality of
life [25]. Besides hybrid interventions, pharma-
cologic interventions such as medroxyproges-
terone, megestrol acetate, L-carnitine, celecoxib,
thalidomide, tetrahydrocannabinol, and
cannabidiol have shown promising results
regarding their respective target endpoints of
increased body weight, pain and fatigue reduc-
tion, improved grip strength, and improved
quality of life [24, 25, 29]. Of note, only two of
the pharmacologic interventions were found to
be widely used and approved in Europe. These
are progestational agents such as medroxypro-
gesterone acetate or megestrol acetate and cor-
ticosteroids [23, 25, 26, 32–35]. Similarly, some
nutritional interventions such as ethanwell/
ethanzyme regimen enriched with omega-3
fatty acids, micronutrients, and probiotics or
control (isocal) were found to be effective in
achieving the targeted endpoints of improved
body weight, higher serum albumin and preal-
bumin levels, and improvement in surgical
wound healing [27]. Other pharmaceutical
interventions such as oxandralone was also
found to show improvements in prealbumin
levels and surgical wound-healing endpoints of
cachectic patients [30] while ghrelin was found
to show improved appetite and provide
stable muscle mass and strength endpoints [31]
(Table 5). Some of the suggested interventions
had been validated through clinical trials or
randomized controlled trials [23, 25, 26, 28, 30]
(Table 5).
Apart from the aforementioned randomized
controlled trials that supported pharmacologic
and nutritional interventions, other examples
of pharmacologic and nutritional interventions
were suggested in some studies, but had not yet
been subjected to controlled trials. For phar-
macologic interventions, these include growth
hormone and anabolic steroids, non-steroidal
anti-inflammatory drugs, TNF-alpha inhibitors,
anticytokines, inflammatory antagonists,
antioxidant agents, and selective androgen
receptor modulators [32, 36–38]. For nutritional
interventions, nutraceuticals, nutritional sup-
port, cyproheptadine, amino acid loading, cur-
cumin, resveratrol, pomegranate, and other
interventions such as physical activity were
suggested [32, 36–38]. The use of pharmacologic
interventions such as cyproheptadine, hydra-
zine, metoclopramide, and pentoxifylline was
found to be ineffective in one study [39]. The
interventional ability of some pharmaceutical
drugs such as eicosapentaenoic acid, cannabi-
noids, and bortezomib was reported to have
failed or produced equivocal results [39]. Thus,
the discussion section of the present review
focuses on interventions with promising results
in the defined endpoints.
DISCUSSION
Cachexia is defined as a multifactorial syn-
drome characterized by the ongoing loss of
skeletal muscle mass with loss of fat mass [11].
Nutritional support and therapy cannot fully
reverse the condition of cachexia, and this will
lead to reduced physical function [11]. It has
been reported that higher energy intakes would
be necessary in patients treated for HNC to
maintain skeletal muscle mass [40]. Patho-
physiologically, cachectic HNC patients have
1516 Adv Ther (2022) 39:1502–1523
reduced food intake and abnormal metabolism
[11]. Precachexia is recognized by early clinical
and metabolic signs that precede substantial
weight loss, i.e.,[2% and\5% [54]. This state
is usually overlooked as an early stage of
cachexia. It usually begins with a slight weight
loss that occurs involuntarily. Nonetheless,
metabolic changes and inflammations occur at
this stage. While cachexia is the main condition
considered in the present study, refractory
cachexia is a clinically resistant catabolic state
[10] (Fig. 3). Hence, it is a more severe syndrome
with a low World Health Organization perfor-
mance status score, an irresponsiveness to
anticancer therapy, and a survival period of \
3 months [12] (Fig. 3).
A concerted effort is still ongoing to obtain a
consensus on the diagnostic standard for
refractory cachexia [10]. Of note, the patients
progress from one stage to the other if timely
and necessary interventions are not introduced
[10] (Fig. 3). The chance of progression depends
on factors such as the HNC subsite and stage,
food intake, level of patient activity, irrespon-
siveness to anticancer treatment, and/or treat-
ment-related sequelae and complications [10].
Therefore, early recognition of cachexia is
important because cachectic patients have
higher rates of postoperative complications and
infections and impaired response to adjuvant
treatment and thus poor quality of life and
higher mortality rates [5, 41, 42]. Similarly,
early initiation of aggressive nutrition inter-
vention with multimodal approach improves
outcomes by helping to maintain patient on the
intended treatment regimen with fewer changes
[43, 44]. Most importantly, cachexia syndrome
should be taken into significant consideration
for the effective development of practice
guidelines, and ultimately, and routine clinical
management of HNC patients.
Several attempts have been made to obtain
unanimous consensus on a diagnostic bench-
mark for cancer cachexia [9, 11, 45]. The most
widely presented criteria in the published
studies include weight loss[5% in the previous
6 months or weight loss [ 2% in individuals
already showing depletion according to current
body mass index\ 20 kg/m2) or reduced skele-
tal muscle mass (sarcopenia) [11, 46]. Of note, it
has been observed that muscle mass depletion is
common in HNC patients with cachectic syn-
drome [47].
Chemotherapeutic, radiotherapeutic, and
surgical complications in HNC cachectic
patients have resulted in a low survival rate [5].
Weight loss remains the primary reason, and it
is one of the main features of a cachectic HNC
patient. Thus, lowering the doses of
(chemo)radiotherapy does not seem to be
helpful for improving overall survival because
of the severe weight loss [48, 49]. Therefore,
weight loss has been found to be a detrimental
factor hindering the proper management of
cachectic HNC patients [5].
The generally accepted principal for the
management of cachexia is based on early
commencement of individualized nutrition
with sufficient protein and energy intake with
sufficient symptom management. Despite the
advancements in diagnostic and treatment
methods for HNC, little or no active attention is
usually given to the recognition, assessment,
and management of cachexia in this patient
population [50–52]. Therefore, it seems to rep-
resent an unmet impending factor that can
hinder maximizing the intended clinical bene-
fits from multimodality treatment aimed at
improving quality of health and chance of sur-
vival in HNC patients [53, 54]. Although
cachexia has been well recognized as a disease
condition, it deserves attention because of its
potential to contribute to the mortality rate in
patients with cancer [5].
This systematic review presents a scoping
approach examining the published studies on
management of cachexia in head and neck
cancer (HNC) patients. The indices of cachexia
include lean body mass, resting energy expen-
diture, fatigue, loss of appetite, reduced grip
strength, inflammation, and impaired quality of
life [25]. First, we found that cachexia has
adverse effects on both functional (impaired
quality of life and quality of health, increased
healthcare expenses) and survival (cancer-re-
lated death) prognoses of cancer. Second,
pharmacologic [24, 26, 29], nutritional
[27, 30, 31], and therapeutic exercise (resistance
training) [28] are the interventions suggested
for managing cachexia in HNC patients (Fig. 2).
Adv Ther (2022) 39:1502–1523 1517
However, for optimal management of cachexia,
a combination of these interventions, i.e., a
multi-interventional approach, is recom-
mended because of the multifactorial nature of
the syndrome [23, 25, 32, 37–39, 55].
Considering weight loss as one of the indi-
cators of cancer cachexia in HNC patients,
nutritional interventions, including nutritional
counseling and support, and supplemental
interventions are poised to offer an effective
management approach for this syndrome. For
example, an oral nutrition supplement, like the
ethanwell/ethanzyme (EE) regimen, which was
enriched with omega-3 fatty acids, micronutri-
ents, and probiotics, was found to enhance
body weight stabilization in HNC cachectic
patients [27]. The levels of serum albumin and
pre-albumin in these patients were found to be
significantly increased [27]. A similar study
further emphasized the importance of a multi-
targeted (multi-interventional) approach by
combining dietary micronutrients such as
omega-3 fatty acids with pharmacologic inter-
vention. This combination was reported to
improve fatigue and lean body mass [25].
The weight of HNC patients should be
monitored and recorded during the disease tra-
jectory for early detection of cachexia. Conse-
quently, nutrition counseling by registered
dietitian and individualized nutrition support
aimed at improving weight loss and physical
functions should be introduced. This will
improve quality of health and aid in achieving
the touted benefits from the cancer treatment.
Because HNC and its treatment have the
potential to affect the route of food intake,
nutrition is usually administered to HNC
patients through enteral route, i.e., percuta-
neous endoscopic gastronomy (PEG), or naso-
gastric tube (NAG). Parenteral feeding is
prescribed only for patients with nonfunctional
or inaccessible enteral route [5]. This insightful
approach to nutrition administration has been
reported to help patients with less weight loss,
improved quality of life, and survival rate
[5, 25, 27, 56]. In addition, numerous guidelines
have been suggested for the proper nutritional
assessment, monitoring, and management of
HNC cachectic patients [57]. Similarly,
numerous articles have been published on the
importance of nutritional interventions [58].
Beyond the spectrum of nutritional inter-
vention is pharmacologic intervention in the
management of cachexia in HNC patients. This
pharmacologic intervention can be divided into
two main categories based on the intended aim
of this intervention. First, these are drugs that
increase appetite (i.e., appetite stimulants) in
cachectic HNC patients. For instance, gluco-
corticoids, progestagens (medroxyprogesterone
and megestrol acetate [megace]), glucodexam-
ethasone, and orexigenic agents (dronabinol,
pentoxifylline, nandrolone, nutritional phar-
macomodulation [omega-3 fatty acids], etc.)
have been used to increase appetite in cachectic
HNC patients [23, 27]. Second, other pharma-
cologic interventions include nonsteroidal anti-
inflammatory and anticytokine drugs and
antioxidant agents [5]. Examples of these drugs
include celecoxib and thalidomide [5, 24, 26].
Of note, it is important to have a multimodal
approach to these pharmacologic interventions
to achieve the best outcomes [5, 23, 25].
Therefore, the onus is on the caregivers to
evaluate the individualized situation of
cachectic HNC patients for the best combina-
tion of pharmacologic therapy (multinutrient
or multitarget) for improved body weight and
appetite and reduced inflammation.
Therapeutic exercise and increased physical
activity are thought to be beneficial for
cachectic HNC patients [28, 59]. As cachexia is
associated with inflammation and anemia, the
potential of muscle pain and weakness increa-
ses. However, exercise therapy can help to
enhance the synthesis of muscle protein. Addi-
tionally, it can reduce the catabolic effects of
cachexia syndrome and the extent of inflam-
mation. This is poised to offer a non-pharma-
cologic treatment of HNC cachectic patients to
improve physical functions and quality of life
[5, 28, 60]. Considering the condition of HNC
cachectic patients, physical exercise may not be
feasible. Thus, an alternative exercise paradigm
such as neuromuscular electrical stimulation
(NEMS) may be considered to strengthen the
muscles [5].
This systematic scoping review emphasizes
that the assessment and management of
1518 Adv Ther (2022) 39:1502–1523
cachexia in HNC patients constitute major
challenges for clinicians [10]. The standard for a
clinically applicable score for cachexia classifi-
cation and assessment should be defined. The
standard endpoints (primary and secondary) for
cancer-induced interventions should be high-
lighted. Similarly, the assessment tool for these
endpoints should be defined. The most effective
interventional approaches should be properly
evaluated. Even though there are neither effec-
tive medical interventions nor approved drugs
to completely reverse cachexia [61], major
caregivers such as oncologic nurses and clini-
cians have an important role in the proper
management of cachectic HNC patients. For
instance, an oncologic nurse should be vigilant
for the early signs of cachexia for prompt
intervention [5, 62]. This includes being active
in the routine assessment of the dietary habits
of patients, nutritional components (status,
deficiencies, and possible interventions), weight
monitoring, swallowing and chewing activities,
and oral care of the HNC patients. Similarly, the
oncologist should offer an open and approach-
able relationship with other members of the
team to ensure that necessary interventions will
be introduced from the onset. The future man-
agement of cachexia will need to consider
combining sufficient nutritional intake, physi-
cal exercise and inflammation reducing and
protein synthesis increasing medical treatment.
In conclusion, increasing muscle volume
and decreasing inflammation remain crucial
components of cachexia management. How-
ever, feasible and partly novel approaches to
enhance the effective management of HNC-in-
duced cachexia warrant further studies. Addi-
tionally, cachexia assessment should be
employed as a routine part of the management
of HNC. Considering the adverse effects of this
syndrome on the quality of health and chance
of survival, it is important that a standard of
care regarding the available interventions
should be considered by the concerned
authorities and organizations.
ACKNOWLEDGEMENTS
Funding. Open Access funding provided by
University of Helsinki including Helsinki
University Central Hospital. The Sigrid Juse´lius
Foundation. The Helsinki University Hospital
Research Fund. The Turku University Hospital
Research Fund. The University of Helsinki
Library funded the Open Access fees for the
publication of this study. No funding or spon-
sorship was received for the journal’s rapid ser-
vice fee for this article.
Medical Writing, Editorial and Other
Assistance. The authors thank Dr. Carl Silver
for his valuable editing of the English of the
manuscript.
Authorship. All mentioned authors meet
the International Committee of Medical Journal
Editors (ICMJE) criteria for authorship for this
article, take responsibility for the integrity of
the work as a whole, and have given their
approval for this version to be published.
Author Contributions. The study was con-
ceived and designed by Antti Ma¨kitie. Alabi
Rasheed and Omar Youssef performed the lit-
erature review. Alabi Rashed, Omar Youssef,
Helena Orell, Alhadi Almangush, and Antti
Ma¨kitie drafted the manuscript. Akhiro
Homma, Robert Tekes, Fernando Lopez, Remco
de Bree, Juan Rodrigo, and Alfio Ferlito were
involved in commenting and revising the
manuscript. All authors approved the final
version.
Discloures. Antti A. Ma¨kitie, Rasheed
Omobolaji Alabi, Helena Orell, Omar Youssef,
Alhadi Almangush, Akihiro Homma, Robert
Takes, Fernando Lo´pez, Remco de Bree, Juan P
Rodrigo, Alfio Ferlito all have nothing to
disclose.
Compliance with Ethics Guidelines. This
article is based on previously conducted studies
and does not contain any new studies with
human participants or animals performed by
any of the authors.
Adv Ther (2022) 39:1502–1523 1519
Data Availability. Data sharing is not
applicable to this article as no datasets were
generated or analyzed during the current study.
Open Access. This article is licensed under a
Creative Commons Attribution-NonCommer-
cial 4.0 International License, which permits
any non-commercial use, sharing, adaptation,
distribution and reproduction in any medium
or format, as long as you give appropriate credit
to the original author(s) and the source, provide
a link to the Creative Commons licence, and
indicate if changes were made. The images or
other third party material in this article are
included in the article’s Creative Commons
licence, unless indicated otherwise in a credit
line to the material. If material is not included
in the article’s Creative Commons licence and
your intended use is not permitted by statutory
regulation or exceeds the permitted use, you
will need to obtain permission directly from the
copyright holder. To view a copy of this licence,
visit http://creativecommons.org/licenses/by-
nc/4.0/.
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