nutrients

Review
Nutritional Approach to Cancer Cachexia: A Proposal
for Dietitians
Kotone Tanaka 1, * , Sho Nakamura 2,3 and Hiroto Narimatsu 2,3,4

1 School of Nutrition and Dietetics, Faculty of Health and Social Services, Kanagawa University of Human
Services 1-10-1 Heiseicho, Yokosuka-shi 238-0013, Japan
2 Cancer Prevention and Control Division, Kanagawa Cancer Center Research Institute 2-3-2 Nakao, Asahi-ku,
Yokohama 241-8515, Japan; research@nakasho.org (S.N.); hiroto-narimatsu@umin.org (H.N.)
3 Graduate School of Health Innovation, Kanagawa University of Human Services, 3-25-10 Research Gate
Building 2-A, Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan
4 Department of Genetic Medicine, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi-ku,
Yokohama 241-8515, Japan
* Correspondence: tanaka-rt8@kuhs.ac.jp

Abstract: Cachexia is one of the most common, related factors of malnutrition in cancer patients.
Cancer cachexia is a multifactorial syndrome characterized by persistent loss of skeletal muscle mass
and fat mass, resulting in irreversible and progressive functional impairment. The skeletal muscle
loss cannot be reversed by conventional nutritional support, and a combination of anti-inflammatory
agents and other nutrients is recommended. In this review, we reviewed the effects of nutrients that
are expected to combat muscle loss caused by cancer cachexia (eicosapentaenoic acid, β-hydroxy-
β-methylbutyrate, creatine, and carnitine) to propose nutritional approaches that can be taken at
present. Current evidence is based on the intake of nutrients as supplements; however, the long-term
and continuous intake of nutrients as food has the potential to be useful for the body. Therefore,
in addition to conventional nutritional support, we believe that it is important for the dietitian to



work with the clinical team to first fully assess the patient’s condition and then to safely incorporate


nutrients that are expected to have specific functions for cancer cachexia from foods and supplements.
Citation: Tanaka, K.; Nakamura, S.;
Narimatsu, H. Nutritional Approach
to Cancer Cachexia: A Proposal for
Keywords: cancer; cachexia; EPA; HMB; creatine; carnitine
Dietitians. Nutrients 2022, 14, 345.
https://doi.org/10.3390/nu14020345

Academic Editors: Peter Pribis and

1. Introduction
Lynnette Ferguson
Cachexia is a common, related factor of malnutrition in patients with cancer [1]. Cancer
Received: 28 November 2021 cachexia is a multifactorial syndrome defined by an ongoing loss of skeletal muscle mass
Accepted: 11 January 2022 (with or without loss of fat mass) that leads to progressive functional impairment [2]. The
Published: 14 January 2022 agreed-upon diagnostic criteria for cachexia are weight loss of 5% or more or weight loss of
Publisher’s Note: MDPI stays neutral 2% or more in a person who is already depleted according to current weight and height
with regard to jurisdictional claims in (body mass index [BMI] less than 20 kg/m2 ) or loss of skeletal muscle mass (sarcopenia) [2].
published maps and institutional affil- Cancer cachexia is caused by a complex combination of anorexia, increased protein
iations. catabolism, systemic inflammation, and increased resting energy expenditure. Its patho-
physiology is characterized by a negative balance of protein and energy caused by various
combinations of reduced food intake and metabolic abnormalities. The main features of
cachexia are a strong tendency toward catabolism and a negative protein–energy balance
Copyright: © 2022 by the authors. that is difficult to restore [2,3]. As a result, total body skeletal muscle mass is irreversibly
Licensee MDPI, Basel, Switzerland. reduced, leading to decreased Activities of Daily Living (ADL), worse prognosis, and
This article is an open access article
decreased quality of life (QOL) [4–6]. Therefore, in supporting cancer patients, nutritional
distributed under the terms and
interventions should be a multimodal approach in conjunction with exercise and pharma-
conditions of the Creative Commons
cotherapy to address muscle mass loss. In addition, nutritional management for cancer
Attribution (CC BY) license (https://
cachexia should focus on preventing the loss of muscle mass based on nutritional risk
creativecommons.org/licenses/by/
assessment and evaluation [7]. Moreover, cancer cachexia gradually worsens as cancer
4.0/).

Nutrients 2022, 14, 345. https://doi.org/10.3390/nu14020345 https://www.mdpi.com/journal/nutrients

Nutrients 2022, 14, 345 2 of 16

progresses and can be divided into three main stages: pre-cachexia, cachexia, and refractory
cachexia [2]. It is not uncommon for cancer patients to have limited food intake due to
anorexia caused by adverse events of treatment or worsening of their general condition [8,9];
in the refractory cachexia stage, aggressive nutritional support is not recommended [10].
Therefore, early nutritional intervention is important for cachexia.
However, it has been reported that conventional nutritional supplements, such as
energy and protein supplementation alone, do not improve cancer cachexia, and nutritional
therapy, such as anti-inflammatory nutrients, should be used in combination [11,12]. In
fact, energy and protein supplementation alone have been reported to improve weight in
cancer patients with cachexia [11,13–17] or subjective outcomes such as QOL [13]. However,
many reports have found no impact on secondary outcomes (e.g., improved ADLs and
reduced mortality) [11,13–17], with few improvement reports [18]. Therefore, conventional
nutritional management should be implemented in the future, such as energy and protein
supplementation, as well as a new nutritional approach to counter cancer cachexia [18].
While the American Society of Clinical Oncology (ASCO) Guideline [19] and the
European Society for Oncology (ESMO) Clinical Practice Guidelines [20] state that the
importance of dietary nutrient intake is emphasized, the evidence for the intake of certain
nutrients, such as n3 fatty acids, is considered insufficient due to lack of data and low
quality. However, these are investigations of intake as supplements, not evidence of long-
term intake of nutrients as a diet. Moreover, even if we focus on the effects of a particular
nutrient, the interaction with other nutrients may result in more favorable effects from
dietary intake than from supplements [21].
The purpose of this study was to review the knowledge of specific nutrient intake as
an approach that can be taken by dietitians in clinical practice among the wide range of
approaches to cancer cachexia and to propose an approach that can be taken at present.

2. Selected Articles for This Review

For this review, we searched at PubMed (MEDLINE) to identify clinical studies pub-
lished from January 1992 to August 2021 that evaluated the effects of each nutrient in cancer
patients with cachexia. Searches were conducted using search terms including “cancer” and
“cachexia”. Study reports were retrieved regardless of whether these were full publications
or abstracts. The studies that evaluated a single nutrient were included in the review; those
that evaluated combinations of multiple nutrients were not included.
Eligible criteria of this review are as follows. First, randomized, controlled trials (RCTs)
that were double blind, single blind, or unblinded and clinical trials were included. Second,
Trials of patients with a confirmed diagnosis of advanced cancer and a clinical judgement
of cachexia or related conditions (independent of gender, age, or race) were included. Third,
studies with the following primary and secondary outcomes measures were reviewed in
the study. The primary outcome measures included weight gain, body composition, and
nutritional status and the secondary outcome measures assessed included side effects and
adverse events.
As a result of the literature search, 127 papers on EPA, 10 papers on HMB, 75 papers
on creatine, and 21 papers on carnitine were retrieved. Of these, four papers on EPA,
two papers on HMB, two papers on creatine, and two papers on carnitine that met the
eligible criteria and included our research questions were selected as the target papers for
this review.

3. Nutritional Interventions to Support Cancer Cachexia Management

3.1. Eicosapentaenoic Acid (EPA)
3.1.1. General Information
EPA is an unsaturated fatty acid that cannot be synthesized by the body [22]. EPA
reduces the production of inflammatory cytokines such as IL-6 and TNF-α and decreases
the activity of proteolysis-inducing factors (PIF) [23,24]. The recommended daily intake
of EPA is 2.0 g/day for men and 1.6 g/day for women [22] between the ages of 30 and
Nutrients 2022, 14, 345 3 of 16

49 years. Fish oil containing high levels of EPA and DHA is prone to developing a fishy or
metallic taste [25]. The side effects associated with EPA overdose include gastrointestinal
symptoms, liver dysfunction, and bleeding tendency [26].

3.1.2. Mechanisms of EPA on Cancer Cachexia

Cancer cells produce pro-inflammatory cytokines such as IL-6 and TNF-α, which
produce inflammatory reactions between cancer cells and their hosts. They also secrete
a PIF, which increases muscle catabolism. These functions are related to the effects of
EPA. Therefore, in recent years, EPA intake has been considered to regulate these cancer-
ous inflammations and bring metabolism back from a hypercatabolic state to a normal
state [23,24].

3.1.3. Clinical Evidence of EPA

Effect of EPA on Cancer Cachexia
The effect of EPA in cancer cachexia patients is currently unknown. Studies in patients
with advanced pancreatic cancer [27,28] or in lung cancer patients undergoing chemother-
apy [29] reported that EPA intake resulted in an increase in body weight or LBM. Conversely,
in a study of advanced cancer patients, EPA intake did not improve nutritional status or
function [30]. Three studies [27–29] found increases in muscle mass and ADLs, suggesting
that EPA may be effective in preventing muscle loss and increasing muscle mass in cancer
cachexia patients.

EPA Intake
The recommended intake of EPA for cancer cachexia patients is about 2 g/day. The
studies that reported EPA-induced increases in body weight or muscle mass [27,29,31]
generally took between 1.8 and 2.2 g. In interpreting this result, we need to consider the
side effects associated with EPA overdose [26]. According to a statement by the European
Food Safety Authority, the upper limit of EPA intake is 1.8 g, even when taken as a medicine.
However, it has been reported that, in general, there are few side effects from excessive
intake of EPA [32], although there have been studies that have shown nausea and loss of
appetite in some subjects after taking up to 6 g of EPA [28]. Therefore, it should not be
considered overly dangerous, but its use in patients with a tendency to bleed from tumors
should be avoided.

The Length of Time It Takes for the Effects of EPA to Appear

It takes about a month for EPA to be effective in muscle protection in cancer cachexia
patients. The rationale is that studies reported that the studies that were found to be
effective had intervention periods of 8–16 weeks [27–29], and a study reported that weight
gain was observed up to week 4, after which weight was maintained [28]. The studies that
found no effect were short interventions of 2 weeks [30]. Therefore, it would be better to
continue EPA supplementation for more than 4 weeks for cancer cachexia.

3.1.4. Clinical Recommendation

Theoretically, EPA may have an effect on cancer cachexia by preventing muscle
catabolism. However, there is no unified view. As long as it is taken appropriately, the
possibility of serious side effects is considered to be low. To increase the number of studies
and obtain accurate evidence, it is advisable to actively take nutrients safely. Currently,
when EPA is to be ingested, the amount of EPA should be about 2 g/day, and the period
until the effect appears should be set at approximately 4 to 12 weeks; it is necessary to
evaluate the effect. EPA is reduced by overheating, especially in fried foods, where it is
reduced the most [33]. Since blue fish such as sardines, tuna, and mackerel contain high
amounts of EPA [22], it is best to eat these fish raw to get the most from their diet.
Nutrients 2022, 14, 345 4 of 16

3.2. β-Hydroxy-β-Methylbutyrate (HMB)

3.2.1. General Information
HMB is a leucine metabolite, one of the essential amino acids. It has been reported
that approximately 5% of leucine is converted to HMB in the body [34]. Although HMB
is believed to promote protein anabolism and inhibit protein catabolism in muscle [35,36],
its mechanism is not clearly understood [37]. However, HMB has been reported to affect
muscle hypertrophy in healthy young men [38,39]. It has also been reported that bedridden
elderly who received HMB through tube feeding received a protective effect on muscle
protein catabolism [40]. The most common way to consume HMB is in the form of HMB
calcium salt, and the recommended intake of HMB alone is 3 g (3000 mg)/day [37]. Regard-
ing the side effects associated with HMB overdose, studies in humans and animals have
not shown any adverse effects associated with HMB supplementation [37].

3.2.2. Mechanisms of HMB on Cancer Cachexia

Cancer-induced cachexia accelerates protein catabolism and decreases protein an-
abolism, resulting in a shortened life expectancy and reduced ADL and QOL. Although
the effects of HMB are not clear [36], it has been suggested that HMB appears to attenuate
phosphorylation of p42/44-mitogen-activated protein kinase by PIF [41]. Therefore, it
is possible that HMB promotes muscle protein anabolism and inhibits muscle protein
catabolism [41].

3.2.3. Clinical Evidence of HMB

Effect of HMB on Cancer Cachexia
The effect of HMB in cancer cachexia patients is currently unknown. A study in which
HMB, arginine, and glutamine were administered to advanced cancer patients reported
that FFM and weight gain were observed [42], while there were reports of no significant
increase in LBM [43]. Therefore, although the protective effect of HMB on muscle proteins
in cancer cachexia patients is unknown, it may be expected to be effective. In interpreting
the results, it is important to note that all of the studies included 3 g of HMB, 14 g of
arginine, and 14 g of glutamine, and none of the studies revealed cancer cachexia with
HMB alone. However, although the effects of arginine and glutamine on cancer cachexia
have been reported [44], the effects of HMB alone on rats and mice assuming a cancer
cachexia state have also been widely reported [45]. Therefore, HMB alone may have a
protective effect on muscle proteins against cancer cachexia. To use a dietary supplement
containing HMB similar to the composition of the above study, it should be considered
using an amino acid beverage containing HMB, L-arginine, and L-glutamine.

HMB Intake
The recommended intake of HMB for cancer cachexia patients is expected to be
approximately 3 g/day. A study of cancer cachexia patients receiving 3 g of HMB, 14 g of
arginine, and 14 g of glutamine reported a significant increase in LBM and FFM [42,43].
Conversely, there are no reports on the maximum tolerable dose for HMB. A study of
healthy subjects reported that ingestion of 6 g of HMB did not result in further muscle
hypertrophy, but no symptoms were associated with overdose [38]. Therefore, whether
there is a new role for muscle protein protection when cancer cachexia patients consume
more than 3 g of HMB is unknown, although the risk of adverse events is thought to be low.

The Length of Time It Takes for the Effects of HMB to Appear

It takes about 4 weeks for HMB to be effective in muscle protection in cancer cachexia
patients. The rationale is that studies performed for 8 weeks tended to have a higher LBM
throughout the study period [43], and studies performed for 24 weeks had weight gain
4 weeks after the beginning of HMB intake, which was then maintained for 24 weeks [42].
In both studies, the effects tended to manifest themselves in the form of physical changes
Nutrients 2022, 14, 345 5 of 16

between 4 and 8 weeks. Therefore, it would be better to continue HMB supplementation

for more than 4 weeks for cancer cachexia.

3.2.4. Clinical Recommendation

Theoretically, HMB may have a protective effect on muscle proteins against cancer
cachexia. However, there is no unified view. As long as it is taken appropriately, the
possibility of serious side effects is considered to be low. To increase the number of studies
and obtain accurate evidence, it is advisable to actively take nutrients safely. Currently,
when HMB is to be ingested, the amount of HMB should be approximately 3 g/day and
the period until the effect appears should be set at more than 4 weeks; it is necessary to
evaluate the effect. Leucine is found in animal proteins, including meat such as beef, loin
ham, and liver; seafood such as horse mackerel, salmon, and bonito flakes; dairy products
such as cheese and skimmed milk powder; and soy products such as dried tofu [46].
Furthermore, since leucine is an essential amino acid, it is necessary to consume leucine
and other essential amino acids in sufficient quantities. Therefore, to obtain HMB from the
diet, animal protein should be actively consumed.

3.3. Creatine
3.3.1. General Information
Creatine is synthesized daily by the liver and kidneys from 1 to 2 g of three amino
acids: glycine, arginine, and methionine. Approximately 95% of synthesized creatine is
included in skeletal muscle and is used primarily as an energy source for muscles [47].
The effects of creatine on muscle mass and strength have been reported in many studies,
especially in young individuals [48,49]. It has been reported that the effect is ambiguous on
the elderly [50,51] and no adverse events were reported [51]. Although there is no clear
daily dose of creatine, it is recommended to take the most common program that involves
an initial loading phase of 20 g/day for 5–7 days, followed by a maintenance phase of
3–5 g/day for different periods of time (1 week to 6 months) [52]. It has been reported that
a long-term intake of 3 g/day can have the same effect as loading [53].

3.3.2. Mechanisms of Creatine on Cancer Cachexia

The proposed mechanisms underlying the beneficial effects of carnitine to prevent
skeletal muscle loss by cancer cachexia are based on stabilization of mitochondrial mem-
brane by lipids’/phospholipids’ synthesis and reduction in the amount of free long-
chain fatty acids and preserving the activities of key mitochondrial enzymes in energy
metabolism, oxidative phosphorylation, and also anti-inflammatory and anti-oxidative
properties [54,55]. Therefore, in recent years, creatine intake has been considered to have a
protective effect on muscles by resisting the catabolic states of cancerous muscle protein
catabolic states [51,54,56].

3.3.3. Clinical Evidence of Creatine

Effect of Creatine on Cancer Cachexia
The effect of creatine in patients with cancer cachexia is currently unknown. Studies
of patients with colorectal cancer undergoing chemotherapy or with cancer cachexia have
shown no changes in muscle mass or body composition [57,58]. Conversely, studies in
rats reported that it inhibited tumor growth and metastasis in cancer-bearing rats [59]
and suppressed weight loss and skeletal muscle atrophy [60]. Thus, although creatine
may influence cancer cachexia, there is no evidence for this. The reason creatine had no
effect on the cancer cachexia pathology in the previous study might be its mechanism of
action. Regarding its effect on cancer patients, it has been reported that it is beneficial in
maintaining and increasing somatic cell mass in patients receiving less invasive chemother-
apy, while it may not be beneficial in patients receiving more invasive chemotherapy [55].
Therefore, we believe that cancer cachexia patients may benefit from taking creatine in
the early stages of cancer development when their metabolic status is relatively similar
Nutrients 2022, 14, 345 6 of 16

to that of healthy individuals. Moreover, some points should be noted in applying the
results of these studies. In general, the main short-term side effects of creatine intake are
decreased kidney function and fluid retention. However, current systematic reviews have
ruled out both impaired renal function and water retention as side effects of excessive
creatine intake [61,62]. Furthermore, reviews of the effects of creatine on cancer cachexia
have reported no serious adverse events [51]. However, care should be taken to avoid
adverse effects when creatine is taken by the elderly, people with renal disease, people
using diuretics, people whose renal function is expected to be impaired by chemotherapy,
and people with ascites or edema due to advanced cancer.

Creatine Intake
Current evidence suggests that creatine intake in cancer cachexia patients is ineffective;
but if taken, the recommended creatine intake is about 3g/day. The rationale is that two
studies in cancer cachexia patients [57,63] found no effect; but, in healthy subjects, 20 g of
creatine for 6 days or 3 g of creatine for about 28 days was reported to be effective [53].
As a caveat in interpreting the results, the study by Jatoi et al. [58] used the study by
Hultman et al. [53] as a reference to determine creatine intake. Nonetheless, cancer cachexia
patients did not show the same effects as healthy indexes. This suggests that metabolic
abnormalities in patients with cancer cachexia may prevent them from benefiting from
creatine. Therefore, taking creatine before cachexia or in the early stages of cachexia may
be effective.

The Length of Time It Takes for the Effects of Creatine to Appear

If creatine effectively prevents muscle catabolism in cancer cachexia patients, it will
take about a month to observe its effects. The rationale is that these studies in healthy
individuals reported positive effects after 6 weeks [48] and 14 weeks [50] of intervention,
and creatine levels in body tissues were completed in about 28 days [53]. However, it is not
clear if the same is true for cancer cachexia patients.

3.3.4. Clinical Recommendation

Theoretically, creatine does not have a muscle protective effect against cancer cachexia,
according to current evidence. However, there is no unified view. As long as it is taken
appropriately, the possibility of serious side effects is considered to be low. To increase the
number of studies and obtain accurate evidence, it is advisable to actively take nutrients
safely. Currently, when creatine is to be ingested, the amount of creatine should be about
3 g/day, the period until the effect appears should be set at more than 4 weeks, and it is
necessary to evaluate the effect. Creatine is found in fish, such as herring, salmon, and tuna,
and meat, such as pork and beef [64]. Therefore, to obtain creatine from the diet, animal
protein should be actively consumed.

3.4. Carnitine
3.4.1. General Information
Carnitine comprises two amino acids, lysine and methionine; most of the carnitine
in the body (95%) is stored in the skeletal muscle [65]. In skeletal muscle, carnitine plays
an important role in increasing fat oxidation while conserving glycogen, delaying fatigue
during prolonged aerobic exercise [66]. Carnitine can be synthesized endogenously or
obtained exogenously from the diet, especially from red meat [65]. Therefore, deficiencies
are usually rare, and the Food and Nutrition Board (FNB) of the National Academies
has not established a recommended Dietary Reference Intakes (DRI) for carnitine per
day [67]. However, many cancer cachexia patients are carnitine deficient [68,69]. This has
been attributed to decreased dietary intake due to the multifactorial etiology of cachexia,
impaired endogenous synthesis [70], increased urinary excretion due to chemotherapy [71],
and decreased skeletal muscle [65]. Therefore, carnitine deficiency has been proposed to be
an underlying cause of cancer cachexia [72] and tumor-associated fatigue [71].
Nutrients 2022, 14, 345 7 of 16

3.4.2. Mechanisms of Carnitine on Cancer Cachexia

In recent years, it has been suggested that carnitine may help cancer patients to main-
tain and increase muscle mass and improve fatigue by antagonizing their hypercatabolic
metabolism [73], playing a predominant role in the generation of cancer cachexia [74].

3.4.3. Clinical Evidence of Carnitine

Effect of Carnitine on Cancer Cachexia
The effect of carnitine in cancer cachexia patients is currently unknown. The rationale
is that in a study of advanced pancreatic cancer patients and advanced tumor patients, the
results showed a significant increase in BMI, and improved nutritional status (body cell
mass, body fat) [75] or nutritional variables (lean body mass and appetite) were significantly
increased [73]. There have been no reports of serious side effects or worsening of the
condition due to carnitine intake. For this study, the effect of carnitine supplementation on
cancer cachexia was based mainly on the assumption that the patient is carnitine deficient.
However, in the study by Cruciani et al. [76], only 30% of the patients were carnitine
deficient. Therefore, in actual clinical practice, it is advisable to test patients for carnitine
deficiency before starting carnitine supplementation, considering the possibility that cancer
cachexia patients may not necessarily be carnitine deficient.

Carnitine Intake
The recommended intake of carnitine in cancer cachexia patients is approximately
3 g/day. The rationale is that studies have shown that an effect in preventing muscle
catabolism has been achieved by taking 4–6 g of carnitine [73,77]. There was no significant
difference from the placebo group in the study of 2 g of carnitine per day [78]. A different
study by the same researchers reported that carnitine may be safely administered at doses
of up to 3000 mg/day [76]. On the other hand, carnitine supplements have been reported
to cause side effects such as nausea, vomiting, abdominal cramps, and diarrhea when
administered [79]. In contrast, the highest dose of carnitine administered in this study was
6 g, but no adverse events occurred. Therefore, the carnitine intake should be set at 3 g,
and the dosage should be maintained.

The Length of Time It Takes for the Effects of Carnitine to Appear

It takes about 4 weeks for carnitine to be effective in muscle protection in cancer
cachexia patients. The rationale is that studies reported that the studies that were found
to be effective had intervention periods of 12 weeks [75] and 4 weeks [73]. Moreover,
a study that also used a 4-week intervention showed that carnitine plasma levels were
reported to increase significantly [78]. Therefore, it would be better to continue carnitine
supplementation for more than 4 weeks for cancer cachexia.

3.4.4. Clinical Recommendation

Theoretically, carnitine may have a protective effect on cancer cachexia by preventing
muscle catabolism. However, there is no unified view. As long as it is taken appropriately,
the possibility of serious side effects is considered to be low. To increase the number
of studies and obtain accurate evidence, it is advisable to actively try to take nutrients
safely. Currently, when carnitine is to be ingested, the amount of carnitine should be about
3 g/day, the period until the effect appears should be set at approximately 4 weeks, and it
is necessary to evaluate the effect. Carnitine is abundant in animal foods such as red meat,
fish meat, poultry, and milk [79]. Usually, the redder the color of the meat, the higher the
carnitine content. Therefore, to obtain carnitine from the diet, red-colored meat, such as
beef, should be actively consumed.

3.5. Combination of Nutrients

The summary table for the nutrients discussed in this review is shown in Table 1.
There is no evidence that the nutrients discussed in this review, when taken as supple-
Nutrients 2022, 14, 345 8 of 16

ments, effectively prevent muscle hypercatabolism due to cancer cachexia. However, as

reviewed in this paper, the nutrients themselves may benefit cancer patients with cachexia.
Furthermore, side effects are extremely rare when taken in the amounts and for the periods
recommended in this review. To increase the number of studies, we believe it is important
to first practice it safely in a clinical setting. The guidelines for cancer cachexia list salmon,
a nutritious food, as a natural source of omega-3 fats [19]; therefore, the idea of taking
each nutrient in the diet is shown in Table 2. Consistent, long-term intake of nutrients as a
diet may be useful for the human body. Besides the effects of nutrients, the intake of tasty
diets can contribute to the improvement of QOL due to the pleasure of eating. Therefore,
it is recommended that these foods be consciously consumed during the early stages of
cancer development.
Nutrients 2022, 14, 345 9 of 16

Table 1. Summary table.

Patients Duration of
Nutrients Author and Year Intervention Results
Total no. of Patients Patient Characteristics Intervention

Patients with unresectable Weight ↑

Fearon (2003) [27] n = 200 620 kcal, protein 32 g +/- EPA 2.2 g/day 8 weeks
pancreatic cancer LBM ↓
EPA EPA starting at 1 g/day, increased to 6
Patients with advanced pancreatic
Wigmore (2000) [28] n = 26 g/day over four weeks followed by 6 12 weeks Weight ↑
cancer
g/day
Patients with nonsmall cell lung
Murphy (2011) [29] n = 40 EPA 2.2 g/day 95 ± 3.8 days Weight →
cancer
EPA 1.8 g and DHA 1.2 g/day or No significant difference in
Bruera (2003) [30] n = 60 Patients with advanced cancer 14 days
placebo nutritional status and fanction
Patients with solid tumors who HMB 3 g, arginine 14 g and glutamine
May(2002) [42] n = 49 had demonstrated a weight loss of 14 g/day or an isocaloric control 4 weeks Weight ↑
HMB
at least 5% mixture of nonessential amino acids
HMB 6 g, arginine 28 g and glutamine
Patients with advanced cancer
Berk (2008) [43] n = 472 28 g/day or an isocaloric control 8 weeks No significant difference in LBM
weight loss of 2% to 10%
mixture of equal nitrogen
Patients with colorectal cancer Creatine 45 g/day load×1 week and BCM ↑( patients undergoing
Norman (2006) [57] n = 30 8 weeks
Creatine undergoing chemotherapy was then reduced to 22.5 g/day less aggressive chemotherapy )
Patients with incurable
Creatine 20 g/day load×5 days No significant difference in
Jatoi (2017) [58] n = 263 malignancy other than a primary 4 weeks
followed by 2 g/day or placebo body composition
brain tumor
Gramignano (2006)
n = 12 Patients with advanced cancer L-Carnitine 6 g/day 4 weeks LBM ↑
Carnitine [73]
Patients with advanced pancreatic
Kraft (2012) [75] n = 72 L-Carnitine 4 g/day or placebo 12 weeks BMI ↑
cancer
Abbreviations: EPA, Eicosapentaenoic acid; HMB, β-hydroxy-β-methylbutyrate; LBM, lean body mass; BCM, body cell mass; ↑,Increase; ↓, Decrease; →, Maintain.
Nutrients 2022, 14, 345 10 of 16

Table 2. List of proposed nutrients.

EPA HMB Creatine Carnitine Combined Nutrition

(leucine) beef, loin ham, liver,
horse mackerel, salmon, fish such as herring, salmon,
blue fish such as sardines, red meat, fish meat, poultry,
Foods with high content bonito flakes, cheese, and tuna, and in meat such as
tuna, and mackerel and milk
skimmed milk powder, dried pork and beef
tofu
beef bowl, beef stew, ham
dishes made with herring, sushi and sashimi platters,
Menu (something easy to eat sandwich, sushi, dishes with pork shabu salad, beef bowl,
sushi and sashimi of sardines, salmon, tuna, pork shabu seafood rice bowls, nabe
when patients have a poor horse mackerel and salmon, fish dish, beef stew, milk,
tuna, and mackerel salad, beef rice bowl, beef dishes, sandwiches, cream
appetite) grilled salmon, cheese, cream cream stew
stew stew
stew, stewed dried tofu
Total recommended daily
2 g/day 3 g/day 3 g/day 3 g/day
consumption
Corresponding literature [23,24] [38–40] [51,54,56] [73,74]
Abbreviations: EPA, Eicosapentaenoic acid; HMB, β-hydroxy-β-methylbutyrate.
Nutrients 2022, 14, 345 11 of 16

4. Discussion
4.1. Multi-Nutrient Combinations
Interventions that combine multiple nutrients may be more effective than single nutri-
ent supplementation. When EPA and the amino acids leucine, arginine, and methionine
were used together, the amount of protein synthesis almost doubled [80]. Alternatively, in
the fish oil study, supplementation of the diet with the all-in combination of high protein,
leucine, and fish oil significantly reduced carcass loss, muscle, and fat mass, and improved
muscle performance. Furthermore, the total daily activity normalized after intervention
with a specific nutritional combination [81]. In a study of mice fed a macronutrient contain-
ing carnitine and mice fed an intervention diet showed a higher cumulative food intake
compared to controls. In addition, the intervention group had a significantly lower tumor
weight and no metastases [59]. However, there is still little evidence on the intake of
multiple nutrients.
As in Section 3.5, with a nutritional approach that aims to replenish a certain nutrient
when deficient, would give benefit with a single nutrient supplement. However, when ad-
ministering nutrients for their effect on cancer cachexia, multiple nutrient intakes are likely
to be more useful than a single intake, provided they are not burdensome to the patient. In
this context, the nutritional approach should first assess the patient’s condition. As in the
past, if energy, protein, and other nutrients are lacking, they need to be supplemented. In
addition, we propose that the new nutritional approach should consider cancer cachexia
and supplement nutrients simultaneously. For example, if a patient is eating well and
maintaining his or her weight, a nutrient approach such as creatine may be a good choice
to increase muscle mass. If the patient is eating well but losing weight, a multi-nutrient
approach may be more effective in preventing the progression of cancer cachexia. Alterna-
tively, for patients who cannot eat and lose weight, a conventional nutritional approach
may be important first, supplementing with nutrients to the extent possible within the
amount of food they can ingest.
Furthermore, many of the nutrients introduced in this review are contained in blue
fish and red meat. Therefore, actively consuming blue fish and red meat is not only a
general nutritional supplement for protein but also a nutrient supplement to counteract
muscle loss due to cancer cachexia. From the perspective of providing more nutrients with
less stress, it is important to consider that food supplements should also be more efficient
than taking a large number of supplements at once.

4.2. Time of Nutrient Supplementation

Cancer cachexia is a condition that gradually worsens as cancer progresses. Fearon et al.
described three stages of cachexia syndrome: pre-cachexia, cachexia, and refractory cachexia [2].
In the pre-cachexia stage, there are relatively few symptoms of cachexia and few metabolic
abnormalities, while, in the refractory cachexia stage, active management is no longer
possible [2]. Therefore, it is important to initiate interventions earlier in the management of
cachexia to control or delay its progression. The above nutritional interventions must be
performed while the progression of cancer cachexia is at an earlier stage. As for creatine in
particular, it is suggested that it may become less effective as the state of muscle anabolism
and catabolism as a result of cancer cachexia progresses, as mentioned earlier. Since it
is difficult to slow the progression of cachexia by conventional nutritional management
alone [2], it is necessary to begin interventions such as nutrient addition early in nutritional
interventions for patients to maintain their nutritional status.
Aggressive administration of nutrition to refractory cachexia is discouraged [4]. In fact,
in patients with refractory cachexia, oral nutrition has been reported to have harmed not
prolonged life [77]. The National Comprehensive Cancer Network Guidelines for Palliative
Care recommend that enteral and parenteral nutrition be considered (as needed) only if
the prognosis is longer than a few weeks to a few days [82]. In the terminal stage, not only
in cancer treatment, the goal shifts from treatment to care and the patient’s QOL should
be the most important consideration. The nutritional approach with the expectation of
Nutrients 2022, 14, 345 12 of 16

improvement in nutritional status is considered to be at least from the pre-cachexia to

cachexia stages.
The nutrients discussed in this study should be administered simultaneously with
conventional energy and protein supplementation. Therefore, the patient’s condition
should be evaluated (assessed) by a dietitian who is in charge of adjusting the entire diet.
Moreover, each nutrient should be added after explaining the level of evidence to the patient
at the same time as the diet is adjusted. To increase the level of evidence for nutritional
approaches, more research is needed on the addition of nutrients to conventional nutritional
management. Since sufficient evidence is needed to make nutritional approaches more
effective and safer for patients, it is necessary to take an active nutritional approach and
gather evidence with full consideration of the risks.

4.3. Case-Oriented Examples

In this review, we introduce nutrient-oriented examples. In this section, we discuss
case-oriented examples that would benefit actual clinical practice.
Case 1: A man with early-stage cancer, preoperatively for radical surgery. Since
postoperative weight (muscle) loss was expected, nutritional guidance was provided before
the surgery. Currently, his appetite is normal, with no weight loss. The patient had no
nutritional problems or inflammatory reactions. His compliance is good. It is expected that
this patient will be able to eat normally, approximately 3 months after the surgery.
In such cases, it is expected that the effects of increased muscle catabolism due to
cancer cachexia have not yet occurred. Since there is no significant inflammatory response,
it is recommended to manage the patient’s nutrition to increase muscle mass as much as
possible. It is recommended that the daily protein requirements should be based on animal
proteins. It is also recommended to add ham sandwiches to meals as snacks. In addition,
muscle training along with protein intake can help increase muscle mass as much as possible
before surgery and prepare for weight loss after surgery. It is important to remember that
the goal of the patient’s treatment is to achieve a cure and that good nutritional management
in the present situation will affect the patient’s recovery after surgery.
Case 2: A woman with metastatic cancer undergoing palliative chemotherapy. The
patient has been losing weight rapidly over the past year and is still progressing. Nutritional
guidance was provided to prevent weight loss. The patient’s physical strength decreased
along with weight loss, and she also had anorexia. The patient had chronic high levels of
inflammatory response. Both the patient and her family had a strong sense of crisis and
were worried about what she should eat. However, due to chemotherapy-induced taste
disorder and nausea, she could not eat as much as she would have liked.
In such cases, the inflammatory response is high, and the catabolism of muscles due to
cancer cachexia is advanced; thus, it is not easy to increase muscle mass even with protein
intake and exercise. Therefore, it is advisable to first determine what foods the patient can
eat and how much of them she can eat, and then recommend the consumption of blue fish
and other foods that contain anti-inflammatory nutrients such as EPA. When a patient has
anorexia or taste disorder, cold or sour foods may be easier to eat. In this case, a small
amount of sushi or marinated fish may be effective. It is important to note that the purpose
of the patient’s treatment is shifting from cure to care; it is not necessary to force the patient
to eat but it is necessary to provide guidance within the scope of what the patient can
currently eat.

4.4. Limitation
One limitation of this study is that the types of cancers in the cited literature were not
examined in detail. Due to the small number of studies, some nutrients were only examined
in the cachexia of biased cancer types and the results may have been influenced by those
cancer types. Furthermore, we could not quantify lean body mass and muscle mass due
to different measurement methods and indices. Molecular or functional elucidation of
the improvement of lean body mass by nutritional supplementation should be studied in
Nutrients 2022, 14, 345 13 of 16

the future. The findings of this study have such limitations to apply for cancer patients;
therefore, it is recommended that appropriate nutrient intake should be reviewed by the
patient’s medical team when practiced in clinical practice.

5. Conclusions
Cancer cachexia is particularly common in patients with cancer and is associated with
various symptoms that decrease the patient’s QOL, such as loss of appetite and muscle
mass. It is conceivable that the nutrients discussed in this review may be effective in
preventing muscle hypermetabolism due to cancer cachexia. We believe that it is important
for the dietitian to work with the clinical team to assess the patient’s condition, symptoms,
QOL, and wishes, and then to safely incorporate nutrients that are expected to have specific
functions for cancer cachexia.

Author Contributions: K.T. and H.N. contributed to the conception and design of the research; K.T.
drafted the manuscript. H.N. and S.N. substantively revised the manuscript. All authors have read
and agreed to the published version of the manuscript.
Funding: This research was funded by the School of Nutrition and Dietetics, Faculty of Health and
Social Services, Kanagawa University of Human Services.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The funders had no role in the design of the study; in the collection, analyses,
or interpretation of data; in the writing of the manuscript: or in the decision to publish the results.

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