Critical Reviews in Oncology / Hematology 153 (2020) 103061

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Critical Reviews in Oncology / Hematology

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Review

Does nutrition for cancer patients feed the tumour? A clinical perspective T
a, b
F. Bozzetti *, Z. Stanga
a
Faculty of Medicine, University of Milan, Milan, Italy
b
Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Bern University Hospital and University of Bern, Bern, Switzerland

ARTICLE INFO ABSTRACT

Keywords: This review aims to answer to two basic questions: a) Which substrates does a tumour utilize and is there a
Nutrition and tumour growth regimen that might potentially favour the host over the tumour? and b) Does nutritional intervention dis-
Cancer cell metabolism proportionally affect tumour growth? Literature to date focuses on humans; although some references to mo-
Nutritive substrates of the cancer cell lecular mechanisms regulating cancer cells metabolism derive from studies on experimental tumours and cell
Nutrition of cancer patients
biology. Literature shows that some tumours, especially those of the brain and head/neck and lung, are glucose-
Calorie restriction
dependent, and patients with these tumours could benefit from a normocaloric ketogenic diet provided these
Ketogenic diet
Calorie restricted diet tumours exhibit high fluorodeoxyglucose (18F-FDG) captation. A high fat-protein, low carbohydrate diet appears
to better fulfil the nutritional requirements of the cancer patient. Current evidence shows no improvement in
tumoral response after restricting patients' caloric intake; whereas malnutrition is acknowledged as an important
negative predictive and prognostic factor in all cancer patients.

1. Introduction dietehave been transferred (perhaps inappropriately) to tumour-

The modern oncologistealso involved in coordinating nutritional
plans for his patientsefinds himself confronted with various conflicting
schools of thought which have increased in popularity over the last 20
years. On the one hand, there is growing awareness of overfeeding, the
obesity epidemic in western countries, and its association with in-
creased rates of cancer, especially in young people. Several studies
(mostly in animals, but also in overweight-obese humans) have shown
the benefits of a calorie restricted diet (CRD) on some markers of
longevity and aging. The current research has alarmed some oncolo-
gists, as the administration of certain nutrients might be deleterious for
cancer patients, and hypocaloric diets have been marketed and widely
advertised in the media. On the other hand, the clinical literature
clearly highlights the risk of short and long-term complications for
malnourished patients undergoing oncologic treatment and its negative
impact on quality of life and survival. The strategy of potentially re-
versing malnutrition is also gaining popularity in clinical practice.
Nutritional interventions (via oral, enteral, and parenteral approaches)
have evolved tremendously thanks to the availability of nutritional
substrates, technological advances, and safety of administration since
their introduction into clinical practice fifty years ago (Schwartz et al.,
1971).
The general impression is that some epidemiologic concepts of
cancer prevention in healthy peopleesuch as adopting a correct
bearing individuals, and some animal or cancer cell culture findings
have been prematurely adopted in clinical practice without considering
the basic metabolic discrepancies between experimental and human
tumours. It is well known, for instance, that the basal metabolic rate is
7-fold lower in humans than in rodents, and in advanced stage tumour
mass can account for up to 20 % of body weight. In humans, it rarely
exceeds 0.1 % of the patient's weight. Such a difference could account
for discrepancies in rodent and human response to dietary manipula-
tions such as CRD, ketogenic diets (KD) etc.
Today's rapid data transmission may have caused information from
epidemiology, basic research and clinical practice to overlap, creating
an atmosphere of uncertainty or, even worse, of absolute fideism re-
garding the benefits or risks of nutritional interventions in cancer pa-
tients.
This appraisal of the literature focuses on clinical research or evi-
dence limited to humans, and aims to answer two main questions:
a Which substrates does the tumour utilize and, consequently, is there
a regimen which might potentially benefit the host and not the tu-
mour?
b Does a nutritional intervention (normocaloric versus a CRD or spe-
cial diet) disproportionally affect tumour growth?

⁎
Corresponding author at: Residenza Querce Milanodue, 20090, Segrate, Italy.
E-mail address: federicobozzetti@gmail.com (F. Bozzetti).

https://doi.org/10.1016/j.critrevonc.2020.103061
Received 10 March 2020; Received in revised form 6 July 2020; Accepted 7 July 2020
Available online 12 July 2020
1040-8428/ © 2020 Elsevier B.V. All rights reserved.
F. Bozzetti and Z. Stanga
2. Biochemical characteristics and mutational alterations of
cancer cell energy metabolism
2.1. Glucose dependency and its pathophysiologic meaning
The idea that nutrition potentially stimulates tumour growth dates
back to 1914. Rous, one century ago (Rous, 1914) showed that the
growth of transplantable tumour grafts could often be prevented or
retarded by underfeeding the new host or by implementing a special
diet. These findings were subsequently replicated in other studies on
experimental brain (Mukherjee et al., 2004, 2002; Shelton et al., 2010;
Yang et al., 2009), prostate, and breast tumours (Mukherjee et al.,
1999; De Lorenzo et al., 2011; Phoenix et al., 2010).
Ten years later, Warburg (Warburg et al. (1927)) observed that
normal cells produce energy in the mitochondria while cancer cells
produce energy in the cytosol, and hypothesized that mitochondrial
function was significantly impaired in cancer cells. Glycolysis, the
major pathway of glucose metabolism, takes place in the cytosol of all
cells and can occur aerobically or anaerobically depending on the
availability of oxygen. This is metabolically significant as oxidation of
glucose under aerobic conditions results in 32−36 mol of ATP/mol of
glucose, whereas only 2 mol of ATP can be produced under anaerobic
conditions. In fact, the process of aerobic glycolysis occurs in two steps:
the first occurs in the cytosol, involves the conversion of glucose to
pyruvate, with resultant production of NADH and two molecules of
ATP. Then, if oxygen is available, the free energy contained in NADH is
further released via re-oxidization of the mitochondrial electron chain
and results in the synthesis of 30 more mol of ATP/mol of glucose.
When oxygen is in short supply, however, the NADH is re-oxidized by
reducing pyruvate to lactate through lactate dehydrogenase, and is
secreted into the extracellular space via monocarboxylate transporters.
This severely limits the amount of ATP formed per mole of glucose
oxidized when compared with aerobic glycolysis.
Warburg (Warburg et al. (1927)) noted that shifting energy deri-
vation away from mitochondrial oxidative phosphorylation serves to
shuffle phosphometabolites into the pentose phosphate pathway for
biosynthesis of nucleic acids and lipids. The process of producing en-
ergy mainly through non-oxidative breakdown of glucose obviously
requires an adequate availability of glucose - as glucose (not oxygen as
in healthy human karyocytes) is used to produce ATP during anaerobic
glycolysis. In cancer cells, the fermentation of glucose to lactate occurs
even with sufficient oxygen supply, and lactate may reach concentra-
tions of up to 10−30 mM in cancer tissue that is 2–20 times higher than
in healthy tissue (Brizel et al., 2001). This phenomenon is variously
termed “aerobic glycolysis”, “aerobic fermentation” (Fig. 1) (Pfeiffer
and Morley, 2014). It was also observed that, for normal cells, the
presence of glucose slightly increased respiration or had no effect on
oxygen consumption. On the contrary, glucose decreased oxygen up-
take by cancer cells (so-called Crabtree effect). The Warburg effect in-
volves the alteration of metabolic enzymes, including hexokinase 2,
pyruvate kinase type M2, glucose transporter 1, lactate dehydrogenase
and lactate transporters (monocarboxilate transporters) (Fantin et al.,
2006; Mayer et al., 2014; Wang et al., 2014; Wong et al., 2015).
Notably, the Warburg phenotype has been associated not only with
an energy gain, but also with the activation of numerous transcription
factors such as c-Myc, NF-kB, and Hypoxia-Inducible Factor 1-a (HIF 1-
a) (Fantin et al., 2006; Johnson and Perkins, 2012; Lu et al., 2002; Shim
et al., 1997). These can affect the expression of metabolic enzymes,
resulting in the deregulated conversion of glucose to lactate (Levine and
Puzio-Kuter, 2010) which promotes a “tumour lactagenesis” state (San-
Millan and Brooks, 2017). Lactate can then be converted into pyruvate
which enters the TCA cycle in the mitochondria in the liver and forms
glucose (Cori cycle). This is subsequently used by cancer cells as a
further energy source (Chen et al., 2016).
There is evidence that genetic mutations can affect tumour cell
metabolism: loss of function mutations/deletions of PTEN, TP53,
2
Critical Reviews in Oncology / Hematology 153 (2020) 103061
NOTCH1 attenuate mitochondrial function, upregulate glycolysis, in-
crease oxidative stress, or decrease oxidative phosphorylation. In ad-
dition, loss of function mutations/amplification of PIK3 and KRAS in-
crease coupling glycolysis to the mitochondrial citric acid cycle, which
yields intermediates for the biosynthetic pathways, or decrease mi-
tochondrial respiration. In a recent study on human oral squamous
cancer cell, Zheng (Zheng et al. (2019)) showed that STAT3 (signal
transducer and activator of transcription 3) promoted migration, in-
vasion, epithelial-mesenchymal transition, as well as aerobic glycolysis
of oral squamous cancer cells by inhibiting FOXO1 transcription. Si-
milar findings were reported in hepatocellular carcinoma (HCC) (Li
et al., 2017). According to Altenberg et al. (Altenberg and Greulich,
2004) glucose transporters and glycolytic enzymes are overexpressed in
24 different types of cancer, including lung cancer.
Finally, recent research has emphasized the role of long non-coding
RNAs (lncRNAs, a class of RNA molecules < 200 bp in length) in the
regulation of cancer cell metabolism; primarily by regulating key en-
zymes in the glucose metabolism pathway (Fan et al., 2017).
Studies on HCC have shown that lncRNA Ftx and lncRNA SNHG3
interfere in glucose metabolism reprogramming through the PPAR-γ
pathway. Furthermore, they stimulate glycolysis by promoting the ex-
pression and activity of phosphofructokinase and lactic-dehydrogenase,
while weakening the activity and expression of key tricarboxylic acid
cycle enzymes such as isocitrate dehydrogenase and α-ketoglutarate
dehydrogenase (Li et al., 2018).
For several decades researchers considered “anaerobic” glycolysis
even in oxygen-rich conditions as simply filling a need for cancer cells
living in a hypoxic environment and an inefficient way of procuring
energy. The potential advantages of the Warburg effect for rapidly
growing cancer cells have only recently become apparent. They can be
summarised as follows (Cameron et al., 2018):
a) ATP is produced approximately 100 times faster than oxi-
dative phosphorylation.
b) ROS generation is reduced, resulting in better preservation
of cancer cell genome.
c) 5-phosphoribose-1-pyrophosphate is produced as an inter-
mediate product of the pentose phosphate pathway, and is
used in the biosynthesis of purine and pyrimidine nucleo-
tides.
d) Lactic acid - for a long time only recognized as a “metabolic
waste product” - is now known to reduce cellular and tu-
mour microenvironment pH (which ranges between
6.0–6.5), as well as promote genetic changes which impair
anti-tumour immune response, reduce adherence cell junc-
tion, and facilitate detachment and metastases (Estrella
et al., 2013; Garcia-Venzor et al., 2019). Lactate concentra-
tion in whole breast tumour was found to correlate with
Nottingham Prognostic Index in women with with invasive
ductal carcinoma (Cheung et al., 2020). Finally, recent re-
search reports that lactate is used continuously as a fuel
under complete aerobic conditions by some tumours like
human lung cancer cells (Gallagher et al., 2009; Hirayama
et al., 2009; Hui et al., 2017; Kennedy et al., 2013).
e) Abnormal metabolism may itself drive cancer progression
through a preference for enzymatic isoforms that favour
anabolism (Ward and Thompson, 2012). For instance, pyr-
uvate kinase type M2 and hexokinase 2, key enzymes in the
cancer cell glycolytic pathway, seem to contribute to the
invasive potential and metastatic ability of the tumour
(Anderson et al., 2017; Li et al., 2016).
F. Bozzetti and Z. Stanga
Fig. 1. The Warburg effect.
2.2. Alternative energy sources and metabolic plasticity of the cancer cells
It is intriguing that human breast cancer cells with a Warburg
phenotype are able to evolve, survive, and proliferate independent of
glucose when they metastasize to brain. This is due to enhanced glu-
coneogenesis and oxidations of glutamine as well as branched chain
amino acids, which together sustain the non-oxidative pentose pathway
for purine synthesis (Chen et al., 2015).
Cancer cells that form dietary-resistant tumours carry mutations
which cause constitutive activation of the PI3K pathway and, in culture,
proliferate in the absence of insulin or IGF-1 (Kalaany and Sabatini,
2009). Approximately half of human melanomas harbour activating
mutations at amino acid V600 in the protein kinase BRAF, leading to
constitutive activation of the mitogen-activated protein kinase (MAPK)
pathway (Davies et al., 2002; Garnett and Marais, 2004). BRAF gene
mutation occurs in 45–50 % of skin melanomas and the most frequent
mutation involves the replacement of valine with glutamic acid at
codon 600 (V600E). BRAF inhibition decreases cellular glucose uptake
in melanoma together with reduction in cell volume (Theodosakis et al.,
2015).
Some studies indicate that in certain tumours, glutamine transport
and metabolism may be upregulated due to the presence of oncogenic
levels of Myc, which induce a transcriptional programme promoting
glutaminolysis and trigger cellular to glutamine dependence as a
bioenergetic substrate (Wise et al., 2008). The utilization of glutamine
within the mitochondria starts with its conversion to α-ketoglutarate
mediated by glutaminase and glutamate dehydrogenase. Then α-ke-
toglutarate can be oxidized to succinate through α-ketoglutarate de-
hydrogenase (the standard tricarboxylic acid cycle reaction) or alter-
natively, can undergo reductive carboxylation by isocitrate
dehydrogenase to isocitrate and then to citrate (reverse tricarboxylic
acid cycle activity). Finally, the glutamine-derived citrate can be
transported to cytoplasm to generate acetyl-CoA for anabolic processes.
In conditions of hypoxic stress, glutamine-derived α-ketoglutarate is
also used to stimulate lipid synthesis (Altman et al., 2016; Metallo et al.,
3
Critical Reviews in Oncology / Hematology 153 (2020) 103061
2011), while carbon and particularly nitrogen are used for biosynthesis.
This provides the substrate for purine and pyrimidine nucleotide
synthesis (Mates et al., 2020, 2009) as well as a supply for amino groups
for non-essential amino acid synthesis. Especially in tumours which
exhibit low glycolytic activity, this cycle may present an alternative to
glucose metabolism, or may simply provide an additional strategy for
cancer cells to produce the energy necessary for continuous growth
(Lieberman et al., 2011).
Under metabolic pressure, some tumour cells are able to take fatty
acids from their surroundings and perform β-oxidation to provide nu-
trients when glucose levels are low (Jeon et al., 2012). Many lncRNAs
are involved in the regulation of lipid metabolism (Higashi et al., 2000;
Nguyen et al., 2007; van Solingen et al., 2018; Zeng et al., 2018). It is
noteworthy that the amount of ATP produced by the full oxidation of
each fatty acid molecule is more than twice that of glucose (Boroughs
and DeBerardinis, 2015).
In conclusion, Warburg phenotype is found in many tumours (colon
cancer, liver metastases from colorectal cancer, squamous cell lung
cancer, soft tissue sarcoma, glioblastoma, HCC, uterus carcinoma, head
and neck cancer, and BRAF-negative melanoma (Brizel et al., 2001;
Kennedy et al., 2013; Ward and Thompson, 2012; Wise et al., 2008;
Lieberman et al., 2011; Jeon et al., 2012; van Solingen et al., 2018;
Zeng et al., 2018; Boroughs and DeBerardinis, 2015; Goodwin et al.,
2017; Jiao et al., 2018; Liu et al., 2017; Marshall et al., 1979;
Nikoobakht et al., 2019; Park et al., 2013; Schuurbiers et al., 2014;
Walenta et al., 2003, 1997; Walenta et al., 2000), and is absent in
prostate adenocarcinoma and diffuse large B cell lymphoma, in 50 % of
skin melanomas, 10 % of colorectal cancer, 100 % of hairy cell leu-
kaemia, 5% of multiple myeloma, and some thyroid cancers.
3. Nutritional support and tumour growth in humans
3.1. Nutrient consumption by the human tumour in vivo
Three studies (Holm et al., 1995; Norton et al., 1980; van der Hulst
F. Bozzetti and Z. Stanga
et al., 1997) measured blood flow using a non-invasive capacitance
plethysmograph. They obtained arterial as well as venous effluent
blood samples from the tumour-bearing limb or intestinal segment, and
control was the healthy limb or the non-affected intestinal segment. The
first study (Norton et al., 1980) showed a linear correlation between the
volume of soft tissue sarcoma of the limb and glucose uptake; which
was approximately 1.3 g/g tumour/d in soft tissue sarcoma and about
0.3 g/g tumour/d in osteosarcoma. The study by Holm (Holm et al.,
1995) showed that the net uptake of glucose by the colonic tumour
exceeded peripheral glucose uptake by a factor of 30 and lactate output
from the tumour was 43 times higher than peripheral release. A net
release of glutamine occurred in 7 patients and net retention in 10.
Finally, the third study (van der Hulst et al., 1997) confirmed that colon
cancer had a higher glucose uptake and lactate release than healthy
intestine and showed that tumour-containing-colon did not extract
more glutamine than did non-tumour-containing colon. They also noted
a higher tumoral uptake of essential amino acid and branched chain
amino acid compared to a low peripheral release (Norton et al., 1980;
Hagmuller et al., 1995).
These studies and others using positron emission tomography with
fluorodeoxyglucose ((Lu et al., 2002)F-FDG) (Bozzetti et al., 2004;
Nolop et al., 1987) attempted to quantify glucose uptake by the tumour
(glucose g per tumour 100 g/d) as well as tumour/healthy tissue up-
take. The approximate results were: colon cancer 8.2 (x4.2 tumour-free
colon), lung cancer 4.1 (x6.7 tumour-free lung), soft tissue sarcoma
(x1.8 tumour-free limb), liver metastases from colorectal cancer (x3.2
tumour-free liver).
It was recently demonstrated that the facilitative glucose transporter
1 (GLUT1) is responsible for augmented glucose uptake and metabolism
in several human cancers (Adekola et al., 2012). Various oncogenic
transcription factors such as c-Myc may directly regulate GLUT1 mRNA
expression (Osthus et al., 2000), as well as the aberrant activation of
growth factor or oncogenic signalling pathways such as PI3K/AKT
(Wieman et al., 2007; Wofford et al., 2008).
Furthermore, microenvironment hypoxia also induces GLUT1 ex-
pression via the transcription factor, HIF-1α and the overexpression of
lncRNA EIF3J-AS1 in hepatocellular carcinoma and lncRNA-HAL in
breast cancer (Garcia-Venzor et al., 2019; Yang et al., 2019). A high
expression of GLUT1 has been reported in oral squamous cell carcinoma
(Wang et al., 2018), non-small-cell lung carcinoma (NSCLC) (Chang
et al., 2019) and gastric cancer (Zhao et al., 2018). In osteosarcoma,
however, both GLUT1 and GLUT3 were highly expressed (Kang et al.,
2018), and in hepatocellular carcinomas GLUT1 and GLUT4 (Li et al.,
2018; Wei et al., 2017) were found abnormally expressed.
Finally, Chen et al. (Chen et al., 2001) and Yun et al. (2009) have
shown that the selective acquisition of KRAS or BRAF mutations in
response to glucose deprivation can upregulate GLUT1 expression. High
GLUT1 expression is clinically relevant to positron emission tomo-
graphy (PET) scanning, with the use of 18F-FDG (Nguyen et al., 2007)
for initial diagnosis and the prognostic evaluation of many tumours
including NSCLC (Li et al., 2018; Higashi et al., 2000; Wei et al., 2017;
Mamede et al., 2005).
Recent studies (Nguyen et al., 2007; Boroughs and DeBerardinis,
2015; Vesselle et al., 2008) have reported significant correlation be-
tween max-SUV and levels of GLUT1, between max-SUV and level of Ki-
67, and SUV and lung tumour growth (Duhaylongsod et al., 1995).
Other noteworthy findings include that high plasma glucose levels
in patients with brain cancer is associated with shorter survival rates
(Chaichana et al., 2010; Derr et al., 2009; McGirt et al., 2008); elevated
SUV portends a poor prognosis in head and neck cancer patients
(Kubicek et al., 2010) as well as those with epithelial ovarian cancer
(Chung et al., 2012); and, again, high GLUT1 expression is a predictor
of distant recurrence and poor prognosis in rectal cancer patients after
preoperative chemo-radiotherapy (Saigusa et al., 2012).
In conclusion, there is evidence that many (but not all) human tu-
mours have a Warburg phenotype which is characterised by high levels
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Critical Reviews in Oncology / Hematology 153 (2020) 103061
of GLUT1 whose expression is due to an oncogenic transcription effect
or to selective mutation. Furthermore, such effects may be lost during
the trajectory of the cancer cell towards metastatic colonization in
distant organs.
3.2. Effects of the nutritional status, food intake or restriction on tumour
growth
The presence of nutrients is associated with high levels of circu-
lating glucose (and consequently of insulin), while the transcription of
IGF-binding protein-1 decreases which in turn increases IGF-1 bioa-
vailability (Rajaram et al., 1997). Through their binding to specific
tyrosine kinase receptors, insulin and free IGF-1 activate the phospha-
tidylinositol-3 kinase (PI3K)-Akt-mammalian target of rapamycin
complex 1 (mTORC1) pathways. TOR is a large (∼280 kDa) serine/
threonine protein kinase belonging to the PI3K-related kinase family. It
has also been shown that mTORC1 is regulated by growth factors
through the phosphoinositide 3-kinase/protein kinase B, also known as
Akt (PI3K/PKB or Akt) pathway, as well as the Ras/mitogen-activated
protein kinase (MAPK) pathway (Dibble and Cantley, 2015). mTORC1
promotes proliferative signalling, increased cell proliferation, resistance
to death, enhanced survival, and altered cellular metabolism - including
increased fermentation of glucose and glutamine (Hanahan and
Weinberg, 2011).
In comparison, dietary restriction activates the Nrf-2 gene (Lewis
et al., 2010); an energy sensing network consisting of adenosine
monophosphate-activated protein kinase (AMPK), NAD-dependent
deacetylase sirtuin-1 (SIRT1) (Sinclair, 2005) and SIRT 2 (Ahmed et al.,
2019), peroxisome proliferator-activated receptor-α (PPAR-α) (Veech,
2004), and peroxisome - a proliferator-activated receptor-γ coactivator
1-α (PGC-α) that counteracts the insulin/IGF-1PI3K-Akt-mTORC1
pathway and promotes mitochondrial function (Cullingford, 2004). The
potential effects (metabolic reactions) of short-term fasting are depicted
in Fig. 2. There is some epidemiologic evidence of slightly increased
risk of some cancers due to higher activity of the IGF system.
In clinical practice, CRD is commonly defined as a long-term 20
%–40 % reduction of caloric intake through different forms of fasting.
These include intermittent fasting, alternate day fasting, two days a
week fasting, periodic fasting lasting three days or longer every two or
more weeks, or simply maintaining a normal frequency of meals with
reduced caloric content.
Literature contains few scattered anecdotal reports showing benefits
(Bell et al., 1964) or deleterious effects of enteral (EN) (English et al.,
1975) or parenteral (PN) (Rice and van Rij, 1987) feeding on tumour
progression. Bozzetti et al. (Bozzetti et al., 1995) speculated that if
nutrients stimulate tumour growth, well-nourished patients should
harbour tumours with higher proliferation indexes as compared losing-
weight patients. However, in a sample of 136 patients with non-
Hodgkin lymphoma they found an inverse statistically significant as-
sociation between poor nutritional status and high labelling indexes.
Malnourished patients had tumours with higher levels of incorporation
of the 3H thymidine labelling index. Several studies (Champ et al.,
2014; Fine et al., 2012; Zuccoli et al., 2010) investigated the potential
role of CRD in very small series of patients undergoing hypocaloric
(sometimes ketogenic) diets of 9.3 (Zuccoli et al., 2010), 17 (Fine et al.,
2012), 21 (Champ et al., 2014) kcal/kg/d for several weeks and only
reported the acceptable compliance of patients with such a regimen.
A 2009 literature review by Bozzetti and Mori (Bozzetti and Mori,
2009) (Table 1) investigating nutritional support and tumour growth in
humans found 12 studies (Baron et al., 1986; Bozzetti et al., 1999; Cao
et al., 1994; Dionigi et al., 1991; Edstrom et al., 1989; Frank et al.,
1992; Jin et al., 1999; McNurlan et al., 1994; Ota et al., 1986; Pacelli
et al., 2007; Rossi-Fanelli et al., 1991; Westin et al., 1991) assessing
tumour proliferation in connection with ornithine decarboxylase ac-
tivity, flow-cytometric DNA distribution, labelling index with tritiated
thymidine or bromodeoxyuridine incorporation, DNA index, DNA
F. Bozzetti and Z. Stanga
content and the percent of cells in S phase.
Eight of the 12 studies reported that nutritional support appeared to
stimulate tumour cell proliferation. However, two considerations are
noteworthy: first, tumour growth reflects the net balance of cell pro-
liferation and cell loss, and the above-mentioned indexes only explored
the first part of this ratio. Secondly, six of the eight studies reporting
tumour growth after nutritional support were in head and neck cancer
patients where tumour cell dependency on glucose is well known. More
relevant information comes from two studies (Demark-Wahnefried
et al., 2017; Henning et al., 2018) in overweight/obese patients with
prostate cancer who underwent a period of CRD before surgery. In the
first RCT (Demark-Wahnefried et al., 2017), 40 patients were rando-
mized either to receive their usual diet, or a regimen ranging from
16.6−14.5 kcal/kg/d during seven weeks to obtain weight loss of about
4.7 kg. Contrary to the expectations (and compared with controls) the
weight-losing arm manifested significantly greater Ki67 proliferation
rates at surgery. The second study (Henning et al., 2018) randomised 44
overweight/obese patients to hypocaloric regimen (minus
500−800 kcal/d from their usual diet) to achieve 3.7 kg loss after 5–8
weeks and found no significant changes in both malignant epithelium
apoptosis (TUNEL) or proliferation levels (Ki67). In keeping with these
biologic findings, a double blind RCT evaluating increases in nutrient
intake through administration of anamorelinea ghrelin analogue able
to improve appetite in cachectic NSLC patientsereported a sharp in-
crease in IGF-1 without any difference in survival at 4-month follow up
of NSCLC patients compared to controls (Katakami et al., 2018;
Takayama et al., 2016).
In conclusion, the combined data would suggest a) that CRD does
not reduce tumour growth, as tumour proliferation is higher when
nutrient intake is reduced or nutritional status is compromised, b) in-
creases in IGF-1 due to increased nutrient intake does not result in a
poorer outcome, c) head and neck tumours exhibiting a Warburg
5
Critical Reviews in Oncology / Hematology 153 (2020) 103061
Fig. 2. Effects of starvation in a normal cell.
KB: ketone bodies; IGF-1: insulin-like growth
factor-1; IGFBP1: insulin-like growth factor-1
binding protein; inh IGFBP1: inhibitor of in-
sulin-like growth factor-1 binding protein; Akt:
protein-kinase B; Ras: rat sarcoma; PI3K:
phosphatidylinositol-3-kinase; Nrf: NF-kappaB
repressing factor; SIRT1: sirtulin1; FOXO:
forkhead box 0.
phenotype may show higher tumour cell proliferation (not necessarily
tumour growth) in response to nutritional intervention and d) some
discrepancies in results may be explained by the varying metabolic
tumour patterns in the different studies.
3.3. Biologic and clinical effects of KD
The KD highlights the interference of nutrients on tumour meta-
bolism, by shifting from a quantitative number of calories to the qua-
litative concept that glucose, regardless of the total calorie amount, is
the preferred fuel for many cancers. However, the mechanism of action
of KD is complex. Experimental studies (Stafford et al., 2010) on brain
tumour indicate that KD effect on tumour growth is not simply due to a
reduction in available glucose, but is more likely to induce complex
interactions amongst several gene networks that regulate important
intracellular signalling cascades and cellular homeostatic mechanisms.
A recent review of this topic (Bozzetti and Zupec-Kania, 2016) lists
three types of nutritional manipulation that produce the ketogenic
state: a) total starvation without carbohydrate (CHO) or caloric intake,
which is associated with the highest levels of ketones (KB) (3−7 mM),
b) semi-starvation KD, similar to the protein-sparing regimen of <
800 kcal/d, where CHO account for about 50 g daily and is associated
with moderate levels of KB and finally c) mildly hypocaloric or nor-
mocaloric KD, providing variable amounts of protein, 70–80 % fat
calories, and usually more than 50 g CHO. These are associated with
levels of KB of about 0.5−1 mM.
A KD for cancer patients can be normocaloric, consisting of 70–80 %
fat calories, no more than 50 g CHO and an adequate intake of high
quality proteins. As already mentioned, glucose dependency is due to
several factors including activation of growth factor receptor/PI 3-ki-
nase/Akt signalling, loss of p53 wild-type activity and reduced ex-
pression of synthesis of cytochrome oxidase 2 necessary for
F. Bozzetti and Z. Stanga Critical Reviews in Oncology / Hematology 153 (2020) 103061

mitochondrial respiratory chain function, and loss of tp53-induced

No change in controls; significant ↑ in TPN; significant

No change in controls; significant ↑ in EN vs. controls
glycolysis and apoptosis regulator (TIGAR) which suppresses glycolysis.

No change in controls; no difference in intervention

No change or ↓ in controls; no change or ↑ in TPN

Finally, tumour hypoxia might stimulate accumulation of HIF-1α and
subsequent expression in the suppression of oxidative phosphorylation.

No change in controls; significant ↑ in TPN

A KD is inappropriate for cancer cells as these cells lack ketolytic en-
zymes, and β-hydroxybutyrate is an endogenous histone deacetylase
inhibitor which induces cell cycle arrest, differentiation and/or apop-
tosis and may improve mitochondrial function. Furthermore, KB has

No change in controls or TPN

also exhibited anticancer effects in several rodent tumour models.

Significant ↑ in IV patients
No change in both groups
Schroeder et al. (2013) investigated 12 patients with head and neck
↑ in TPN vs. controls
cancer. Using ultrasound, they implanted control small catheters inside
group vs. controls

vital tumour tissue or regional lymph node metastases, as well as in

Tumour growth

tumour-free submucosal tissue of the buccal region. After three days of

KD the mean lactate concentration declined to a greater extent in the
tumour tissue than in the tumour-free mucosa; demonstrating in vivo
the feasibility of interfering in tumour metabolism.
Bozzetti et al. (Bozzetti et al., 2004) studied 18F-FDG uptake in 12
Nutritional intervention (n, nutritional

35kcal and 1.4 g AA/kg as TPN

30kcal and 1.2 g AA/kg as TPN

42kcal/kg; 2.3 g AA/kg as TPN

25kcal/kg and 1.2 g AA/kg by

59kcal/kg and 1.9 g AA/kg as
Harris-Benedict x 1.2−1.5 as

Harris-Benedict x 1 and 1.5 g

Harris-Benedict x 1.5 as TPN

patients with metastatic liver from colorectal cancer who received

during the night alternatively a glucose-based or a lipid-based PN in-
fusion containing glucose 4 mg/kg/min or lipid 2 mg/kg/min, respec-
tively. Glucose captation by the metastases was 3.2 times higher than
AA/kg as TPN

by healthy liver tissue, increased very little after glucose PN and de-
creased very little after lipid PN. This was in contrast to captation by
IV route

the healthy liver, which increased 60 % with glucose PN and decreased

or EN

TPN

8% after lipid infusion. These findings suggested that metabolic activity

regimen)

EN

worked at a maximal regimen and was minimally affected (even if in

13

10
23

10

18

GI: gastrointestinal; AA: amino acid; iv: intravenous; EN: enteral nutrition; TPN: total parenteral nutrition; ↑: increase; ↓: decrease.

opposite directions) by glucose or lipid infusion.

9

Clinical application of KD was initially limited to a few case reports

19kcal; 1.1 g AA/kg by mouth or iv

Harris-Benedict x 1 and 1.5 g AA/

43kcal/kg; 1.4 g AA/kg by mouth

only assessing feasibility and tolerance of the regimen (Bozzetti et al.,

1996; Branca et al., 2015; Klement and Sweeney, 2016; Nebeling et al.,
Controls (n, usual hospital food)

1995). One interesting case was described by Seyfried et al. (Seyfried

Standard hospital food

et al., 2019) and Elsakka et al. (Elsakka et al., 2018) concerning glio-
blastoma: a patient who initially underwent an incomplete resection of
glioblastoma, followed by standard therapy with radiation and temo-
Regular food
Not reported

kg by mouth
< 1000kcal

zolomide, received KD for two years with progressive regression of the

Fasting

tumour, and died following complications from cerebral radionecrosis

without evidence of residual tumour. Another interesting case P. Kelly
(Children with Cancer UK, 2020) received, as the only treatment, KD
RCTs and comparative trials investigating nutritional support and tumour growth in humans.

13

23

10
7

for two years and four months after a diagnosis of inoperable glio-
blastoma, then had a probably complete tumour resection and is now
Malnourished, head and neck

still on KD and disease-free three years later.

Well-nourished, GI cancer

Well-nourished, GI cancer

More structured research is listed in Table 2 where only series of

Head and neck cancer

patients undergoing KD without oncologic treatment were included

(Bozzetti et al., 2004; Fine et al., 2012; Rossi-Fanelli et al., 1991;
Schroeder et al., 2013; Chu-Shore et al., 2010; Jansen and Walach,
2016; Rieger et al., 2014; Schmidt et al., 2011; Schwartz et al., 2015;
GI cancer

GI cancer
GI cancer

GI cancer
Primary

Tan-Shalaby et al., 2016). Ten studies (51 patients) evaluated the re-
cancer

sponse to KD, and stable disease or regression was reported in 20 (39

%). Although the potential for treating some patients with KD appears
Study duration (d)

promising, it should also be considered that at times study evaluation of

tumour response was suboptimal.
In conclusion, despite the presence of a biologic rationale for using a
Randomized clinical trials in malnourished patients

10−12
8−18

3−17

ketogenic regimen in patients with tumours showing a glucose de-

6−8

Comparative non- randomised clinical trials

10

15

pendency, clinical studies, albeit promising, are up to now confined to

7

small uncontrolled series with a short clinical follow up.

Rossi Fanelli (1991) [(Rossi-Fanelli et al.,
Edström (1989) [(Edstrom et al., 1989)

Bozzetti (1999) [(Bozzetti et al., 1999)

Dionigi (1991) [(Dionigi et al., 1991)

Pacelli (2007) [(Pacelli et al., 2007)

McNurlan (1994) [(McNurlan et al.,

3.4. Hypocaloric versus KD

Baron (1986) (Baron et al., 1986)
Jin (1999) [(Jin et al., 1999)

For reasons of exposition we dealt with CRD and KD separately,

however they share a common mechanism of action as they both rely
on increased body level of KB. Both CRD and KD lead to high rates of
fatty acid oxidation which increases production of acetyl-CoA. When
Author¨(year)

acetyl-CoA exceeds the capacity of tricarboxylic acid cycle to utilize it,

1991)

1994)

the production of β-hydroxybutyrate and acetoacetate, available as an

Table 1

energy source to the brain and other tissues (Cahill and Veech, 2003;
Morris, 2005; VanItallie and Nufert, 2003), increases. β-

6
F. Bozzetti and Z. Stanga Critical Reviews in Oncology / Hematology 153 (2020) 103061

hydroxybutyrate inhibits glycolysis (Cullingford, 2004) which explains

Non-significant ↓ in FDG uptake

why both fasting and KD can potentially improve antioxidative defense
= thymidine labelling index

Tumour mass ↓/= in 6/10

mechanisms in normal tissues (Veech, 2004; Shimazu et al., 2013;

= Tumour mass ↓ in 0/17

= Tumour mass in 7/11

Tumour mass ↓ in 3/11

Veech, 2006; Veech et al., 2001) but not in cancer cells. In humans, KB

Tumour mass ↓ in 0/2

Tumour mass ↓ in 7/7

Tumour lactate ↓ rise in the blood within 8−12 h after the start of fasting, reaching levels
= Tumour mass
up to 2−5 mM by 24 h (Cahill and Veech, 2003; Patel et al., 2019).
KB cannot be simply considered as fuel used during fasting as they
Outcome

are signalling molecules affecting cell and organ functions through the
expression of activity of several proteins and molecules, with capacity
to strongly influence metabolism (Newman and Verdin, 2017). These
include poly(adenosinediphosphate [ADP]–ribose) polymerase 1
(PARP1), and ADP ribosyl cyclase (CD38) (Lee, 2001), nicotinamide
adenine dinucleotide (NAD+), sirtuins (Imai and Guarente, 2016), the
< 70 g CHO (hypocaloric, normocaloric)
Fat vs. CHO, PN vs. oral diet (isocaloric)

PGC-1α, and the fibroblast growth factor 21 (Fisher and Maratos-Flier,

2016; Galman et al., 2008).
Cancer cells are unable to metabolize KB (Mates et al., 2020;
20−40 g CHO (normocaloric)
Fat vs. CHO PN (isocaloric)

Duhaylongsod et al., 1995; Maurer et al., 2011; Skinner et al., 2009)

Hypocaloric/normocaloric

due to mitochondrial defects (Wei et al., 2017; Zhou et al., 2007) and,
hence KB are toxic to some of them (Mates et al., 2020; Derr et al.,
2009; McGirt et al., 2008; Maurer et al., 2011; Skinner et al., 2009;
Non specified
Normocaloric
Normocaloric

Normocaloric

Magee et al., 1979; Scheck et al., 2010).

KD regimen

60 g CHO

KB could also act through an alteration of the expression of genes

involved in the cellular response to oxidative stress in tumour tissue -
notably COX-2, leading to a reduction in ROS (Chaichana et al., 2010;
Stafford et al., 2010). Cancer cells often have increased levels of ROS
(Fruehauf and Meyskens, 2007) which have been implicated in angio-
Colorectal cancer with liver metastases

genesis induction and tumour growth through the regulation of vas-

Head and neck squamous carcinoma

cular endothelial growth factor and HIF 1-α (Phoenix et al., 2010;
Weinberg and Chandel, 2009).
The rationale for adopting a CRD is based on preclinical data sug-
Tuberous sclerosis complex

gesting that the insulin pathway (including insulin, IGF-1 and the IGF-1
Miscellaneous cancers
Miscellaneous cancers

Miscellaneous cancers
Miscellaneous cancers

receptor) may be associated with cancer initiation and progression, and

that this pathway is upregulated through dietary consumption of CHO
and minimized by CHO restriction. Furthermore, cancer cells are unable
Glioblastoma
Glioblastoma

to use KB to their altered OXPHOS (Abdelwahab et al., 2012).

GI: gastrointestinal; CHO: carbohydrates; PN: parenteral nutrition; mths: months; ↑:increase; ↓:decrease.
GI cancer
Primary

Whereas the adoption of CRD in cancer patients undergoing onco-

logic treatment is at odds with the recommendations of both the
European Society for Clinical Nutrition and Metabolism (ESPEN)
(Arends et al., 2017) and American Society for Parenteral and Enteral
Nutrition (ASPEN) (August and Huhmann, 2009), some authors believe
Patients (n)

that the different utilization of KB by normal and cancer cell lines might
justify short-term fasting prior to chemotherapy. More precisely,
Effects of KD regimes on tumour outcome in patients without oncologic therapy.

27
12
12

10
16
17

14

healthy and tumour cells' contrasting reactions to nutrient scarcity is

4

2
7

termed "differential stress resistance" and may render tumour cells more
susceptible to the effects of chemotherapy; while at the same time
helping protect healthy cells against the toxic effects of chemotherapy
During infusion
Study duration

3 mths – 5 yrs

(Raffaghello et al., 2008). A recent RCT on 50 patients with glio-

3−12 mths

blastoma failed to find a benefit in survival for the arm receiving a CRD-
3 mths

5 mths
4 mths
6 wks

KG when compared to patients on a standard diet but an explorative

14 d

28 d
4d

analysis revealed that treated arm patients who had a glucose of less
than the median (83.5 mg/dl) on day 6 had a significantly longer sur-
vival compared to those above the median (Voss et al., 2020).
Without examining this emerging approach further, we'd like to cite
Rossi Fanelli (1991) [(Rossi-Fanelli et al., 1991)

Tan-Shalaby (2016) [(Tan-Shalaby et al., 2016)

the excellent reviews by de Cabo and Mattson (2019), and Shingler

Chu-Shore (2010) [(Chu-Shore et al., 2010)

Jansen (2016) [(Jansen and Walach, 2016)

Schroeder (2013) [(Schroeder et al., 2013)

et al. (Shingler et al., 2019) who collected 10 studies on KD, four studies
Schwartz (2015) [(Schwartz et al., 2015)
Schmidt (2013) [(Schmidt et al., 2011)
Bozzetti (2004) [(Bozzetti et al., 2004)

on fasting, and four combining some form of ketogenic or low CHO diet
Rieger (2014) [(Rieger et al., 2014)

with additional interventional aspects such as increased physical ac-

tivity or additional dietary changes.
Fine (2012) (Fine et al., 2012)

It is noteworthy that all seven KD studies which included KB levels

showed ketosis, or an increase in KB that was, however, not always
linked with a corresponding reduction in blood glucose. Meidenbauer
et al. and other suggest maintaining the ‘Glucose Ketone Index’ (the
Author (year)

molar ratio of circulating glucose over β-hydroxybutyrate)

(Meidenbauer et al., 2015) near one or below to achieve the highest
Table 2

benefit (Zuccoli et al., 2010; Rieger et al., 2014; Schwartz et al., 2015;
Winter et al., 2017).

7
F. Bozzetti and Z. Stanga
The underlying hypothesis for a benefit in cancer is the reduction of
signalling through insulin and growth hormone receptors, and an en-
hancement of FOXO and nuclear factor erythroid 2–related factor 2
(Nrf2) transcription factors. However current evidence from interven-
tional and dose escalation fasting studies does not show any reduction
in blood glucose (Dorff et al., 2016); with glucose even increasing after
24 h in the RCT (de Groot et al., 2015). In addition, IGF analysis showed
lower than expected reductions in IGF-1 at 72 h (Dorff et al., 2016).
This finding is is in keeping with a recent meta-analysis which reported
that a CRD was not associated with a significant change in circulating
IGF-1 (Kazemi et al., 2020). It is interesting that short-term fasting
contradicts all Societies of Anaesthesiology, which now suggest limiting
preoperative fasting as much as possible to avoid increases in insulin
resistance and the consequent anabolic resistance which is deleterious
for patient recovery.
Shingler et al. (Shingler et al., 2019) concluded that no re-
commendation is possible at the moment and future research with
adequately powered studies is required to test the effects of each dietary
restriction intervention on treatment toxicities and outcomes.
In conclusion, with reference to a hypothetical potentiation of
chemotherapy or a better compliance with its administration of KD or a
CR regimen, clinical experience with variously combined KD or fasting
regimens is rather scanty and did not provide any strong re-
commendation for the clinical practice. The preliminary findings of a
quite recent RCT on CRD was inconclusive and failed to demonstrate a
better tolerance of chemotherapy in patients undergoing CRD (de Groot
et al., 2020).
4. Further considerations on the practical approach to feed the
cancer patient
In the everyday practice, however, two other issues warrant con-
sideration to correctly plan a nutritional regimen to the cancer patient,
namely the capability of substrate metabolic utilization of the tumour-
bearing patient and the effect of some nutrients on restoring the fat-free
mass of depleted patients. Various investigations on energy metabolism
in cancer patients (Li et al., 2017; Altenberg and Greulich, 2004; Fan
et al., 2017; Li et al., 2018; Cameron et al., 2018; Arbeit et al., 1984;
Garcia-Canaveras et al., 2019; Hansell et al., 1986; Korber et al., 1999;
Legaspi et al., 1987; Selberg et al., 1990; Shaw and Wolfe, 1987) have
shown efficient mobilisation and oxidation of endogenous fat in the
post-absorptive state, both in weight-stable and weight-losing cancer
patients. Fat utilization ranged from 0.7 to 1.9 g/kg/d; that is about
6.3−17 kcal/kg/d and approximately 60–78 % of the resting energy
expenditure of a patient. Similarly, another large study reported that
cancer patients had a consistent non-protein respiratory quotient < 1,
indicating efficient use of fat substrates (Cao et al., 2010). Korber et al.
(Korber et al., 1999) have shown improved clearance and oxidation of
lipid after administration of long-chain triglycerides or mixed long-
chain/medium-chain triglycerides emulsions in cancer patients, as
compared with healthy controls. Metabolic and clinical experience with
high fat regimens are limited: Fearon et al. (Fearon et al., 1988) found
that KD maintained the nitrogen balance and whole-body protein
synthesis, degradation, or turnover rates; Breitkreutz et al. (Breitkreutz
et al., 2005) showed in a RCT that malnourished patients on high-fat
diet for 8 weeks gained weight and exhibited better fat-free and body
cell mass. They also reported enhanced quality of life compared with
patients receiving standard nutrition. Cohen et al. (Cohen et al., 2018a,
b) recently found that overweight cancer patients on a hypocaloric KD
(∼5% of energy from CHO = 20 g/d, 25 % energy from protein
=100 g/d, and 70 % energy from fat =125 g/d) lost total body fat
while maintaining soft lean tissue and, compared with a standard diet,
showed improved physical function and increased energy. There is also
evidence that such metabolic benefit may be potentiated by combining
nutrition with physical exercise and anti-inflammatory agents (Solheim
et al., 2019).
8
Critical Reviews in Oncology / Hematology 153 (2020) 103061
If patients have a tumours with a high 18F-FDG captation, we might
expect that such regimen maximally benefits the nutritional status of
the host in absence of a specific stimulation of the tumour growth. As
there is no correlation between blood glucose levels and 18 F-FDG
captation, there is no need for any correction in presence of hypergly-
caemia (Eskian et al., 2019), even if for patients undergoing PN, it is
better withdrawing the infusion 4 h prior to the PET scan. A further test
to assess the glucose dependency of the tumour is the determination of
the transketolase‑like‑1 (TKTL1), a tumour-marking enzyme associated
with aerobic glycolysis of tumour cells which enhances the production
of glucose-6-phosphate and glyceraldheide-3-phosphate. TKTL1 en-
zyme is a mutation of the transketolase gene, which seems to boost the
glucose metabolism of cancer cells (Coy et al., 2005; Langbein et al.,
2006; Sun et al., 2010) and parallels the progression of the tumour
(Jansen and Walach, 2016). It can be reliably measured using an im-
munological assay, called the epitope detection in monocyte (EDIM)
test, with 94 % sensitivity and 82 % specificity.
5. Conclusion
In conclusion, it appears that below the seemingly simple question
whether feeding a cancer patient also feeds the tumour, there is a
complex interplay of metabolic processes which also involve the acti-
vation of numerous transcription factors and the over- or under-
expression of oncogenes. Whereas the exact scenario remains in a large
part unknown, this review of the literature allows clarifying some main
points:
1 Metabolic alterations (namely aerobic glycolysis) of the cancer cells
does not simply represent an obligatory adaptation to a hostile en-
vironment, but may confer them an advantage in terms of growth
and survival;
2 Cancer cells express a metabolic plasticity, which allows them to
overcome conditions of some substrates deprivation through the use
of alternative metabolic pathways;
3 Approximately 50 % of human tumours utilize glucose as preferred
fuel and this is the main rationale for CR or KD regimens;
4 CR does not reduce the tumour growth in humans as well as non-
restricted diet do not increase tumour growth;
5 The use of KD regimens maintains a strong nutritional rationale in
the cancer patient, with a good evidence as regards the effects on the
nutritional status of the patient and a little evidence regarding the
tumour growth control;
6 There is no evidence, nowadays, of a strong clinical rationale for
using a calorie restricted diet in the malnourished cancer patient
and that no study has yet determined whether intermittent fasting
affects cancer recurrence in humans (Nencioni et al., 2018).
Funding
None declared.
Declaration of Competing Interest
The authors have declared no conflicts of interest.
Acknowledgements
The authors express their gratitude to Erica Holt for editing work
and Emilie Reber for providing support for the preparation of the
manuscript.
References
Abdelwahab, M.G., Fenton, K.E., Preul, M.C., Rho, J.M., Lynch, A., Stafford, P., et al.,
2012. The ketogenic diet is an effective adjuvant to radiation therapy for the
F. Bozzetti and Z. Stanga
treatment of malignant glioma. PLoS One 7 (5), e36197.
Adekola, K., Rosen, S.T., Shanmugam, M., 2012. Glucose transporters in cancer meta-
bolism. Curr. Opin. Oncol. 24 (6), 650–654.
Ahmed, M.A., O’Callaghan, C., Chang, E.D., Jiang, H., Vassilopoulos, A., 2019. Context-
dependent roles for SIRT2 and SIRT3 in tumor development upon calorie restriction
or high fat diet. Front. Oncol. 9, 1462.
Altenberg, B., Greulich, K.O., 2004. Genes of glycolysis are ubiquitously overexpressed in
24 cancer classes. Genomics 84 (6), 1014–1020.
Altman, B.J., Stine, Z.E., Dang, C.V., 2016. From Krebs to clinic: glutamine metabolism to
cancer therapy. Nat. Rev. Cancer 16 (10), 619–634.
Anderson, M., Marayati, R., Moffitt, R., Yeh, J.J., 2017. Hexokinase 2 promotes tumor
growth and metastasis by regulating lactate production in pancreatic cancer.
Oncotarget 8 (34), 56081–56094.
Arbeit, J.M., Lees, D.E., Corsey, R., Brennan, M.F., 1984. Resting energy expenditure in
controls and cancer patients with localized and diffuse disease. Ann. Surg. 199 (3),
292–298.
Arends, J., Bachmann, P., Baracos, V., Barthelemy, N., Bertz, H., Bozzetti, F., et al., 2017.
ESPEN guidelines on nutrition in cancer patients. Clin. Nutr. (Edinburgh, Scotland).
36 (1), 11–48.
August, D.A., Huhmann, M.B., 2009. A.S.P.E.N. Clinical guidelines: nutrition support
therapy during adult anticancer treatment and in hematopoietic cell transplantation.
South Afr. J. Clin. Nutr. 33 (5), 472–500.
Baron, P.L., Lawrence Jr, W., Chan, W.M., White, F.K., Banks Jr, W.L., 1986. Effects of
parenteral nutrition on cell cycle kinetics of head and neck cancer. Arch. Surg.
(Chicago, Ill : 1960) 121 (11), 1282–1286.
Bell, J.W., Jesseph, J.E., Leighton, R.S., 1964. Spontaneous regression of bronchogenic
carcinoma with five year survival. J. Thorac. Cardiovasc. Surg. 48, 984–990.
Boroughs, L.K., DeBerardinis, R.J., 2015. Metabolic pathways promoting cancer cell
survival and growth. Nat. Cell Biol. 17 (4), 351–359.
Bozzetti, F., Boracchi, P., Costa, A., Cozzaglio, L., Battista, A., Giori, A., et al., 1995.
Relationship between nutritional status and tumor growth in humans. Tumori 81
(1), 1–6.
Bozzetti, F., Cozzaglio, L., Gavazzi, C., Brandi, S., Bonfanti, G., Lattarulo, M., et al., 1996.
Total nutritional manipulation in humans: report of a cancer patient. Clin. Nutr.
(Edinburgh, Scotland) 15 (4), 207–209.
Bozzetti, F., Gavazzi, C., Cozzaglio, L., Costa, A., Spinelli, P., Viola, G., 1999. Total par-
enteral nutrition and tumor growth in malnourished patients with gastric cancer.
Tumori 85 (3), 163–166.
Bozzetti, F., Gavazzi, C., Mariani, L., Crippa, F., 2004. Glucose-based total parenteral
nutrition does not stimulate glucose uptake by humans tumours. Clin. Nutr.
(Edinburgh, Scotland) 23 (3), 417–421.
Bozzetti, F., Mori, V., 2009. Nutritional support and tumour growth in humans: a nar-
rative review of the literature. Clin Nutr. 28 (3), 226–230. https://doi.org/10.1016/j.
clnu.2009.02.006.
Bozzetti, F., Zupec-Kania, B., 2016. Toward a cancer-specific diet. Clin. Nutr. (Edinburgh,
Scotland) 35 (5), 1188–1195.
Branca, Jj, Pacini, S., Ruggiero, M., 2015. Effects of pre-surgical vitamin D supple-
mentation and ketogenic diet in a patient with recurrent breast cancer. Anticancer
Res. 35 (10), 5525–5532.
Breitkreutz, R., Tesdal, K., Jentschura, D., Haas, O., Leweling, H., Holm, E., 2005. Effects
of a high-fat diet on body composition in cancer patients receiving chemotherapy: a
randomized controlled study. Wien. Klin. Wochenschr. 117 (19-20), 685–692.
Brizel, D.M., Schroeder, T., Scher, R.L., Walenta, S., Clough, R.W., Dewhirst, M.W., et al.,
2001. Elevated tumor lactate concentrations predict for an increased risk of metas-
tases in head-and-neck cancer. Int. J. Radiat. Oncol. Biol. Phys. 51 (2), 349–353.
Cahill Jr, G.F., Veech, R.L., 2003. Ketoacids? Good medicine? Trans. Am. Clin. Climatol.
Assoc. 114, 149–161 discussion 62-63.
Cameron, M.E., Yakovenko, A., Trevino, J.G., 2018. Glucose and lactate transport in
pancreatic cancer: glycolytic metabolism revisited. J. Oncol. 2018, 6214838.
Cao, W.X., Xiao, H.B., Yin, H.R., 1994. [Effects of preoperative parenteral nutritional
support with chemotherapy on tumor cell kinetics in gastric cancer patients].
Zhonghua zhong liu za zhi [Chin. J. Oncol.] 16 (2), 137–140.
Cao, D.X., Wu, G.H., Zhang, B., Quan, Y.J., Wei, J., Jin, H., et al., 2010. Resting energy
expenditure and body composition in patients with newly detected cancer. Clin. Nutr.
(Edinburgh, Scotland) 29 (1), 72–77.
Chaichana, K.L., McGirt, M.J., Woodworth, G.F., Datoo, G., Tamargo, R.J., Weingart, J.,
et al., 2010. Persistent outpatient hyperglycemia is independently associated with
survival, recurrence and malignant degeneration following surgery for hemispheric
low grade gliomas. Neurol. Res. 32 (4), 442–448.
Champ, C.E., Palmer, J.D., Volek, J.S., Werner-Wasik, M., Andrews, D.W., Evans, J.J.,
et al., 2014. Targeting metabolism with a ketogenic diet during the treatment of
glioblastoma multiforme. J. Neurooncol. 117 (1), 125–131.
Chang, L., Xu, W., Zhang, Y., Gong, F., 2019. Long non-coding RNA-NEF targets glucose
transportation to inhibit the proliferation of non-small-cell lung cancer cells. Oncol.
Lett. 17 (3), 2795–2801.
Chen, C., Pore, N., Behrooz, A., Ismail-Beigi, F., Maity, A., 2001. Regulation of glut1
mRNA by hypoxia-inducible factor-1. Interaction between H-ras and hypoxia. J. Biol.
Chem. 276 (12), 9519–9525.
Chen, J., Lee, H.J., Wu, X., Huo, L., Kim, S.J., Xu, L., et al., 2015. Gain of glucose-in-
dependent growth upon metastasis of breast cancer cells to the brain. Cancer Res. 75
(3), 554–565.
Chen, Y.J., Mahieu, N.G., Huang, X., Singh, M., Crawford, P.A., Johnson, S.L., et al., 2016.
Lactate metabolism is associated with mammalian mitochondria. Nat. Chem. Biol. 12
(11), 937–943.
Cheung, S.M., Husain, E., Masannat, Y., et al., 2020. Lactate concentration in breast
cancer using advanced magnetic resonance spectroscopy. Br J Cancer. 123 (2),
9
Critical Reviews in Oncology / Hematology 153 (2020) 103061
261–267. https://doi.org/10.1038/s41416-020-0886-7.
Children with Cancer UK, 2020. Pablo Kelly. London (UK). Available from:. http://
www.childhoodcancer2018.org.uk/speakers/pablo-kelly.asp.
Chung, H.H., Kwon, H.W., Kang, K.W., Park, N.H., Song, Y.S., Chung, J.K., et al., 2012.
Prognostic value of preoperative metabolic tumor volume and total lesion glycolysis
in patients with epithelial ovarian cancer. Ann. Surg. Oncol. 19 (6), 1966–1972.
Chu-Shore, C.J., Major, P., Camposano, S., Muzykewicz, D., Thiele, E.A., 2010. The
natural history of epilepsy in tuberous sclerosis complex. Epilepsia 51 (7),
1236–1241.
Cohen, C.W., Fontaine, K.R., Arend, R.C., Alvarez, R.D., Leath III, C.A., Huh, W.K., et al.,
2018a. A ketogenic diet reduces central obesity and serum insulin in women with
ovarian or endometrial cancer. J. Nutr. 148 (8), 1253–1260.
Cohen, C.W., Fontaine, K.R., Arend, R.C., Soleymani, T., Gower, B.A., 2018b. Favorable
effects of a ketogenic diet on physical function, perceived energy, and food cravings
in women with ovarian or endometrial cancer: a randomized, controlled trial.
Nutrients 10 (9).
Coy, J.F., Dressler, D., Wilde, J., Schubert, P., 2005. Mutations in the transketolase-like
gene TKTL1: clinical implications for neurodegenerative diseases, diabetes and
cancer. Clin. Lab. 51 (5-6), 257–273.
Cullingford, T.E., 2004. The ketogenic diet; fatty acids, fatty acid-activated receptors and
neurological disorders. Prostaglandins Leukot. Essent. Fatty Acids 70 (3), 253–264.
Davies, H., Bignell, G.R., Cox, C., Stephens, P., Edkins, S., Clegg, S., et al., 2002. Mutations
of the BRAF gene in human cancer. Nature 417 (6892), 949–954.
de Cabo, R., Mattson, M.P., 2019. Effects of intermittent fasting on health, aging, and
disease. N. Engl. J. Med. 381 (26), 2541–2551.
de Groot, S., Vreeswijk, M.P., Welters, M.J., Gravesteijn, G., Boei, J.J., Jochems, A., et al.,
2015. The effects of short-term fasting on tolerance to (neo) adjuvant chemotherapy
in HER2-negative breast cancer patients: a randomized pilot study. BMC Cancer 15,
652.
de Groot, S., Lugtenberg, R.T., Cohen, D., et al., 2020. Fasting mimicking diet as an ad-
junct to neoadjuvant chemotherapy for breast cancer in the multicentre randomized
phase 2 DIRECT trial. Nat Commun. 11 (1), 3083. https://doi.org/10.1038/s41467-
020-16138-3. Published 2020 Jun 23.
De Lorenzo, M.S., Baljinnyam, E., Vatner, D.E., Abarzua, P., Vatner, S.F., Rabson, A.B.,
2011. Caloric restriction reduces growth of mammary tumors and metastases.
Carcinogenesis 32 (9), 1381–1387.
Demark-Wahnefried, W., Rais-Bahrami, S., Desmond, R.A., Gordetsky, J.B., Hunter, G.R.,
Yang, E.S., et al., 2017. Presurgical weight loss affects tumour traits and circulating
biomarkers in men with prostate cancer. Br. J. Cancer 117 (9), 1303–1313.
Derr, R.L., Ye, X., Islas, M.U., Desideri, S., Saudek, C.D., Grossman, S.A., 2009.
Association between hyperglycemia and survival in patients with newly diagnosed
glioblastoma. J. Clin. Oncol. 27 (7), 1082–1086.
Dibble, C.C., Cantley, L.C., 2015. Regulation of mTORC1 by PI3K signaling. Trends Cell
Biol. 25 (9), 545–555.
Dionigi, P., Jemos, V., Cebrelli, T., Ferrari, C., Ferrari, A., Berizzi, F., et al., 1991. Pre-
operative nutritional support and tumour cell kinetics in malnourished patients with
gastric cancer. Clin. Nutr. (Edinburgh, Scotland) 10 (Suppl), 77–84.
Dorff, T.B., Groshen, S., Garcia, A., Shah, M., Tsao-Wei, D., Pham, H., et al., 2016. Safety
and feasibility of fasting in combination with platinum-based chemotherapy. BMC
Cancer 16, 360.
Duhaylongsod, F.G., Lowe, V.J., Patz Jr, E.F., Vaughn, A.L., Coleman, R.E., Wolfe, W.G.,
1995. Lung tumor growth correlates with glucose metabolism measured by fluoride-
18 fluorodeoxyglucose positron emission tomography. Ann. Thorac. Surg. 60 (5),
1348–1352.
Edstrom, S., Westin, T., Delle, U., Lundholm, K., 1989. Cell cycle distribution and or-
nithine decarboxylase activity in head and neck cancer in response to enteral nutri-
tion. Eur. J. Cancer Clin. Oncol. 25 (2), 227–232.
Elsakka, Ama, Bary, Ma, Abdelzaher, E., Elnaggar, M., Kalamian, M., Mukherjee, P., et al.,
2018. Management of glioblastoma multiforme in a patient treated with ketogenic
metabolic therapy and modified standard of care: a 24-month follow-up. Front. Nutr.
5, 20.
English 2nd, Wj, Suskind, R., Damrongsak, D., Kulapongs, P., Olson, Re., 1975. Can the
growth of a neuroblastoma be influenced by a child’s nutritional state? Observations
in a patient treated for kwashiorkor and later given a restricted diet. Clin. Pediatr.
(Phila) 14 (9), 868–869.
Eskian, M., Alavi, A., Khorasanizadeh, M., Viglianti, B.L., Jacobsson, H., Barwick, T.D.,
et al., 2019. Effect of blood glucose level on standardized uptake value (SUV) in (18)
F- FDG PET-scan: a systematic review and meta-analysis of 20,807 individual SUV
measurements. Eur. J. Nucl. Med. Mol. Imaging 46 (1), 224–237.
Estrella, V., Chen, T., Lloyd, M., Wojtkowiak, J., Cornnell, H.H., Ibrahim-Hashim, A.,
et al., 2013. Acidity generated by the tumor microenvironment drives local invasion.
Cancer Res. 73 (5), 1524–1535.
Fan, C., Tang, Y., Wang, J., Xiong, F., Guo, C., Wang, Y., et al., 2017. Role of long non-
coding RNAs in glucose metabolism in cancer. Mol. Cancer 16 (1), 130.
Fantin, V.R., St-Pierre, J., Leder, P., 2006. Attenuation of LDH-A expression uncovers a
link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer
Cell 9 (6), 425–434.
Fearon, K.C., Borland, W., Preston, T., Tisdale, M.J., Shenkin, A., Calman, K.C., 1988.
Cancer cachexia: influence of systemic ketosis on substrate levels and nitrogen me-
tabolism. Am. J. Clin. Nutr. 47 (1), 42–48.
Fine, E.J., Segal-Isaacson, C.J., Feinman, R.D., Herszkopf, S., Romano, M.C., Tomuta, N.,
et al., 2012. Targeting insulin inhibition as a metabolic therapy in advanced cancer: a
pilot safety and feasibility dietary trial in 10 patients. Nutrition (Burbank, Los
Angeles County, Calif). 28 (10), 1028–1035.
Fisher, F.M., Maratos-Flier, E., 2016. Understanding the physiology of FGF21. Annu. Rev.
Physiol. 78, 223–241.
F. Bozzetti and Z. Stanga
Frank, J.L., Lawrence Jr, W., Banks Jr, W.L., McKinnon, J.G., Chan, W.M., Collins, J.M.,
1992. Modulation of cell cycle kinetics in human cancer with total parenteral nu-
trition. Cancer 69 (7), 1858–1864.
Fruehauf, J.P., Meyskens Jr, F.L., 2007. Reactive oxygen species: a breath of life or death?
Clin. Cancer Res. 13 (3), 789–794.
Gallagher, C.N., Carpenter, K.L., Grice, P., Howe, D.J., Mason, A., Timofeev, I., et al.,
2009. The human brain utilizes lactate via the tricarboxylic acid cycle: a 13C-labelled
microdialysis and high-resolution nuclear magnetic resonance study. Brain 132 (Pt
10), 2839–2849.
Galman, C., Lundasen, T., Kharitonenkov, A., Bina, H.A., Eriksson, M., Hafstrom, I., et al.,
2008. The circulating metabolic regulator FGF21 is induced by prolonged fasting and
PPARalpha activation in man. Cell Metab. 8 (2), 169–174.
Garcia-Canaveras, J.C., Chen, L., Rabinowitz, J.D., 2019. The tumor metabolic micro-
environment: lessons from lactate. Cancer Res. 79 (13), 3155–3162.
Garcia-Venzor, A., Mandujano-Tinoco, E.A., Lizarraga, F., Zampedri, C., Krotzsch, E.,
Salgado, R.M., et al., 2019. Microenvironment-regulated lncRNA-HAL is able to
promote stemness in breast cancer cells. Biochim. Biophys. Acta Mol. Cell Res. 1866
(12), 118523.
Garnett, M.J., Marais, R., 2004. Guilty as charged: B-RAF is a human oncogene. Cancer
Cell 6 (4), 313–319.
Goodwin, J., Neugent, M.L., Lee, S.Y., Choe, J.H., Choi, H., Jenkins, D.M.R., et al., 2017.
The distinct metabolic phenotype of lung squamous cell carcinoma defines selective
vulnerability to glycolytic inhibition. Nat. Commun. 8, 15503.
Hagmuller, E., Kollmar, H.B., Gunther, H.J., Holm, E., Trede, M., 1995. Protein meta-
bolism in human colon carcinomas: in vivo investigations using a modified tracer
technique with L-[1-13C]leucine. Cancer Res. 55 (5), 1160–1167.
Hanahan, D., Weinberg, R.A., 2011. Hallmarks of cancer: the next generation. Cell 144
(5), 646–674.
Hansell, D.T., Davies, J.W., Shenkin, A., Burns, H.J., 1986. The oxidation of body fuel
stores in cancer patients. Ann. Surg. 204 (6), 637–642.
Henning, S.M., Galet, C., Gollapudi, K., Byrd, J.B., Liang, P., Li, Z., et al., 2018. Phase II
prospective randomized trial of weight loss prior to radical prostatectomy. Prostate
Cancer Prostatic Dis. 21 (2), 212–220.
Higashi, K., Ueda, Y., Sakurai, A., Mingwang, X., Xu, L., Murakami, M., et al., 2000.
Correlation of Glut-1 glucose transporter expression with [(18)F]FDG uptake in non-
small cell lung cancer. Eur. J. Nucl. Med. 27 (12), 1778–1785.
Hirayama, A., Kami, K., Sugimoto, M., Sugawara, M., Toki, N., Onozuka, H., et al., 2009.
Quantitative metabolome profiling of colon and stomach cancer microenvironment
by capillary electrophoresis time-of-flight mass spectrometry. Cancer Res. 69 (11),
4918–4925.
Holm, E., Hagmuller, E., Staedt, U., Schlickeiser, G., Gunther, H.J., Leweling, H., et al.,
1995. Substrate balances across colonic carcinomas in humans. Cancer Res. 55 (6),
1373–1378.
Hui, S., Ghergurovich, J.M., Morscher, R.J., Jang, C., Teng, X., Lu, W., et al., 2017.
Glucose feeds the TCA cycle via circulating lactate. Nature 551 (7678), 115–118.
Imai, S.I., Guarente, L., 2016. It takes two to tango: NAD(+) and sirtuins in aging/
longevity control. NPJ Aging Mech. Dis. 2, 16017.
Jansen, N., Walach, H., 2016. The development of tumours under a ketogenic diet in
association with the novel tumour marker TKTL1: a case series in general practice.
Oncol. Lett. 11 (1), 584–592.
Jeon, S.M., Chandel, N.S., Hay, N., 2012. AMPK regulates NADPH homeostasis to pro-
mote tumour cell survival during energy stress. Nature 485 (7400), 661–665.
Jiao, L., Zhang, H.L., Li, D.D., Yang, K.L., Tang, J., Li, X., et al., 2018. Regulation of
glycolytic metabolism by autophagy in liver cancer involves selective autophagic
degradation of HK2 (hexokinase 2). Autophagy 14 (4), 671–684.
Jin, D., Phillips, M., Byles, J.E., 1999. Effects of parenteral nutrition support and che-
motherapy on the phasic composition of tumor cells in gastrointestinal cancer. South
Afr. J. Clin. Nutr. 23 (4), 237–241.
Johnson, R.F., Perkins, N.D., 2012. Nuclear factor-kappaB, p53, and mitochondria: reg-
ulation of cellular metabolism and the Warburg effect. Trends Biochem. Sci. 37 (8),
317–324.
Kalaany, N.Y., Sabatini, D.M., 2009. Tumours with PI3K activation are resistant to dietary
restriction. Nature 458 (7239), 725–731.
Kang, Y., Zhu, X., Xu, Y., Tang, Q., Huang, Z., Zhao, Z., et al., 2018. Energy stress-induced
lncRNA HAND2-AS1 represses HIF1alpha-mediated energy metabolism and inhibits
osteosarcoma progression. Am. J. Cancer Res. 8 (3), 526–537.
Katakami, N., Uchino, J., Yokoyama, T., Naito, T., Kondo, M., Yamada, K., et al., 2018.
Anamorelin (ONO-7643) for the treatment of patients with non-small cell lung cancer
and cachexia: results from a randomized, double-blind, placebo-controlled, multi-
center study of Japanese patients (ONO-7643-04). Cancer 124 (3), 606–616.
Kennedy, K.M., Scarbrough, P.M., Ribeiro, A., Richardson, R., Yuan, H., Sonveaux, P.,
et al., 2013. Catabolism of exogenous lactate reveals it as a legitimate metabolic
substrate in breast cancer. PLoS One 8 (9), e75154.
Kazemi, A., Speakman, J.R., Soltani, S., Djafarian, K., 2020. Effect of calorie restriction or
protein intake on circulating levels of insulin like growth factor I in humans: A sys-
tematic review and meta-analysis. Clin Nutr. 39 (6), 1705–1716. https://doi.org/10.
1016/j.clnu.2019.07.030.
Klement, R.J., Sweeney, R.A., 2016. Impact of a ketogenic diet intervention during
radiotherapy on body composition: I. Initial clinical experience with six prospectively
studied patients. BMC Res. Notes 9, 143.
Korber, J., Pricelius, S., Heidrich, M., Muller, M.J., 1999. Increased lipid utilization in
weight losing and weight stable cancer patients with normal body weight. Eur. J.
Clin. Nutr. 53 (9), 740–745.
Kubicek, G.J., Champ, C., Fogh, S., Wang, F., Reddy, E., Intenzo, C., et al., 2010. FDG-PET
staging and importance of lymph node SUV in head and neck cancer. Head Neck
Oncol. 2, 19.
10
Critical Reviews in Oncology / Hematology 153 (2020) 103061
Langbein, S., Zerilli, M., Zur Hausen, A., Staiger, W., Rensch-Boschert, K., Lukan, N.,
et al., 2006. Expression of transketolase TKTL1 predicts colon and urothelial cancer
patient survival: warburg effect reinterpreted. Br. J. Cancer 94 (4), 578–585.
Lee, H.C., 2001. Physiological functions of cyclic ADP-ribose and NAADP as calcium
messengers. Annu. Rev. Pharmacol. Toxicol. 41, 317–345.
Legaspi, A., Jeevanandam, M., Starnes Jr, H.F., Brennan, M.F., 1987. Whole body lipid
and energy metabolism in the cancer patient. Metab. Clin. Exp. 36 (10), 958–963.
Levine, A.J., Puzio-Kuter, A.M., 2010. The control of the metabolic switch in cancers by
oncogenes and tumor suppressor genes. Science (New York, NY). 330 (6009),
1340–1344.
Lewis, K.N., Mele, J., Hayes, J.D., Buffenstein, R., 2010. Nrf2, a guardian of healthspan
and gatekeeper of species longevity. Integr. Comp. Biol. 50 (5), 829–843.
Li, C., Zhao, Z., Zhou, Z., Liu, R., 2016. PKM2 promotes cell survival and invasion under
metabolic. stress by enhancing Warburg effect in pancreatic ductal adenocarcinoma.
Dig. Dis. Sci. 61 (3), 767–773.
Li, M., Jin, R., Wang, W., Zhang, T., Sang, J., Li, N., et al., 2017. STAT3 regulates gly-
colysis via targeting hexokinase 2 in hepatocellular carcinoma cells. Oncotarget 8
(15), 24777–24784.
Li, X., Zhao, Q., Qi, J., Wang, W., Zhang, D., Li, Z., et al., 2018. lncRNA Ftx promotes
aerobic glycolysis and tumor progression through the PPARgamma pathway in he-
patocellular carcinoma. Int. J. Oncol. 53 (2), 551–566.
Lieberman, B.P., Ploessl, K., Wang, L., Qu, W., Zha, Z., Wise, D.R., et al., 2011. PET
imaging of glutaminolysis in tumors by 18F-(2S,4R)4-fluoroglutamine. J. Nucl. Med.
52 (12), 1947–1955.
Liu, Y., Murray-Stewart, T., Casero Jr, R.A., Kagiampakis, I., Jin, L., Zhang, J., et al., 2017.
Targeting hexokinase 2 inhibition promotes radiosensitization in HPV16 E7-induced
cervical cancer and suppresses tumor growth. Int. J. Oncol. 50 (6), 2011–2023.
Lu, H., Forbes, R.A., Verma, A., 2002. Hypoxia-inducible factor 1 activation by aerobic
glycolysis implicates the Warburg effect in carcinogenesis. J. Biol. Chem. 277 (26),
23111–23115.
Magee, B.A., Potezny, N., Rofe, A.M., Conyers, R.A., 1979. The inhibition of malignant
cell growth by ketone bodies. Aust. J. Exp. Biol. Med. Sci. 57 (5), 529–539.
Mamede, M., Higashi, T., Kitaichi, M., Ishizu, K., Ishimori, T., Nakamoto, Y., et al., 2005.
[18F]FDG uptake and PCNA, Glut-1, and Hexokinase-II expressions in cancers and
inflammatory lesions of the lung. Neoplasia (New York, NY). 7 (4), 369–379.
Marshall, M.J., Neal, F.E., Goldberg, D.M., 1979. Isoenzymes of hexokinase, 6-phos-
phogluconate dehydrogenase, phosphoglucomutase and lactate dehydrogenase in
uterine cancer. Br. J. Cancer 40 (3), 380–390.
Mates, J.M., Segura, J.A., Campos-Sandoval, J.A., Lobo, C., Alonso, L., Alonso, F.J., et al.,
2009. Glutamine homeostasis and mitochondrial dynamics. Int. J. Biochem. Cell Biol.
41 (10), 2051–2061.
Mates, J.M., Di Paola, F.J., Campos-Sandoval, J.A., Mazurek, S., Marquez, J., 2020.
Therapeutic targeting of glutaminolysis as an essential strategy to combat cancer.
Semin. Cell Dev. Biol. 98, 34–43.
Maurer, G.D., Brucker, D.P., Bahr, O., Harter, P.N., Hattingen, E., Walenta, S., et al., 2011.
Differential utilization of ketone bodies by neurons and glioma cell lines: a rationale
for ketogenic diet as experimental glioma therapy. BMC Cancer 11, 315.
Mayer, A., Schmidt, M., Seeger, A., Serras, A.F., Vaupel, P., Schmidberger, H., 2014.
GLUT-1 expression is largely unrelated to both hypoxia and the Warburg phenotype
in squamous cell carcinomas of the vulva. BMC Cancer 14, 760.
McGirt, M.J., Chaichana, K.L., Gathinji, M., Attenello, F., Than, K., Ruiz, A.J., et al., 2008.
Persistent outpatient hyperglycemia is independently associated with decreased
survival after primary resection of malignant brain astrocytomas. Neurosurgery 63
(2), 286–291 discussion 91.
McNurlan, M.A., Heys, S.D., Park, K.G., Broom, J., Brown, D.S., Eremin, O., et al., 1994.
Tumour and host tissue responses to branched-chain amino acid supplementation of
patients with cancer. Clin. Sci. 86 (3), 339–345.
Meidenbauer, J.J., Mukherjee, P., Seyfried, T.N., 2015. The glucose ketone index calcu-
lator: a simple tool to monitor therapeutic efficacy for metabolic management of
brain cancer. Nutr Metab. 12, 12.
Metallo, C.M., Gameiro, P.A., Bell, E.L., Mattaini, K.R., Yang, J., Hiller, K., et al., 2011.
Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia.
Nature 481 (7381), 380–384.
Morris, A.A., 2005. Cerebral ketone body metabolism. J. Inherit. Metab. Dis. 28 (2),
109–121.
Mukherjee, P., Sotnikov, A.V., Mangian, H.J., Zhou, J.R., Visek, W.J., Clinton, S.K., 1999.
Energy intake and prostate tumor growth, angiogenesis, and vascular endothelial
growth factor expression. J. Natl. Cancer Inst. 91 (6), 512–523.
Mukherjee, P., El-Abbadi, M.M., Kasperzyk, J.L., Ranes, M.K., Seyfried, T.N., 2002.
Dietary restriction reduces angiogenesis and growth in an orthotopic mouse brain
tumour model. Br. J. Cancer 86 (10), 1615–1621.
Mukherjee, P., Abate, L.E., Seyfried, T.N., 2004. Antiangiogenic and proapoptotic effects
of dietary restriction on experimental mouse and human brain tumors. Clin. Cancer
Res. 10 (16), 5622–5629.
Nebeling, L.C., Miraldi, F., Shurin, S.B., Lerner, E., 1995. Effects of a ketogenic diet on
tumor metabolism and nutritional status in pediatric oncology patients: two case
reports. J. Am. Coll. Nutr. 14 (2), 202–208.
Nencioni, A., Caffa, I., Cortellino, S., Longo, V.D., 2018. Fasting and cancer: molecular
mechanisms and clinical application. Nat. Rev. Cancer 18 (11), 707–719.
Newman, J.C., Verdin, E., 2017. Beta-hydroxybutyrate: a signaling metabolite. Annu.
Rev. Nutr. 37, 51–76.
Nguyen, X.C., Lee, W.W., Chung, J.H., Park, S.Y., Sung, S.W., Kim, Y.K., et al., 2007. FDG
uptake, glucose transporter type 1, and Ki-67 expressions in non-small-cell lung
cancer: correlations and prognostic values. Eur. J. Radiol. 62 (2), 214–219.
Nikoobakht, M., Shamshiripour, P., Azimi Nekoo, Z., Fallah Haghmohammadi, S., 2019.
Elevated lactate and total protein levels in stereotactic brain biopsy specimen;
F. Bozzetti and Z. Stanga
potential biomarkers of malignancy and poor prognosis. Arch. Iran. Med. 22 (3),
125–131.
Nolop, K.B., Rhodes, C.G., Brudin, L.H., Beaney, R.P., Krausz, T., Jones, T., et al., 1987.
Glucose utilization in vivo by human pulmonary neoplasms. Cancer 60 (11),
2682–2689.
Norton, J.A., Burt, M.E., Brennan, M.F., 1980. In vivo utilization of substrate by human
sarcoma-bearing limbs. Cancer 45 (12), 2934–2939.
Osthus, R.C., Shim, H., Kim, S., Li, Q., Reddy, R., Mukherjee, M., et al., 2000.
Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc. J.
Biol. Chem. 275 (29), 21797–21800.
Ota, D.M., Nishioka, K., Grossie, B., Dixon, D., 1986. Erythrocyte polyamine levels during
intravenous feeding of patients with colorectal carcinoma. Eur. J. Cancer Clin. Oncol.
22 (7), 837–842.
Pacelli, F., Bossola, M., Teodori, L., Trinca, M.L., Tortorelli, A., Rosa, F., et al., 2007.
Parenteral nutrition does not stimulate tumor proliferation in malnourished gastric
cancer patients. South Afr. J. Clin. Nutr. 31 (6), 451–455.
Park, S.I., Suh, D.S., Kim, S.J., Choi, K.U., Yoon, M.S., 2013. Correlation between biolo-
gical marker expression and F-fluorodeoxyglucose uptake in cervical cancer mea-
sured by positron emission tomography. Onkologie 36 (4), 169–174.
Patel, S., Alvarez-Guaita, A., Melvin, A., Rimmington, D., Dattilo, A., Miedzybrodzka,
E.L., et al., 2019. GDF15 provides an endocrine signal of nutritional stress in mice and
humans. Cell Metab. 29 (3), 707–718 e8.
Pfeiffer, T., Morley, A., 2014. An evolutionary perspective on the Crabtree effect. Front.
Mol. Biosci. 1, 17.
Phoenix, K.N., Vumbaca, F., Fox, M.M., Evans, R., Claffey, K.P., 2010. Dietary energy
availability affects primary and metastatic breast cancer and metformin efficacy.
Breast Cancer Res. Treat. 123 (2), 333–344.
Raffaghello, L., Lee, C., Safdie, F.M., Wei, M., Madia, F., Bianchi, G., et al., 2008.
Starvation-dependent differential stress resistance protects normal but not cancer
cells against high-dose chemotherapy. Proc. Natl. Acad. Sci. U. S. A. 105 (24),
8215–8220.
Rajaram, S., Baylink, D.J., Mohan, S., 1997. Insulin-like growth factor-binding proteins in
serum and other biological fluids: regulation and functions. Endocr. Rev. 18 (6),
801–831.
Rice, Ml, van Rij, Am., 1987. Parenteral nutrition and tumour growth in the patient with
complicated abdominal cancer. Aust. N. Z. J. Surg. 57 (6), 375–379.
Rieger, J., Bahr, O., Maurer, G.D., Hattingen, E., Franz, K., Brucker, D., et al., 2014.
ERGO: a pilot study of ketogenic diet in recurrent glioblastoma. Int. J. Oncol. 44 (6),
1843–1852.
Rossi-Fanelli, F., Franchi, F., Mulieri, M., Cangiano, C., Cascino, A., Ceci, F., et al., 1991.
Effect of energy substrate manipulation on tumour cell proliferation in parenterally
fed cancer patients. Clin. Nutr. (Edinburgh, Scotland) 10 (4), 228–232.
Rous, P., 1914. The influence of diet on transplanted and spontaneous mouse tumors. J.
Exp. Med. 20 (5), 433–451.
Saigusa, S., Toiyama, Y., Tanaka, K., Okugawa, Y., Fujikawa, H., Matsushita, K., et al.,
2012. Prognostic significance of glucose transporter-1 (GLUT1) gene expression in
rectal cancer after preoperative chemoradiotherapy. Surg. Today 42 (5), 460–469.
San-Millan, I., Brooks, G.A., 2017. Reexamining cancer metabolism: lactate production
for carcinogenesis could be the purpose and explanation of the Warburg Effect.
Carcinogenesis 38 (2), 119–133.
Scheck, A.C., Abdelwahab, M., Stafford, P., Kim, D.-Y., Iwai, S., Preul, M.C., et al., 2010.
Mechanistic studies of the ketogenic diet as an adjuvant therapy for malignant
gliomas. AACR.
Schmidt, M., Pfetzer, N., Schwab, M., Strauss, I., Kammerer, U., 2011. Effects of a keto-
genic diet on the quality of life in 16 patients with advanced cancer: a pilot trial.
Nutr. Metab. 8 (1), 54.
Schroeder, U., Himpe, B., Pries, R., Vonthein, R., Nitsch, S., Wollenberg, B., 2013. Decline
of lactate in tumor tissue after ketogenic diet: in vivo microdialysis study in patients
with head and neck cancer. Nutr. Cancer 65 (6), 843–849.
Schuurbiers, O.C., Meijer, T.W., Kaanders, J.H., Looijen-Salamon, M.G., de Geus-Oei, L.F.,
van der Drift, M.A., et al., 2014. Glucose metabolism in NSCLC is histology-specific
and diverges the prognostic potential of 18FDG-PET for adenocarcinoma and squa-
mous cell carcinoma. J. Thorac. Oncol. 9 (10), 1485–1493.
Schwartz, G.F., Green, H.L., Bendon, M.L., Graham 3rd, W.P., Blakemore, W.S., 1971.
Combined parenteral hyperalimentation and chemotherapy in the treatment of dis-
seminated solid tumors. Am. J. Surg. 121 (2), 169–173.
Schwartz, K., Chang, H.T., Nikolai, M., Pernicone, J., Rhee, S., Olson, K., et al., 2015.
Treatment of glioma patients with ketogenic diets: report of two cases treated with an
IRB-approved energy-restricted ketogenic diet protocol and review of the literature.
Cancer Metab. 3, 3.
Selberg, O., McMillan, D.C., Preston, T., Carse, H., Shenkin, A., Burns, H.J., 1990.
Palmitate turnover and its response to glucose infusion in weight-losing cancer pa-
tients. Clin. Nutr. (Edinburgh, Scotland) 9 (3), 150–156.
Seyfried, T.N., Shelton, L., Arismendi-Morillo, G., Kalamian, M., Elsakka, A., Maroon, J.,
et al., 2019. Provocative question: should ketogenic metabolic therapy become the
standard of care for glioblastoma? Neurochem. Res. 44 (10), 2392–2404.
Shaw, J.H., Wolfe, R.R., 1987. Fatty acid and glycerol kinetics in septic patients and in
patients with gastrointestinal cancer. The response to glucose infusion and parenteral
feeding. Ann. Surg. 205 (4), 368–376.
Shelton, L.M., Huysentruyt, L.C., Mukherjee, P., Seyfried, T.N., 2010. Calorie restriction
as an anti-invasive therapy for malignant brain cancer in the VM mouse. ASN Neuro 2
(3), e00038.
Shim, H., Dolde, C., Lewis, B.C., Wu, C.S., Dang, G., Jungmann, R.A., et al., 1997. c-Myc
transactivation of LDH-A: implications for tumor metabolism and growth. Proc. Natl.
Acad. Sci. U. S. A. 94 (13), 6658–6663.
Shimazu, T., Hirschey, M.D., Newman, J., He, W., Shirakawa, K., Le Moan, N., et al.,
11
Critical Reviews in Oncology / Hematology 153 (2020) 103061
2013. Suppression of oxidative stress by beta-hydroxybutyrate, an endogenous his-
tone deacetylase inhibitor. Science (New York, NY). 339 (6116), 211–214.
Shingler, E., Perry, R., Mitchell, A., England, C., Perks, C., Herbert, G., et al., 2019.
Dietary restriction during the treatment of cancer: results of a systematic scoping
review. BMC Cancer 19 (1), 811.
Sinclair, D.A., 2005. Toward a unified theory of caloric restriction and longevity reg-
ulation. Mech. Ageing Dev. 126 (9), 987–1002.
Skinner, R., Trujillo, A., Ma, X., Beierle, E.A., 2009. Ketone bodies inhibit the viability of
human neuroblastoma cells. J. Pediatr. Surg. 44 (1), 212–216 discussion 6.
Solheim, T.S., Vagnildhaug, O.M., Laird, B.J., Balstad, T.R., 2019. Combining optimal
nutrition and exercise in a multimodal approach for patients with active cancer and
risk for losing weight: rationale and practical approach. Nutrition (Burbank, Los
Angeles County, Calif). 67–68 110541.
Stafford, P., Abdelwahab, M.G., Kim, D.Y., Preul, M.C., Rho, J.M., Scheck, A.C., 2010. The
ketogenic diet reverses gene expression patterns and reduces reactive oxygen species
levels when used as an adjuvant therapy for glioma. Nutr Metab. 7, 74.
Sun, W., Liu, Y., Glazer, C.A., Shao, C., Bhan, S., Demokan, S., et al., 2010. TKTL1 is
activated by promoter hypomethylation and contributes to head and neck squamous
cell carcinoma carcinogenesis through increased aerobic glycolysis and HIF1alpha
stabilization. Clin. Cancer Res. 16 (3), 857–866.
Takayama, K., Katakami, N., Yokoyama, T., Atagi, S., Yoshimori, K., Kagamu, H., et al.,
2016. Anamorelin (ONO-7643) in Japanese patients with non-small cell lung cancer
and cachexia: results of a randomized phase 2 trial. Support. Care Cancer 24 (8),
3495–3505.
Tan-Shalaby, J.L., Carrick, J., Edinger, K., Genovese, D., Liman, A.D., Passero, V.A., et al.,
2016. Modified Atkins diet in advanced malignancies - final results of a safety and
feasibility trial within the Veterans Affairs Pittsburgh Healthcare System. Nutr Metab.
13, 52.
Theodosakis, N., Held, M.A., Marzuka-Alcala, A., Meeth, K.M., Micevic, G., Long, G.V.,
et al., 2015. BRAF inhibition decreases cellular glucose uptake in melanoma in as-
sociation with reduction in cell volume. Mol. Cancer Ther. 14 (7), 1680–1692.
van der Hulst, R.R., von Meyenfeldt, M.F., Deutz, N.E., Soeters, P.B., 1997. Glutamine
extraction by the gut is reduced in depleted [corrected] patients with gastrointestinal
cancer. Ann. Surg. 225 (1), 112–121.
van Solingen, C., Scacalossi, K.R., Moore, K.J., 2018. Long noncoding RNAs in lipid
metabolism. Curr. Opin. Lipidol. 29 (3), 224–232.
VanItallie, T.B., Nufert, T.H., 2003. Ketones: metabolism’s ugly duckling. Nutr. Rev. 61
(10), 327–341.
Veech, R.L., 2004. The therapeutic implications of ketone bodies: the effects of ketone
bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin re-
sistance, and mitochondrial metabolism. Prostaglandins Leukot. Essent. Fatty Acids
70 (3), 309–319.
Veech, R.L., 2006. The determination of the redox states and phosphorylation potential in
living tissues and their relationship to metabolic control of disease phenotypes.
Biochem. Mol. Biol. Educ. 34 (3), 168–179.
Veech, R.L., Chance, B., Kashiwaya, Y., Lardy, H.A., Cahill Jr, G.F., 2001. Ketone bodies,
potential therapeutic uses. IUBMB Life 51 (4), 241–247.
Vesselle, H., Salskov, A., Turcotte, E., Wiens, L., Schmidt, R., Jordan, C.D., et al., 2008.
Relationship between non-small cell lung cancer FDG uptake at PET, tumor histology,
and Ki-67 proliferation index. J. Thorac. Oncol. 3 (9), 971–978.
Voss, M., Marlies, Wagner., von Mettenheim, N., et al. ERGO2: A prospective randomized
trial of calorie restricted ketogenic diet and fasting in addition to re-irradiation for
malignant glioma [published online ahead of print, 2020 Jun 30]. Int J Radiat Oncol
Biol Phys. 2020;S0360-3016(20)31308-0. doi:10.1016/j.ijrobp.2020.06.021.
Walenta, S., Salameh, A., Lyng, H., Evensen, J.F., Mitze, M., Rofstad, E.K., et al., 1997.
Correlation of high lactate levels in head and neck tumors with incidence of metas-
tasis. Am. J. Pathol. 150 (2), 409–415.
Walenta, S., Wetterling, M., Lehrke, M., Schwickert, G., Sundfor, K., Rofstad, Ek, et al.,
2000. High lactate levels predict likelihood of metastases, tumor recurrence, and
restricted patient survival in human cervical cancers. Cancer Res. 60 (4), 916–921.
Walenta, S., Chau, T.V., Schroeder, T., Lehr, H.A., Kunz-Schughart, L.A., Fuerst, A., et al.,
2003. Metabolic classification of human rectal adenocarcinomas: a novel guideline
for clinical oncologists? J. Cancer Res. Clin. Oncol. 129 (6), 321–326.
Wang, L., Xiong, H., Wu, F., Zhang, Y., Wang, J., Zhao, L., et al., 2014. Hexokinase 2-
mediated Warburg effect is required for PTEN- and p53-deficiency-driven prostate
cancer growth. Cell Rep. 8 (5), 1461–1474.
Wang, Y., Zhang, X., Wang, Z., Hu, Q., Wu, J., Li, Y., et al., 2018. LncRNA-p23154 pro-
motes the invasion-metastasis potential of oral squamous cell carcinoma by reg-
ulating Glut1-mediated glycolysis. Cancer Lett. 434, 172–183.
Warburg, O., Wind, F., Negelein, E., 1927. The metabolism of tumors in the body. J. Gen.
Physiol. 8 (6), 519–530.
Ward, P.S., Thompson, C.B., 2012. Metabolic reprogramming: a cancer hallmark even
warburg did not anticipate. Cancer Cell 21 (3), 297–308.
Wei, S., Fan, Q., Yang, L., Zhang, X., Ma, Y., Zong, Z., et al., 2017. Promotion of glycolysis
by HOTAIR through GLUT1 upregulation via mTOR signaling. Oncol. Rep. 38 (3),
1902–1908.
Weinberg, F., Chandel, N.S., 2009. Reactive oxygen species-dependent signaling regulates
cancer. Cell. Mol. Life Sci. 66 (23), 3663–3673.
Westin, T., Stein, H., Niedobitek, G., Lundholm, K., Edstrom, S., 1991. Tumor cytokinetic
response to total parenteral nutrition in patients with head and neck cancers. Am. J.
Clin. Nutr. 53 (3), 764–768.
Wieman, H.L., Wofford, J.A., Rathmell, J.C., 2007. Cytokine stimulation promotes glu-
cose uptake via phosphatidylinositol-3 kinase/Akt regulation of Glut1 activity and
trafficking. Mol. Biol. Cell 18 (4), 1437–1446.
Winter, S.F., Loebel, F., Dietrich, J., 2017. Role of ketogenic metabolic therapy in ma-
lignant glioma: a systematic review. Crit. Rev. Oncol. Hematol. 112, 41–58.
F. Bozzetti and Z. Stanga
Wise, D.R., DeBerardinis, R.J., Mancuso, A., Sayed, N., Zhang, X.Y., Pfeiffer, H.K., et al.,
2008. Myc regulates a transcriptional program that stimulates mitochondrial gluta-
minolysis and leads to glutamine addiction. Proc. Natl. Acad. Sci. U. S. A. 105 (48),
18782–18787.
Wofford, J.A., Wieman, H.L., Jacobs, S.R., Zhao, Y., Rathmell, J.C., 2008. IL-7 promotes
Glut1 trafficking and glucose uptake via STAT5-mediated activation of Akt to support
T-cell survival. Blood. 111 (4), 2101–2111.
Wong, N., Ojo, D., Yan, J., Tang, D., 2015. PKM2 contributes to cancer metabolism.
Cancer Lett. 356 (2 Pt A), 184–191.
Yang, C., Sudderth, J., Dang, T., Bachoo, R.M., McDonald, J.G., DeBerardinis, R.J., 2009.
Glioblastoma cells require glutamate dehydrogenase to survive impairments of glu-
cose metabolism or Akt signaling. Cancer Res. 69 (20), 7986–7993.
Yang, X., Yao, B., Niu, Y., Chen, T., Mo, H., Wang, L., et al., 2019. Hypoxia-induced
lncRNA EIF3J-AS1 accelerates hepatocellular carcinoma progression via targeting
miR-122-5p/CTNND2 axis. Biochem. Biophys. Res. Commun. 518 (2), 239–245.
Yun, J., Rago, C., Cheong, I., Pagliarini, R., Angenendt, P., Rajagopalan, H., et al., 2009.
12
Critical Reviews in Oncology / Hematology 153 (2020) 103061
Glucose deprivation contributes to the development of KRAS pathway mutations in
tumor cells. Science (New York, NY) 325 (5947), 1555–1559.
Zeng, Y., Ren, K., Zhu, X., Zheng, Z., Yi, G.Long, 2018. Noncoding RNAs: advances in lipid
metabolism. Adv. Clin. Chem. 87, 1–36.
Zhao, Y., Liu, Y., Lin, L., Huang, Q., He, W., Zhang, S., et al., 2018. The lncRNA MACC1-
AS1 promotes gastric cancer cell metabolic plasticity via AMPK/Lin28 mediated
mRNA stability of MACC1. Mol. Cancer 17 (1), 69.
Zheng, M., Cao, M.X., Yu XH, Li L., Wang, K., Wang, S.S., et al., 2019. STAT3 promotes
invasion and aerobic glycolysis of human oral squamous cell carcinoma via inhibiting
FoxO1. Front. Oncol. 9, 1175.
Zhou, W., Mukherjee, P., Kiebish, M.A., Markis, W.T., Mantis, J.G., Seyfried, T.N., 2007.
The calorically restricted ketogenic diet, an effective alternative therapy for malig-
nant brain cancer. Nutr. Metab. 4, 5.
Zuccoli, G., Marcello, N., Pisanello, A., Servadei, F., Vaccaro, S., Mukherjee, P., et al.,
2010. Metabolic management of glioblastoma multiforme using standard therapy
together with a restricted ketogenic diet: case report. Nutr Metab. 7, 33.