07.1 Scientific Rationale

7 Scientific Rationale
7.1 Rationale
Supportan®
Tube and sip feed adapted to the special
needs of cancer patients
KIC/MSA-EN/Dr. Christina Schneid Status 20/06/07 page 1 of 50

Contents
1 Main product features and intended use ............................................................. 6
2 Scientific Rationale for disease adapted feeds in cancer patients ................... 7

2.1 Prevalence and pathogenesis of cancer........................................................... 7
2.2 Cancer related weight loss ............................................................................... 8
2.2.1 Malnutrition in cancer patients................................................................... 8
2.2.2 Cancer cachexia........................................................................................ 9
2.2.3 Cachexia is not simply malnutrition ......................................................... 10
2.3 Metabolic changes in cancer and cancer cachexia related to nutrition........... 11
3 Nutritional strategies in cancer related weight loss and cancer cachexia..... 13

3.1 Recommendations of ESPEN on nutritional strategies in cancer patients ..... 13
3.2 Goal directed nutritional strategies of cancer patients.................................... 14
4 The key nutrient in Supportan® - EPA................................................................ 15

4.1 Metabolism of n-3 and n-6 fatty acids............................................................. 15
4.2 Evidence and effective dose of EPA in cancer cachexia................................ 16
4.3 Safety of EPA + DHA...................................................................................... 20
4.3.1 Short term use of fish oil – impact on bleeding time................................ 20
4.3.2 Impact of long-term n-3 fatty acid consumption....................................... 21
4.3.3 Clinical nutrition including fish oil in cancer patients and side effects...... 22
4.3.4 Conclusion for the use of fish oil in long-term clinical nutrition ................ 22
5 Product concept and nutrient composition....................................................... 24

5.1 Product concept – for supplemental use ........................................................ 25
5.2 Product concept – for complete nutrition ........................................................ 25
5.3 Usage guide.................................................................................................... 26
5.4 Product composition ....................................................................................... 27
5.4.1 Energy content ........................................................................................ 27
5.5 Macronutrients ................................................................................................ 28
5.5.1 Fat ........................................................................................................... 28
5.5.2 Protein ..................................................................................................... 30
5.5.3 Carbohydrate........................................................................................... 31
5.5.4 Dietary fibres ........................................................................................... 31

5.6 Micronutrients ................................................................................................. 32
5.6.1 Minerals and trace elements ................................................................... 32
5.6.2 Antioxidant vitamins................................................................................. 33
5.6.3 Other components ................................................................................... 33
6 Instructions for use ............................................................................................. 34

6.1 Indications, contraindications, important notes and warnings......................... 34
6.1.1 Indications ............................................................................................... 34
6.1.2 Contra indications.................................................................................... 34
6.1.3 Important notes and warnings ................................................................. 35
6.2 Dosage and storage recommendations.......................................................... 36
6.2.1 Dosage .................................................................................................... 36
6.2.2 Storage recommendations ...................................................................... 36
7 Selected publications on clinical evidence for EPA supplementation in cancer

patients................................................................................................................ 37
8 References ........................................................................................................... 41
9 Annex .................................................................................................................... 46
9.1 Nutritional Profile comparison with recommendations 46

List of figures
Figure 1: Pathogenic pathway of cancer .................................................................................... 8
Figure 2: Differentiation of malnutrition, cachexia and sarcopenia ........................................... 10
Figure 3: Eicosanoids derived from EPA and AA ..................................................................... 16
Figure 4 : Weight change of patients with advanced pancreatic cancer receiving a fish-oil
enriched nutritional supplement. ............................................................................ 18
Figure 5: Change in body weight of patients before and after EPA supplementation ............... 19
Figure 6: Example for the use of Supportan tube feed ........................................................... 26
Figure 7: The “two Tetras” concept of the Supportan DRINK ................................................. 27
List of tables
Table 1: Factors influencing nutritional intake in cancer patients................................................ 9
Table 2: Side effects associated with malnutrition and cachexia in cancer patients ................ 11
Table 3: Resulting derangements of metabolism include ......................................................... 12
Table 4: Beneficial effects of enteral nutrition support in cancer patients ................................. 13
Table 5: Patients benefiting from disease adapted enteral nutritional support.......................... 13
Table 6: Nutritional strategies in cancer patients...................................................................... 14
Table 7: Risk evaluation of potential side effects due to n-3 fatty acid consumptions in relation
to the dose administered .......................................................................................... 23
Table 8: Physiological advantages of MCT .............................................................................. 29
Table 9: Selected publications ................................................................................................. 39

Abbreviations
APR = Acute Phase Protein
BCAA = Branched Chain Amino Acid
CRP = C-reactive Protein
DHA = Docosahexaeic acid
EN = Enteral Nutition
EPA = Eicosapentaenoic acid
FDA = Food and Drug Administration
FSMP = Food for Special Medical Purposes
IL = Interleukin
MCT = Medium Chain Triglyceride
ONS = Oral Nutritional Supplement
PBMC = Peripheral blood mononuclear cells
PIF = proteolysis inducing factor
PUFA = Polyunsaturated Fatty Acid
RDA = Recommended daily allowance
REE = Resting Energy Expenditure
SCFA = Short Chain Fatty Acid
TNF-α = Tumour Necrosis Factor α
UV = ultraviolet
WHO = World health organisation

1 Main product features and intended use
Supportan and Supportan DRINK are indicated for tube and sip feeding of patients with
cancer, chronic catabolic disease and/or cachexia and for patients at risk of malnutrition with
high energy and protein needs. Therefore Supportan and Supportan DRINK are designed to
meet the specific metabolic substrate requirements of cancer patients. Key features of Suppor-
tan and Supportan DRINK are:
High in eicosapentaenoic acid (EPA) from fish oil (0.4 and 0.5 g EPA/100 ml tube
and sip feed
• to ensure a supply of 2 g EPA per day.
• to counteract muscle wasting and support immune function.
High in fat (40 energy %), low in carbohydrates (33 energy %)
• providing energy for the patient, not for the tumour.
Enriched in MCT
• to ensure a good intestinal tolerance and absorption.
• For improved energy supply.
High in protein (27 energy %)
• to counteract loss of muscle mass.
High energy density
• to ensure a tolerable volume and high long-term compliance.
Provides recommended dosage of all vitamins and trace elements
Available as tube and sip feed

• providing optimal supply to all patient conditions.
Available in three tasting flavours
• to ensure high compliance.
Crucial aim is to assure the uptake of the effective dose of the key component, EPA, which is
met by reducing as much as possible the daily volume in which EPA is given. Consequently, the
sip as well as the tube feed is primarily designed for supplementary nutrition. This concept
assures the uptake of the effective dose of 2 g EPA/day within 500 ml (one EasyBag) of Sup-
portan tube feed or 2 x 200 ml TetraBriks of Supportan DRINK. Additional caloric needs
can be supplied by standard tube and sip feeds or normal food, according to patients’ individ-
ual requirements and abilities.
Supportan and Supportan DRINK are also suitable for complete nutrition.

2 Scientific Rationale for disease adapted feeds in cancer
patients
2.1 Prevalence and pathogenesis of cancer

Cancer has been designated an “expensive disease”, since it is associated with extremely high
costs in terms of both costs of treatment and care as well as quality of life.(1)
Cancer is a leading cause of death worldwide. From a total of 58 million death worldwide in
2005 (1), cancer accounts for 7.6 million (or 13%) of all deaths [WHO].
Main patient groups herein are:
• Lung (1.3 million deaths/year)

• Stomach (1 million deaths/year)
• Liver ( 662 000 deaths/year)
• Colon (655 000 deaths/year
• Breast (502 000 deaths/year)
Death from cancer in the world are projected to continue rising with an estimated 9 million peo-
ple dying from cancer in 2015 and 11.4 million dying in 2030 [WHO].
Cancer occurs because of changes of the genes responsible for cell growth and repair. These
changes are the result of the interaction between genetic host factors and external agents
which can be categorised as:
• Physical carcinogens such as ultraviolet (UV) and ionising radiation
• Chemical carcinogens such as asbestos and tobacco smoke
• Biological carcinogens such as infections by virus and bacteria or contamination of food

by myotoxins.
The induction of a tumour is a multi-event process occurring over time, divided into three sepa-
rate steps as shown in Figure 1. Beside these factors nutrition and cancer are closely related,
each affecting the other. Nutrients can act at any of these steps to promote or inhibit tumour
initiation, promotion, and progression.(1)

INITIATION PROMOTION PROGRESSION
Food -borne- Expression in Neoplasms

carcinogen altered cellular
information
Electrophilic Metastasis
reactant or „free
rad ical“
Growth of
altered cells by
Binding of proliferation
carcinogen to promoter
DNA/protein
Alterations in
DNA/proteins/car
cinogen/
damaged cell
Figure 1: Pathogenic pathway of cancer (adopted from Laviano & Meguid, 1996)(1)
2.2 Cancer related weight loss
2.2.1 Malnutrition in cancer patients

Cancer patients are frequently malnourished at the time of diagnosis.(2) Indeed, weight loss
arises early in the course of the disease and appears to be a prominent feature.(3) Depending
on the site and stage of the tumour, as many as 31-87% of patients have been reported to lose
weight already prior to diagnosis; highest frequencies have been seen in patients with pancre-
atic cancer (85%), gastrointestinal cancer (80%), lung cancer (69%) or in those with more ad-
vanced cancer disease.(4-7) Nutritional intake in cancer patients may be reduced for a multi-
tude of reasons (Table 1).

Table 1: Factors influencing nutritional intake in cancer patients: (2;5;8-10)
• physical abnormalities associated with a tumour

• variations in taste and smell sensations
• nausea, constipation
• the host response to the tumour causing anorexia and altered metabolism
• physiological problems such as depression, grief or anxiety
• pain
• side effects of anticancer treatment (radio-, chemotherapy)
• extensive resection with loss of functional capacity
2.2.2 Cancer cachexia

To survive and grow, tumours transform host stores into their energy fuel, thus affecting host
metabolism and nutritional status even before it becomes clinically evident. In response, the
host produces a number of specific immune-derived factors in a futile attempt to isolate, starve,
and kill the tumour cells. From these opposing effects, anorexia, malnutrition and, eventually,
cachexia occur.(1)
Patients with cancer frequently develop weight loss and in a proportion which becomes so se-
vere that they even die of wasting. The syndrome of cachexia has been considered to be syn-
onymous with severe weight loss. However, it is important to recognise that it is a multilayered,
multifaceted syndrome of complex aetiology of which weight loss is only one component. At the
core of the cancer cachexia syndrome lies the problem of progressive tumour growth and the
catabolic side-effects of conventional anti-neoplastic therapy. These two phenomena subse-
quently give rise to alterations in the activity of the neuro-endocrine system, to the production of
a variety of pro-inflammatory cytokines, neurotransmitters, prostaglandins, catabolic hormones
and regulatory peptides as well as to the release of cancer-specific catabolic/cachectic fac-
tors.(8) This systemic inflammatory response again is presumably associated with loss of appe-
tite and body weight and may also facilitate tumour progression.(4) In turn, these mediators
cause either a reduction in food intake (=anorexia), abnormalities in metabolism (including hy-
permetabolism) or a combination of both.
Anorexia is a major contributing factor in the development of the cachectic state. It is charac-
terised by a marked decrease of appetite which is caused by the systemic inflammatory reac-
tion associated with many types of cancer, leading to weight loss in up to 50% of newly diag-
nosed cancer patients.(4;9;11)

Yet, weight loss in cancer patients does not primarily arise from the reduction in food intake.(9)
The term cancer cachexia describes a complex physiological process characterised by a
number of symptoms such as progressive weight loss, anorexia, fatigue, tissue wasting and
organ dysfunction, ultimately leading to death.(2;5) Cancer cachexia is present in 50-80% of
patients with malignancies, with the highest incidence in patients with advanced cancer of the
stomach, pancreas, lung and colon.(1;8)
Cachexia or cancer anorexia-cachexia syndrome is characterised by decreased appe-

tite, weight loss, cytokine-induced metabolic alterations and a pro-inflammatory state, ap-
parently blocking anabolism and, thus, preventing cachectic patients from regaining body
cell mass during nutritional support.(4)
2.2.3 Cachexia is not simply malnutrition
Malnutrition Cachexia Sarcopenia
Does reverse Does not reverse Does not reverse
Pure caloric deficiency Inflammatory or neo- Body composition

Metabolic adaptation to plastic conditions changes: loss of
conserve LBM & in- evoke acute phase skeletal muscle in
crease fat metabolism response: loss of the absence of
roughly equal amounts weight loss
of lean and fat mass
Refeeding
Figure 2: Differentiation of malnutrition, cachexia and sarcopenia
Cachexia and starvation are the two major paradigms of weight loss. Starvation is characterised
by pure caloric deficiency (=malnutrition). The organism adapts metabolically to conserve lean
body mass and increase fat metabolism (12), and the changes can be reversed by appropriate
feeding. Intestinal disease with malabsorption is a form of starvation characterised by excess
fecal losses of ions and water, in addition to nutrients. In contrast, cachexia is associated with
inflammatory or neoplastic conditions that evoke an acute-phase response, and feeding does
not reverse the macronutrient changes. A third paradigm of malnutrition is sarcopenia (13),
which is characterised by subnormal contents of skeletal muscle in the absence of weight loss.
The term sarcopenia is most commonly used to refer to body composition changes in elderly

persons but can also apply to patients who have repeatedly tried to lose weight by dieting, pa-
tients with growth deficiency and patients with limited physical activity.
The change in body composition in cachexia markedly differs from that found in anorexia or
uncomplicated starvation: During starvation, there is an adaptation to conserve protein and re-
duce energy expenditure. Thus, gluconeogenesis is decreased and muscle mass preserved;
ketone bodies derived from fat being the major energy source. Cancer cachexia, on the other
hand, is characterised by a continuing breakdown of body stores equally affecting skeletal
muscle mass and fat.(3;7;9)
Due to its unwanted side effects, cancer cachexia severely impairs the quality of life and sur-
vival of patients. Cachexia is the most common cause of death in cancer patients, causing
over 20% of deaths from malignancies (Table 2).(1;3;4;8;10)
Table 2: Side effects associated with malnutrition and cachexia in cancer patients(1-
3;5;6;8;14;15)
• poor prognosis
• increased risk of complications in surgery and radiotherapy
• impaired response to chemotherapy
• fatigue
• decreased performance status
• diminished ability to tolerate treatment
• diminished quality of life and sense of well-being
Cachexia is not reversible by the provision of standard nutrition alone, dietary coun-
selling or nutritional supplementation cannot halt the wasting process.(4;8;9;16)
2.3 Metabolic changes in cancer and cancer cachexia related to nu-

trition
The complications associated with the appearance of the cachectic syndrome affect both the
physiological and biochemical balance of the patient and influence the efficiency of anti-cancer
treatment.
In cancer patients for instance, energy expenditure is highly variable from <60 up to >150% of
the predicted value, depending on tumour type.(2;8;16;17) This variability is caused by the in-
herent heterogeneity of cancer and the host response to tumours.(5) For non-obese patients,
total energy expenditure can be estimated using the following equations:(4)
Ambulant patients: 35-40 kcal/kg b.w./d
Bedridden patients: 25-30 kcal/kg b.w./d
In the tumour bearing host, a number of pro-inflammatory metabolic processes are activated
and contribute to weight loss. Mediators responsible for these changes are thought to be both
tumour and host derived and include pro-inflammatory cytokines, the neuroendocrine
system, and certain tumour-specific factors such as proteolysis-inducing factor (PIF).(18)
Table 3: Resulting derangements of metabolism include:(1;2;4;8;9;15;19-21)
Insulin resistance
• Impaired glucose tolerance has been observed in more than 60% of neoplastic patients.
This is due to insulin resistance and increased rates of glucose turnover, gluconeogene-
sis, and glucose recycling via lactate (Cori cycle).
Hyperlipidaemia and loss of adipose tissues

• Increased lipolysis while its suppression by glucose administration is impaired in combi-
nation with nearly undisturbed lipid oxidation.
Muscle wasting and loss of muscle protein

• Increased net skeletal muscle proteolysis and a >50% increase in whole body protein
turnover, closely related to the hepatic acute phase protein response.
Increased hepatic production of acute phase proteins

• Interleukin (IL)-6 is the possible principal regulator of the hepatic acute phase protein
response. Also importantly, an elevated level of C-reactive protein (CRP), an inflamma-
tory marker, has been considered to be a predictor of poor survival in pancreatic can-
cer.
These alterations in substrate metabolism may be explained by the need to provide a ready
supply of adopted nutrients and proteins for host defence and tissue repair. Although beneficial
in short-term insults such as infection or trauma, in cancer cachexia they also cause a diversion
of nutrients from anabolism, finally leading to organ failure and death when the energy re-
serves of the body are exhausted.(8;10;16)
Importantly, the pro-inflammatory milieu, and thus, the metabolic mechanisms ultimately leading
to the development of the anorexia-cachexia syndrome are activated already at an early stage
of the disease. Therefore, the onset of cachexia may be prevented or at least delayed by
means of early nutritional intervention.(4)

3 Nutritional strategies in cancer related weight loss and
cancer cachexia
3.1 Recommendations of ESPEN on nutritional strategies in cancer
patients
Important therapeutic goal in cancer patients is, thus, the improvement of function and outcome
by prevention and treatment of undernutrition and maintain physical capacities.(4) Specialised
nutritional support by means of enteral nutrition (EN) is recommended when nutritional status
cannot be maintained by means of normal nutrition. According to the ESPEN guidelines on
enteral nutrition in non-surgical oncology, EN should be started in cases of already existing
malnutrition or if food intake is anticipated to be reduced by <60% of estimated energy ex-
penditure for more than 7-10 days.(4;14)The provision of enteral nutrition support gives the
patient an opportunity to marshal host defences in support of healing and convalescence and
may also improve the quality of life (Table 4).
Table 4: Beneficial effects of enteral nutrition support in cancer patients (1;10)
• increases body weight and prevention of weight loss

• reduces incidence of infections and delayed wound healing
• improves nitrogen balance
• suppresses protein catabolism
• attenuates unwanted side effects associated with radiation therapy
• improved quality of life
In a number of studies it has been suggested, that specially designed disease adapted enteral
formulations might augment immune competence and beneficially modulate metabolic altera-
tions associated with neoplastic disease. (4;5;10;14;22;23) (Table 5).
Table 5: Patients benefiting from disease adapted enteral nutritional support
• Patients with severe nutritional risk 10-14 days prior to major surgery
• Patients with pancreatic carcinoma and continuing weight loss
• Patients with gastrointestinal tumours or head and neck cancer
• Patients with therapeutical interventions promoting gastrointestinal dysfunction (ex-
tensive surgery, stomatotoxic chemotherapy)
• Patients with intensive radio-/chemotherapy due to the concomitant mucositis.(24)

In these patients, EN should be provided to improve or maintain nutritional status, thus contrib-
uting to the maintenance of patients quality of life.(4)
3.2 Goal directed nutritional strategies of cancer patients

Carefully directed nutritional support should start as early as the first signs of reduced nutri-
tional intake are apparent, in order to prevent metabolic derangements and the transition to the
catabolic state.(10)
Attempts to modulate the metabolic response to cancer should form a part of the inte-
grated care of patients(8)
In the face of extensive malnutrition and pronounced cachexia, nutritional therapy gains utmost
importance in order to prevent further decline of the patient.(10) Yet, in the presence of sys-
temic inflammation, it seems to be extremely difficult to achieve whole body protein anabolism,
and standard nutritional regimens frequently fail to reverse the metabolic abnormalities
and meet the demands of the host.(4;25;26) Thus, novel strategies for the effective nutritional
support of cancer patients should be also directed to modulate the mediators and mechanisms
involved in the process of cancer cachexia:(3)
Table 6: Nutritional strategies in cancer patients:
Provision of EPA
• EPA, the major n-3 fatty acid component of fish oil, seems to affect a number of
mediators of cachexia, thus beneficially modulating the cachectic process.(8)
High in fat, low in carbohydrate
• Impaired glucose tolerance as well as the alterations in lipid metabolism as seen

in cancer patients support the recommendation to increase the
fat/carbohydrate ratio in feeding cancer patients.(4) Importantly, while in host
tissues fat can be used normally for energy production without any restrictions,
fat utilisation in tumour cells is poor. In fact, these cells lack key enzymes for
free fatty acid and ketone body degradation. So, tumour tissues might be ex-
pected to utilise glucose as the predominant metabolic substrate.(1;2;15;21;27)
Increased supply of protein
• For the compensation of increased gluconeogenesis and skeletal muscle prote-
olysis, an increased supply of protein is recommended in cancer patients. Rec-
ommendations for optimum nitrogen supply are as follows:(4)
Minimum supply: 1 g/kg b.w./d (28)
Target supply: 1.2-2 g/kg b.w./d (29)
If patients refuse to consume the full volume of normocaloric EN, high-

energy, high protein enteral formulations are to be preferred.
Provision of adequate amounts of antioxidants
• Electrolytes, trace elements and vitamins must be supplied with EN, recommendations
are based on RDA levels.(23) Since markers of oxidative stress have been shown to be
elevated and levels of antioxidants are decreased in cancer, inclusion of increased
doses of antioxidants (Vitamins A, C, E, β -carotene, selene) has been suggested.(4)
Inclusion of prebiotic, soluble fibre
• Due to known intestinal perturbations as a consequence of chemo-/and/or radiotherapy,
cancer patients could profit from prebiotic, soluble fibre, such as inuline (personal
communication Prof. A. Giacosa).
4 The key nutrient in Supportan® - EPA
Supplementation with fish-oil rich in the n-3 polyunsaturated fatty acids EPA seems to affect a
number of potential mediators of cachexia, thus beneficially modulating the cachectic proc-
ess.(8;20;30)
Weight loss in cancer patients is often refractory to therapeutic nutritional intervention. Even
though enteral feeding significantly increased nutrition intake in patients with advanced cancer
undergoing chemotherapy, it failed to improve weight, anthropometric measures, response rate,
survival, or quality of life.(16) It seems that the metabolic processes contributing to weight loss,
including pro-inflammatory cytokines, the neuroendocrine system, and certain tumour-specific
factors, lead to a partial block to the accretion of lean tissues.(18;20) Consequently, effective
treatment of cancer cachexia requires correction of the underlying metabolic abnormalities.(18)
Numerous pharmacological agents have been suggested to be useful in cachexia, yet, up to
now none of these agents has kept its promise and many have significant side effects.(7) With
the upcoming appreciation of the role of eicosanoids in cachexia, non steroidal anti-
inflammatory drugs have been investigated in cancer patients.(16) Supplementation with fish-
oil rich in the n-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahex-
aenoic acid (DHA) seems to affect a number of potential mediators of cachexia, thus benefi-
cially modulating the cachectic process.(8;20;30)
4.1 Metabolism of n-3 and n-6 fatty acids

Dietary intake of n-3 PUFA influences the composition of membrane phospholipids, an effect
that is already detectable at low fish oil intake. In particular, EPA and DHA replace the n-6
PUFA arachidonic acid (AA) 20:4 (n-6) in the structural phospholipids of platelets and vascular
cells. Release of AA from membrane phospholipids by the cytosolic enzyme phospholipase A2
in the course of inflammatory activation is, thus, lowered. As a consequence, less AA is avail-
able for further metabolism to prostaglandins and leukotriens by cyclooxygenase and lipoxy-
genase in platelets and vascular cells, as shown in Figure 3.
This means, dietary fish oil reduces formation of the n-6 PUFA derived pro-inflammatory pros-
taglandins and leukotriens, and increases the formation of n-3 PUFA derived anti-inflammatory
homologues of these prostanoids.(40) For platelets, it was shown that fish oil influences the so-
called thromboxane-prostaglandine balance, controlling platelet activation in a favourable, i.e.
less platelet-stimulatory way.
Anti-inflammatory mediators
C20:5 n-3
Leukotrienes of the Prostanoids of the
5-series, e.g. EPA 3-series, e.g.
•LTB5 •PGE3
Cyclooxygenase
Lipoxygenase
•LTC5 •PGI3
•LTD5 •TXA3
Leukotrienes of the Prostanoids of the

4-series, e.g. 2-series, e.g.
•LTB4 AA •PGE2
•LTC4 •PGF2α
•LTD4 C20:4 n-6 •TXA2
Pro-inflammatory mediators
Figure 3: Eicosanoids derived from EPA and AA (adopted from(41))
4.2 Evidence and effective dose of EPA in cancer cachexia

EPA is the major metabolically-active n-3 fatty acid in man.(7) In various animal models and
carcinoma cell lines, anti-tumour and anti-cachectic properties of EPA have been demonstrated
as well as an increased efficiency of chemo- and radiation therapy (31-34). EPA inhibits fat and
protein breakdown in animal models of cancer cachexia,(31) as well as in clinical stud-
ies.(18;32;33) Fish oil supplementation have been shown to reduce production of the pro-
inflammatory cytokines IL-1, IL-6 and TNF-α by mononuclear cells in normal volunteers, and
this effect is even maintained for some weeks after supplementation has been stopped.(7;8;34)

In patients with pancreatic cancer, Wigmore and colleagues demonstrated a reduced produc-
tion of IL-6 and TNF-α following 4 weeks of supplementation with escalating doses of EPA (1-6
g/day).(19) Administration of EPA also down-regulated pro-inflammatory cytokine release and
produced a fall in the CRP level, a marker of the acute phase protein response.(19) Indeed, the
acute phase protein response may be stabilized in pancreatic cancer patients by means of a
fish-oil enriched nutritional supplement, suggesting a profound modulation of the cachectic
process.(16;32) The proportion of patients excreting proteolysis-inducing factor (PIF), a fac-
tor displaying muscle tumour-induced catabolism also fell significantly. Thus, it seems that n-3
fatty acids can affect not only the production of pro-inflammatory mediators but also their ef-
fects on metabolism.(7)
In a placebo controlled trial, provision of 3 g EPA/day in a mixed group of 60 cancer patients

showed a significantly prolonged survival in the EPA-supplemented group; the effect on
weight loss was not reported.(35) Barber and colleagues tested the combined effects of fish oil
to down regulate cachexia and additional nutrients providing substrate for potential anabolism
by applying a fish-oil enriched nutritional supplement with 2 g EPA and 600 kcal daily to 20 un-
resectable pancreatic cancer patients. The EPA containing oral nutritional supplement (ONS)
increased weight significantly after 7 weeks of treatment (Figure 4) and patients tolerated
the supplement well. Body composition analysis using bioimpedance suggested no change in
fat mass but a significant gain in lean body mass. Negative nitrogen balance was reversed and
Karnofsky Performance score, reflecting the functional ability of patients, improved significantly
with consumption of the supplement. Also functional aspects of quality of life improved or were
stabilised.(36)

Figure 4 : Weight change of patients with advanced pancreatic cancer receiving a fish-oil enriched nutri-
tional supplement after 3 and 7 weeks. Weight gain at 3 weeks was +1 kg; at 7 weeks + 2 kg (p<0.05)
From Barber 1999(36)
In order to define an effective dose of EPA, a number of studies were conducted using pre-
scribed doses at 2 and 6 g EPA/day (19;20;30;33;36) without any difference in the effects be-
tween these two concentrations. Therefore 2 g EPA/day could be considered as effective dos-
age.
Yet, there seems to be a minimum effective dose of EPA required to achieve these bene-
ficial effects. Indeed, with patients frequently taking as little as 1.5 g EPA/day, this dosage has
shown no benefit on muscle mass and cachexia.
In a large, randomised controlled trial in 200 patients with un-resectable pancreatic cancer,
Fearon and colleagues compared the advantage of an oral nutritional supplement (ONS) with
EPA with ONS alone. Before the intervention trial, patients were loosing weight at a median rat
of 3.3 kg/month. In this study both groups stabilised at 4 and 8 weeks their weight. The intake
of the EPA containing supplement correlated with increased weight. Lean body mass was posi-
tively correlated with increased lean body mass. There was no correlation in the control group.
Due to the suboptimal compliance, the daily EPA dose was as low as 1.5 g/day.(18) Above
that, measurements of plasma EPA revealed that fish oil capsules had been taken by the pa-
tients receiving ONS without fish oil, thereby invalidating the results of the study.(4)

A post-hoc analysis of the study, suggests, that if taken in sufficient quantity, only the EPA en-
riched energy and protein-dense supplement results in net gain of weight, lean body mass and
improved quality of life. This effect was confirmed by a sub-group analysis stratifying patient’s
according to their plasma EPA levels. (37)
Bruera and colleagues studied 60 weight loosing patients with advanced cancer over a short
period of 2 weeks and found no significant effects on nutritional status and various parameters
of well-being.(38) The results indicate that 2 weeks may be too short to induce clinically meas-
urable effects. (4)
Consequently, as demonstrated by the studies of Barber, Fearon, Wigmore and colleagues,

(19;20;30;33;36) 2 g EPA/day over 8 weeks must be considered as the minimum effective
dose in cancer cachexia treatment.
The effect of a daily dose of 2 g EPA/day on weight loss in pancreatic cancer patients is shown
in Figure 5.
Figure 5: Change in body weight of patients before and after EPA supplementation (2 g/day; from Wig-
more , 2000(20))
Wigmore and collegues evaluated in 26 weight loosing patients with advanced pancreatic can-
cer the effect of high-purity EPA in form of gelatine capsules. In this 12-week study patients
received EPA supplementation starting at 1 g/day for the first week and increasing up to 6g/day
in week 4 until the end of the study. Before EPA supplementation theses patients had been
loosing a median of 2 kg/month and had lost approximately 13% of their usual body weight.
After 1 month of supplementation 16 participants had become weight-stable or had gained
some weight. A median weight gain of 0.5 g/kg was observed after 4 weeks of supplementa-
tion. However this study also revealed that increasing the maximum daily dosage of EPA from 2
g to 6 g did not appear to enhance the anti-cachectic effects.
One primary goal of nutritional supplementation is to assure the provision of the effective dose
of the key nutrient EPA, respectively 2g/day under long term use in order to counteract tissue
wasting and metabolic disorder to gain weight. This is achieved by providing the effective dose
within a small volume, which assures the complete intake. Additional calories and protein for
restoration of body cell mass are necessary and should be provided by means of a high energy-
high nutritional support.
4.3 Safety of EPA + DHA

There is growing concern with regard to the use of nutrients at pharmacological high doses by
the US Food and Drug Administration (FDA). They reflect this concern in their “Agency Letter
regarding Dietary Supplement Health Claim for n-3 Fatty Acids and Coronary Heart Dis-
ease”. (39)
Based upon this review of safety, the FDA declares that:

Consumption of EPA and DHA as dietary supplements is safe, provided that daily intakes
do not exceed 3 g/day.
Gastrointestinal disturbances and nausea are the most commonly reported side effects for con-
centrations above this FDA-safety limit. Decreased platelet aggregation and modest prolonga-
tion of bleeding times are reported, as well. Some evidence indicates that fish oil supplementa-
tion may enhance fibrolysis. Side effects depend on dosage, duration of supply and route of
administration. (rf. 4.2.2 – 4.2.5)
Thus a safety limit should also be considered for diseases specific enteral feeds in long term
use, as it is the case for Supportan®.
4.3.1 Short term use of fish oil – impact on bleeding time

Current literature gives little rise to be concerned about disadvantageous effects, at least when
fish oil is not combined with anticoagulant treatment. Fish oil intervention studies with healthy
subjects do not provide indications for increased bleeding, even after a daily intake of ≥ 6 g n-3
PUFA. (40) Various papers explicitly mention the absence of easy bruising or clinical signs

of (postoperative) bleeding after fish oil intake by patients with cardiovascular diseases.
Interactions between n-3 PUFA intake and oral anticoagulants have been noted, but these ap-
pear to occur in the absence of clinically bleeding signs. (40) In human studies a case of
clinical bleeding has not been reported, even in patients undergoing angioplasty while they
were on fish oil supplements. (42;43)
However, some in vitro and animals studies have reported that high intakes of n-3 PUFA may
impair the immune response by causing excessively prolonged bleeding times, possibly result-
ing in hemorrhagic stroke and causing oxidative damage to various tissues.(44-46) Up to now
these results could not be confirmed in humans.
4.3.2 Impact of long-term n-3 fatty acid consumption

Greenland Inuit are of special interest for the evaluation of long term effects of EPA and DHA,
since they are exposed to a life-long diet rich in fish oil.(47;48) Excessive cutaneous bleeding
time and reduced in vitro platelet agreeability have been reported in those who ingest an aver-
age of 6.5 g/day of EPA and DHA derived mainly from seal. A tendency of bleeding in the nose
and urinary tract was observed among the Greenland Inuit. One study comparing peri-renal
adipose tissue fatty acid profiles in human autopsy cases from Greenland showed that the
amounts of EPA and DHA in the adipose tissue of 4 hemorrhagic stroke victims was greater
than in control cases with no cerebral pathology. Yet, it has to be kept in mind, that their fish oil
uptake is a life long consumption and it is quite difficult to compare these intakes with clinical
nutrition under medical supervision (49).

Until today there are no sufficient data to support establishing an obligatory upper
limit for EPA and DHA. Nevertheless the proposed FDA limit should be taken into
consideration for long-term application of fish-oil.
• Although excessively prolonged bleeding times and increased incidence of bleeding have
been observed in Inuit, whose diet is rich in EPA and DHA, information is lacking to con-
clude that EPA and DHA were the sole reason for these observations.
4.3.3 Clinical nutrition including fish oil in cancer patients and side effects
Parenteral application
Parenteral nutrition with fish oil after major abdominal surgery over an observation period of 5
days did not result in an alteration of coagulation and platelet function(50) Fish oil administra-
tion up to 0.2 g/kg per day was shown to be safe in terms of intrinsic and extrinsic coagulation
and did not influence platelet aggregation. Concerning parenteral administration of fish oil, it
has to be taken into account that the application of TPN in general is of short term, so anti-
cachectic effects are not to be expected.
Enteral application
No increased bleeding times or influence on vessels was reported in supplemental studies con-
ducted with EPA containing nutritional supplements. No effects were also observed during the
supplementation of 2 g EPA as fish oil capsules.(16;18;20;32;33;36;51)
Up to date no relevant side effects occurred concerning the use of fish oil in the clinical setting.
4.3.4 Conclusion for the use of fish oil in long-term clinical nutrition
Following the first n-3 fatty acid advisory board, the FDA has ruled out the intakes of up to 3
g/d of marine n-3 fatty acids are safe for inclusion in the diet [GRAS notice FDA; 2002].
This ruling includes specific consideration of the reported effects of n-3 fatty acids on glycaemia
control in patients with diabetes, on bleeding tendencies and on LDL cholesterol.(52). FDA re-
viewed the available evidence that noted changes in bleeding times associated with the use of
EPA and DHA and concluded that there is no significant risk for increased bleeding time
below 3 grams of EPA and DHA per day.
Main adverse side effects of fish oil supplements, although generally well tolerated, could be a
mild gastrointestinal discomfort, appearing as a fishy aftertaste, erructation, nausea, flatu-
lence or loose stools (Table 7).
Table 7: Risk evaluation of potential side effects due to n-3 fatty acid consumptions in relation to
the dose administered:
Gastrointestinal Clinical Fishy after- Worsening Rise in LDL

upset bleeding taste glycaemia cholesterol
Up to 1 g/d Very low Very low Low Very low Very low
1 to 3 g/d Moderate Very low Moderate Low Moderate
> 3g/d Moderate Low Likely Moderate Likely
As side effects of long chain fatty acids are depending on the dose administered as well as on
the duration of administration, a safety limit should also be considered for enteral feeds and
long-term uptake should not exceed 3 g EPA + DHA per day.
As cancer patients are receiving multiple drug treatments, side effects and the risk of interac-
tions should be minimised. We thus postulate that an upper intake of 3 g EPA+DHA per day, as
suggested by FDA for long-term treatment of at least 8 weeks, is without any risk.

5 Product concept and nutrient composition
Nutritional therapy is an essential component of cancer management. Nutrition status has an

important effect on the quality of life and sense of well-being in cancer patients and weight loss
in cancer patients is of prognostic significance.(23) In summary, primary goals of nutrition man-
agement in cancer patients should be: (4)
• preventing and treating undernutrition
• enhancing anti-tumour treatment effects
• reducing adverse effects of anti-tumour therapies
• improving quality of life
Specialised nutrition support is clearly indicated in cancer patients. Yet, providing enteral nutri-
tion to cancer patients, the fear might arise that, with the provision of nutrients, tumour growth
and metastasis might be stimulated.(23) It is, thus, of utmost importance, to optimally feed the
patient and at the same time minimise the growth of the tumour tissue. (53)
An insufficient nutrient supply is always more harmful for the patient than it is for the tu-
mour!(54) The nutritional goal is to prevent starvation of the patient; any attempt to
starve the tumour would certainly be unrealistic!
Importantly, up to date there are no reliable data in humans showing any effect of enteral nutri-
tion on the promotion of tumour growth.(4)
Supportan and Supportan DRINK are designed to meet the specific metabolic substrate
requirements of cancer patients: high in fish oil (EPA+DHA), high in energy, high in protein,
high in fat including MCT, enriched with antioxidants and containing fibre.

5.1 Product concept – for supplemental use
The prominent feature of the product concept for Supportan and Supportan DRINK is to
provide a supplemental nutrition for the tube as well as for the sip feed. This concept will
ensure patients needs to receive the effective dose of 2g EPA as a one-shot pharmacological
dose, which is safe and effective and enabling the patient to adopt its nutrition regimes to its
specific needs and wishes.
The tube feed Supportan is available in 500 ml EasyBag and the sip feed Supportan DRINK
in 200 ml Tetrabricks with the flavours: cappuccino, tropical fruit and pineapple-coconut.
Consequently, the sip as well as the tube feed is primarily designed for supplementary nutri-
tion by reducing as much as possible the daily volume in which EPA is given. The uptake of the
effective dose of 2 g EPA is assured within one 500 ml EasyBag or two Tetra Briks (400 ml),
respectively, independent of patients’ individual energy requirements.
In summary, main features of the Supportan product concept are:
• Providing a supplemental nutrition to ensure provision of the effective dose of the

key nutrient, EPA
• Meeting the specific metabolic needs of the cancer patient
• Low dosage volume to assure optimum tolerability and compliance
The overall nutrient composition along with the European Population Reference Intake (PRI)
(55), the US Dietary Reference Intakes (DRI) (56;57) and the European legal limits are given in
the annex .
5.2 Product concept – for complete nutrition
Supportan and Supportan DRINK can also be used for short term complete nutrition provid-
ing high amounts of energy, protein and fish oil. For complete nutrition a thorough medical fol-
low-up is recommended du to the high protein amount given per daily dosage and the low so-
dium concentration of Supportan®. In some cases additional salt administration might be advis-
able.

5.3 Usage guide
The Supportan concept assures the uptake of the effective dose of 2 g EPA/day within 500
ml (1 EasyBag) of Supportan tube feed or 2 x 200 ml Tetra Briks of Supportan DRINK.
Additional calories can be provided by a standard tube feed not containing high amounts of n-3
fatty acids (Fresubin energy fibre), a standard nutritional supplement (Fresubin protein
energy DRINK), parenteral nutrition or normal food, according to the patients’ individual re-
quirements, compare Figures 6 and 7.
This takes into respect that the long-term uptake should not exceed 3 g EPA + DHA per
day.
Supportan ® - 500 ml/day for tube feeding

2 g EPA
750 kcal
2 g EPA
1500 kcal
2 g EPA
750 kcal
2250 kcal
2 g EPA
3000 kcal
2 g EPA
Safety limit 3g EPA + DHA


Figure 6: Example for the use of Supportan tube feed

Supportan ® - 2 tetras/day for sip feeding
2 g EPA
600 kcal
2 g EPA
300
kcal 900 kcal
2 g EPA
1200 kcal
2 g EPA
Safety limit 3g EPA + DHA


Figure 7: The “two Tetras” concept of the Supportan DRINK
Important note: a duration of use of at least 8 weeks is recommended for Supportan

and Supportan DRINK, since this period has been shown to be necessary to produce the
beneficial effects of EPA supplementation on muscle metabolism in cancer patients (compare
3.2.5).
5.4 Product composition
5.4.1 Energy content

Supportan and Supportan DRINK are designed as high energy tube and sip feed, provid-
ing 1.5 kcal /ml of energy. The high energy density enables a reduction of the given volume,
thereby assuring better compliance and provision of at least a minimum supply of energy and
nutrients.

5.5 Macronutrients
5.5.1 Fat
It is known that carcinomas predominantly meet their energy requirements by glucose utilization
while utilization of fatty acids and ketone bodies is poor. In contrast, in the cancer bearing host
glucose utilization is reduced, while the rate of fatty acid oxidation is increased.(54) Körber and
colleagues found an increased lipid oxidation as well as an enhanced utilisation of exogenous
lipids in cancer patients.(25;25) Consequently, Supportan and Supportan DRINK are high
in fat and low in carbohydrate in order to meet these altered metabolic needs of the tumour
patient.
Supportan and Supportan DRINK contain 40% energy of fat as a main energy source. The
fat composition of Supportan and Supportan DRINK is designed according to the specific
requirements of cancer patients.
Fish oil
• providing anti-cachectic and immunostimulating n-3 fatty acids (EPA)
Medium chain triglycerides (MCT)

• to ensure a good intestinal tolerance and an improved energy supply
Vegetable oil
• providing essential polyunsaturated fatty acids
5.5.1.1 Fish-oil
Supportan and Supportan DRINK contain fish oil at doses of 0.4 and 0.5 g EPA/100 ml
(total fish oil 0.62 and 0.78 g), the ratio n-6/n-3 fatty acids is 1.5:1 for the tube and sip feed. The
supply of n-3 fatty acids from fish oil has been shown to counteract cancer cachexia (Table
7), with EPA being the major metabolically-active n-3 fatty acid in man.(7) In order to induce
clinically measurable effects on muscle catabolism, 2 g EPA/day must be considered as the
minimum effective dose in cancer cachexia treatment. (19; 20; 30; 33; 36)
Yet, in clinical practice, compliance with fish-oil containing nutritional support is frequently poor
in cancer patients. Supportan and Supportan DRINK are, thus, primarily designed as nutri-
tional supplements in order to uncouple the administration of the key nutrient, EPA, from caloric
administration. This means, the uptake of the effective dose, 2 g of EPA is assured within one
500 ml EasyBag or two TetraBriks (400 ml), respectively, independent of patients’ individual
energy requirements.
It is possible that patients will profit of bolus administration of the key nutrients. Kinetic studies
for highly dosed key nutrients showed that the mode of administration of enteral nutrition may
be decisive for the generation of key metabolites.(58;59) These studies favour bolus admini-
stration over continuous infusion. It is thought that nutrients with pharmacological properties, as
it is the case for EPA, are more effective in this way, due to saturation of certain metabolic
pathways. This goal could easily be achieved with the new Supportan® concept.
5.5.1.2 MCT
Supportan and Supportan DRINK contain a certain amount of MCT (2.3 and 1.6 g/100 ml,
respectively 13.8 energy% and 9.5 energy%). Due to their smaller molecular weight, MCTs are
hydrolysed both faster and more completely by pancreatic lipase than long chain triglycerides
(LCT). They are thus, absorbed faster and easier in the gastrointestinal tract and the small in-
testine has a greater capacity to absorb MCT than LCT (Table 8).(60;61)
Table 8: Physiological advantages of MCT (from Ruppin, 1980(61))
• More rapid and complete intraluminal hydrolysis
• Do not require incorporation into micelles and therefore bile salts
• Small amounts of MCT may enter cell without prior hydrolysis
• More efficient penetration of diseased mucosal surfaces
• No chylomicron formation – portal transport of MCT as medium chain fatty acids
Cancer patients often suffer from maldigestion or malabsorption as a result of mucosal damage
from radiation or chemotherapy.(10) Due to their specific absorption properties, MCT help to
avoid intestinal side effects in any form of severe malabsorption which otherwise might arise
from the comparable high amount of LCT. Providing approximately 9 kcal/g, they are a valuable
component of specialised nutritional support in patients with fat malabsorption or poor nutri-
tional status, such as in pancreatic or gastrointestinal cancer.(61)
When MCTs are supplied with the diet, they are rapidly oxidized, rendering a high amount of
ketone bodies and supplying a quick source of energy. They are, therefore, a suitable source of
energy for any organism that has increased energy needs.(60) Tisdale concluded from animal
studies that utilization of free fatty acids as well as of ketone bodies derived from MCT by
tumour tissue is only minimal. On the other hand, normal tissues would be able to use both
substrates as an effective energy source and hyperketonaemia would, thus, promote nitrogen
conservation.(62)
5.5.2 Protein
Supportan and Supportan DRINK are high in protein (27% energy) in order to compen-
sate for increased protein turnover, prevent catabolic malnutrition and support immune compe-
tence. Due to its high biological value, Supportan and Supportan DRINK contain whole milk
protein as the major protein source. Importantly, whole milk protein is particularly rich in
branched-chain amino acids (BCAA).
Branched-chain amino acids (BCAA)
The essential BCAA valine, leucine, and isoleucine are important regulators of muscle protein
anabolism, precursors for glutamine and alanine synthesis as well as key sources of energy for
the muscle.(63-66) In the tumour bearing state, like in other catabolic states, rates of BCAA
oxidation and gluconeogenesis are elevated, concurrent with an activation of proteolysis and
suppression of protein synthesis in skeletal muscle, ultimately leading to the erosion of lean
tissue mass.(63;66;67)
Cancer anorexia has been suggested to occur through increased brain serotonergic activity.
(68) During tumour growth, increasing amounts of unmetabolised tryptophan, resulting from
the breakdown of muscle protein, compete with BCAA for blood-brain barrier transport. As a
result, an increase in the tryptophan derived neurotransmitter serotonin, is observed.(67)
BCAA competitively inhibits tryptophan entry into the brain, thereby reducing serotonergic activ-
ity eventually resulting in an improvement of food intake. (68)
Since dietary intake and amino acid release from protein degradation are the only sources of
the essential BCAA, dietary supplementation has been suggested.
Even though overall results from clinical trials on BCAA supplementation are still inconclusive, a
number of trials evaluating clinical outcome show promising results on morbidity and quality of
life in hepatocellular carcinoma patients undergoing major liver resection and chemo-
embolization.(63)
Supportan and Supportan DRINK provide due to the use of whole milk protein 11.25g of
BCAA per daily dosage EasyBag and 9 g with two Tetras Supportan DRINK.

5.5.3 Carbohydrate
According to the specific nutrient requirements of cancer patients, Supportan and

Supportan DRINK are low in carbohydrates, containing 33 energy% of CHO.
Maltodextrins and saccharose are the favourable sources of carbohydrates in enteral feeds
because they have a good solubility and digestibility. The osmolarity and the viscosity of the
formulas are only slightly affected. Supportan contains only maltodextrins as carbohydrate
source, while saccharose is added to the sweet flavours of Supportan DRINK.
5.5.4 Dietary fibres
The dietary fibre blend of Supportan and Supportan DRINK provides 1.2 and 1.5 g of pre-
biotic dietary fibre per 100 ml, corresponding to 6 g of dietary fibre within one 500 ml EasyBag
or two TetraBriks (400 ml), respectively. Since the product is designed as a nutritional supple-
ment, additional fibre can be provided by means of additional enteral nutrition and/or via normal
food in order to meet current dietary recommendations by the different nutritional socie-
ties.(23;69;70)
Currently, a specific fibre blend is not described for cancer patients. Due to known intestinal
perturbations as a consequence of chemo-and/or radiotherapy, cancer patients may benefit
from prebiotic, soluble fibre. Thus, the fibre component of Supportan and Supportan
DRINK is composed of inulin (83%) and wheat dextrin fibre (17%).
• Inulin derived from chicory roots is a naturally occurring prebiotic fructo-oligosaccharide

consisting primarily of linear chains of fructose.(71) Inuline has shown a significant stimu-
lating effect on the growth of bifidobacteria in healthy subjects, thus beneficially affecting
colonic microflora, while being well tolerated without causing gastrointestinal distur-
bances.(72)
• Wheat dextrin fibre is a food dextrin fibre obtained from wheat starch having a good in-
testinal tolerance. In contrast to maltodextrin wheat dextrin is incompletely hydrolysed and
incompletely absorbed in the small intestine. The incomplete hydrolysis and absorption
are due to many α-1,6 linkages and the presence of nondigestible glucosidase linkages
(e.g. α-1,2 and α-1,3), as present in dietary fibres leading to a mainly soluble and fer-
mentable component.
Inulin and dextrin fibre are both soluble, well fermented fibre types. They reach the human co-
lon where they will be fermented by the colonic microflora.(71) Fermentable fibre is the indis-

pensable substrate for the bacterial formation of short chain fatty acids (SCFA) (73-76), the
essential fuel for normal colonic functions.
Some soluble dietary fibres induce intestinal discomfort due to the increased water content re-
lated to the osmotic power of these molecules and due to the production of gases. In order to
increase the tolerance and avoid gastrointestinal side effects such as bloating and flatulence
the mode of administration is important. In patients not adapted to fibre intake, fibre containing
feeds should be introduced gradually.
5.6 Micronutrients
Supportan and Supportan DRINK supply all essential vitamins, minerals and trace ele-
ments. If used for nutritional supplementation, 500 ml of the Supportan tube feed and respec-
tively 400 ml Supportan DRINK meet at least the recommended daily requirements for vita-
mins, minerals and trace elements according to the current European and American recom-
mendations (see annex). Amounts of vitamins, minerals and trace elements do not exceed the
maximum levels as defined by the Commission Directive on Dietary Foods for Special Medical
Purposes (FSMP) of the European Communities, 1999. (FSMP: Commission of the European
Communities, 1999)
5.6.1 Minerals and trace elements

Selenium is an essential trace element and plays a major role in antioxidant defence through
its involvement in glutathione peroxidase activity. It is also postulated, that the selenium status
can influence both susceptibility to infectious disease and the severity of the disease if con-
tracted.(77) Chemotherapy has been found to be associated with alteration of serum concentra-
tion of a number of trace elements.(78) This has been related to organic immunodepression
caused by cytostatics. This, in turn may lead to impairment of the nutritional status. However,
whether chemotherapy-induced alteration of trace element serum concentration is due to a di-
rect effect of drugs or is rather contributed to by chemotherapy-related malnutrition is not clear.
In head and neck cancer patients, the supplementation of 200 µg Se per day during radio-
chemotherapy resulted in a significantly enhanced cell-mediated immune responsiveness, re-
flected in the ability of the patients lymphocytes to respond to stimulation and tumour cell de-
struction (79)
Supportan and Supportan DRINK contain 13.5 µg/100 ml of selenium, providing 54 and
67.5 µg of selenium per recommended daily dose for supplemental nutrition (500 ml and 400
ml, respectively).
5.6.2 Antioxidant vitamins
Total antioxidant status declines during cancer treatment. Possible reasons for this decline in-
clude decreased dietary intake, increased oxidative stress and adverse side effects of treat-
ment. Cancer patients might, thus, benefit from an adequate antioxidant supply to enhance
effectiveness of treatment, alleviate side effects and maintain or improve general health and
well-being.(80;81) As a component of specialized nutritional support in cancer patients, antioxi-
dants vitamins may prevent cellular damage by reacting with and eliminating oxidizing free radi-
cals, improve immune function and promote anti-inflammatory response, and help to maintain
redox-state and membrane integrity.(82;82-85)
Vitamin A may increase immunity to tumours through several mechanisms, including en-
hancement of T cytotoxic lymphocyte activity, natural killer cell activity, macrophage activity and
apoptosis.(85) Vitamin E protects cells from oxidative damage and may work synergistically
with Vitamin C in enhancing immune function.(82;84) Moreover, Vitamin C plays an important
role in wound healing.(82) β -Carotene is a precursor of vitamin A, but also has important anti-
oxidant effects.(82)
Antioxidants may enhance the effects of cytotoxic therapy by inducing cellular differentiation
and altering the intracellular redox state, thereby selectively inhibiting the growth of tumour
cells.(81;86) Antioxidants have been found to prolong survival and reduce some of the adverse
events associated with chemotherapy and radiation. In patients with small lung cell cancer, an-
tioxidant treatment in combination with chemotherapy and irradiation increased survival time
and was associated with good tolerance of treatment.(87)
Supportan and Supportan DRINK deliver therefore, antioxidant vitamins A,C, E, and β -
carotene as well as in selenium to cover the daily recommended dosages.
5.6.3 Other components

Supportan and Supportan DRINK are clinically free from lactose, low in cholesterol, gluten
and purine free. Therefore these products are suitable for patients with lactose intolerance, glu-
ten enteropathy, high cholesterol level or gout.

6 Instructions for use
6.1 Indications, contraindications, important notes and warnings
6.1.1 Indications
Supportan and Supportan DRINK are indicated for tube or sip feeding, respectively, in pa-
tients with cancer, chronic catabolic disease and/or tumour cachexia and for patients at risk of
malnutrition with high energy and protein needs including patients with
• Radiation therapy
• Chemotherapy
• Dysphagia
• Chewing and swallowing disorders
• Obstructions in the upper gastrointestinal tract
Supportan and Supportan DRINK are also suitable for complete nutrition with ≤1000 ml/day
(see also important notes).
6.1.2 Contra indications

Supportan and Supportan DRINK are not suitable for children under 1 year. The nutrition
requirements of infants under the age of 1 year differ in many aspects from those of older chil-
dren and adults because of the special characteristics of growth and development in the first
months of life.
Of course, Supportan and Supportan DRINK are not suitable where enteral nutrition in gen-
eral is not permitted
• Gut atonia
• Occlusive (mechanical) ileus
• Small bowel necrosis
• Severe organ diseases e.g. liver insufficiency, kidney insufficiency
• Congenital pathologic metabolism of nutrients contained in Supportan and
Supportan DRINK
Enteral nutrition can further be contraindicated depending on the severity of the following condi-
tions:

• Abdominal distension and cramps
• Reflux, nausea and vomiting
• Diarrhoea
• Intestinal fistulas
• Paralytic ileus
6.1.3 Important notes and warnings

Supportan and Supportan DRINK should be administered under medical control only. Sup-
portan and Supportan DRINK are suitable for total or supplementary enteral and oral nutri-
tion. They are not suitable for parenteral nutrition.
Important note for complete nutrition
For complete nutrition particularly for long term use special medical advice is recommended
related to high protein and high fish oil intake and very low sodium administration. In this case
regular sodium status has to be monitored and sodium supplementation should be eventually
been considered.
Monitoring of adequate fluid supply is mandatory.
Precaution for gravity feeding
When gravity feeding is practised special care has to be taken for the controls of the delivery
rate. Accidental sudden application of the complete volume may be life threatening in somno-
lent or unconscious patients.

6.2 Dosage and storage recommendations
6.2.1 Dosage
Supplementary nutrition:
• The recommended daily dose for supplementary nutrition is 500 ml (1 EasyBag) of Sup-
portan tube feed or 2 x 200 ml Tetra Briks of Supportan DRINK, respectively; pro-
vides the recommended daily dosage of 2 g/EPA.
Complete nutrition:
• The recommended average daily dosage of Supportan for complete enteral nutrition is
1000 ml providing 1500 kcal. The application should be started as usual with low volumes
and flow rates. The flow rate should be increased daily until the final dosage is reached.
Of course, the individual daily dosage of Supportan depends on the individual body
weight and the current nutritional status of the patient.
Application recommendation
• Recommended tube size: for pump assisted feeding ≥ CH/FR 5
for gravity feeding ≥ CH/FR 8.
6.2.2 Storage recommendations

• Tetra Brik and EasyBag could be stored at room temperature (20 – 25 °C)
• Shake well before use!
• Do not use the EasyBag if it is damaged or swollen or the content coagulated. Once
open, use within 24h.
• Opened cartons may be stored in a refrigerator up to 24 hours

7 Selected publications on clinical evidence for EPA sup-
plementation in cancer patients
Malnutrition and cachexia are indicators of poor prognosis in cancer patients.(4) Consequently,
the primary aim of intensive nutritional therapy in cancer is to maintain the nutritional and
functional status of the patient, thereby increasing quality of life as well as tolerance re-
garding therapeutic interventions.
As summarized below, numerous clinical studies provide clinical evidence for the anti-wasting
actions of dietary EPA supplementation and EPA-containing oral nutritional support (Table
9).
Clinical evidence – beneficial effects of EPA supplementation

Inhibition of proteolysis by counteracting production of pro-inflammatory cytokines
and PIF
Improved performance status and appetite
Improved nutritional status (weight gain, increase in lean body mass)
Beneficial modulation of the acute phase protein response
Although the general recommendation for enteral nutrition in cancer patients are given in the
ESPEN guidelines on enteral Nutrition in non-surgical oncology(4) authors state concern-
ing the evidence of EPA that: –
“randomised clinical trial evidence at present is contradictory/controversial and at present it is

not possible to reach any firm conclusion with regard to improved nutritional status/physical
function.”
This statement might be questionable for the following reasons:
As discussed in detail under 3.1 an effective dose of 2 g EPA/day has to be provided in

order to beneficially modulate muscle catabolism. This dose, however, was not always
achieved.
EPA supplementation might also fail to produce any significant beneficial effects in case
the duration of EPA application is too short. Indeed 8 weeks are recommended to influ-
ence muscle metabolism (compare 3.2.5).
The outcome of the large multi-centre trial conducted by Fearon and colleagues(18) was
invalidated by low compliance and/or the uncontrolled consumption of fish oil cap-
sules by the patients (compare 3.1).

As stated by the authors it is of utmost importance to enhance patients compliance in order to
increase the efficacy of treatment with EPA containing specialised oral nutritional support.(4) In
order to achieve an optimum patient compliance, the daily volume in which the effective dose
of EPA, 2 g/day, is given with Supportan and Supportan DRINK has been reduced as much
as possible.

Table 9: Selected publications
Authors Patients Nutritional regi- Outcome

men
Wigmore, et al. Unresectable pan- Dietary supplement. After 3 months (vs. baseline)
1996 (30) creatic cancer (n=18) with fish oil cap- - weight ↑ (p<0.002)
sules, escalating - stabilisation of REE.
doses: 2-16 g/d
(Median 12 g/d) After 1 month (vs. baseline)
- CRP ↓ (p<0.002)
Wigmore, et al. Unresectable pan- Supplemental high- Pre EPA vs. post EPA:
1997 (19) creatic cancer (n=6) purity EPA, escalat-
- serum CRP ↓ (p<0.05)
ing doses (1-6 g/d)
over 4 weeks - IL-6 production by isolated
PBMC ↓ (p<0.05)
→ Suppression of APR
Gogos, et al. Incurable malignan- Supplementation of No weight and serum protein
1998 (35) cies, including cancer fish oil capsules: changes.
of breast, GI tract, 1.2 g/day and 200
Karnofsky performances
liver and pancreas mg vitamin E
status improved significantly
(n=64), placebo con-
trolled Significantly prolonged survival
in well-nourished supple-
mented patients.
Barber et al. Unresectable pan- EPA containing After 3/7 weeks vs. baseline:
1999a (36) creatic cancer (n=20) ONS, 2 g EPA/d - weight ↑ (p<0.04)
over 7 weeks - dietary intake ↑ (p=0.002)
- REE ↓ (p<0.03)
- performance status
↑(p<0.05)
- appetite ↑ (p<0.01)
Barber et al. Advanced pancreatic Fish oil enriched After 3 weeks:
1999b (32) cancer (n=36) and ONS (n=18) vs. full - stabilisation of the APR in the
healthy controls (n=6) supportive care supplemented vs. unsupple-
alone (n=18) mented group
- weight ↑ (p=0.0001 between
patient groups)
Barber et al. Unresectable pan- Fish oil enriched After 3 weeks vs. baseline of
2000 (33) creatic cancer (n=16) ONS (2 g EPA/d) each group:
and healthy controls over 3 weeks - weight ↑ (p<0.05)
(n=6) - lean body mass ↑ (p<0.05)
- serum insulin↑ (p<0.01)
- normalization of the meta-
bolic response
Wigmore et al. Unresectable pan- Supplemental high- - weight stabilisation over a 12
2000 (20) creatic cancer (n=23) purity EPA, escalat- week study period
ing doses (1-6 g/d)
over 4 weeks

Fearon et al. Unresectable pan- n-3-fatty acid and - no therapeutic advantage of
2003 (18) creatic cancer antioxidant enriched the EPA enriched supplement
(n=200, randomised, ONS vs. ONS → low compliance
double blind multi- alone, 1.5 g → uncontrolled intake of fish-
centre trial EPA/day oil capsules.
Moses et al. Unresectable pan- EPA containing Improvement of physical activ-
2004 (51) creatic cancer (n=24) ONS, 2 g EPA/d ity and Quality of life.
and healthy controls over 8 weeks
Bauer et al. 2005 Unresectable pan- n-3-fatty acid and Significant difference in energy
(37) creatic cancer antioxidant enriched and protein intake.
(n=200, randomised, ONS vs. ONS
Significant increase in weight.
double blind multi- alone,
centre trial No inhibition of meal intake by
supplement.
Remark: Restratifica-
tion of patients ac-
cording to fish-oil
intake and compari-
son of compliant and
non-compliant pa-
tients
Fearon et al. Advanced gastroin- Eicosapentaenoic No significant data on survival
2006 (88) testinal or lung can- acid diester, 2 or 4 were shown.
cer (n=500, double g/day over 8 weeks.
Remark: This study used a
blind placebo con-
synthetic EPA diester, and not
trolled multicentre
the marine fish oil.
study).
Patients included were GI and
lung cancer patients, GI pa-
tients increased their body
weight by 1.9 kg, and lung
cancer patients only by 0.5 g.
It is suggested, that these pa-
tients had problems in taking
the whole amount of fish oil.
It is noteworthy that 4 g EPA
were not effective on lean
body mass, but 2 g were it
supporting the recommended
dosage of Supportan.®
APR Acute phase response
REE Resting energy expenditure
PBMC Peripheral blood mononuclear cells
ONS Oral nutritional supplement
Signed by Dr. Christina Schneid, KSBC MSA-NT

Bad Homburg, March 21st, 2007

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9 Annex

Supportan tube and sip feed
9.1 Nutritional Profile comparison with recommendations

Micronutrient Supply with Supportan® tube feed
Compared to European and American Daily Recommendations for Adults (70 kg)
Supportan tube
EU-SCF (1993)
Per 500 ml = 750 D-A-CH (2000) USA (1997 – 2001)
1)
kcal
AR2) PRI3) NRI4) RDA5)/AI6)
Vitamin A mg 0.75 0.4 – 0.5 0.6 – 0.7 0.8 – 1.0 0.7 – 0.9
Vitamin E mg 18.8 Not defined ≥3–4 11 – 15 15
Vitamin K mg 105 Not defined 70 60 – 80 90 - 120
Vitamin D mg 12.5 Not defined 0 – 10 5 – 10 5 - 15
Vitamin B1 mg 1.5 0.6 – 0.8 0.9 – 1.1 1.0 - 1.3 1.1 – 1.2
Vitamin B2 mg 2.0 1.1 – 1.3 1.3 – 1.6 1.2. – 1.5 1.1 -.1.3
Vitamin B6 mg 2.2 1 – 1.3 1.1 – 1.5 1.2. – 1.5 14 – 16
Niacin mg 18.8 11 – 15 14 – 18 13 – 17 1.3 – 1.7
Vitamin B12 mg 3.8 1.0 1.4 3 2.4
Pantothenic mg 7.5 3 – 12 6 5
acid
Biotin mg 47 15 – 100 30 - 60 30
Folic Acid mg 313 0.14 0.2 0.4 0.4
Vitamin C mg 94 30 45 100 75 - 90
status 21/03/07 Page 47 of 50

Micronutrient Supply with Supportan® tube feed

Supportan® tube feed EU-SCF (1993) D-A-CH (2000) USA (1997 – 2001)
Per 500 ml = 750 kcal1)
Na mg 238 575 – 3000 ≥ 550 -
K mg 640 3100 ≥ 2000 -
Cl mg 250 ≥ 830 -
Ca mg 1015 550 700 100 1000 – 1200
P mg 600 400 550 700 700
Mg mg 130 150 – 500 300 – 400 310 – 420
Fe mg 12.5 7 9 – 16 10 – 15 8 – 18
Zn mg 10 5.5 –7.5 7 – 9.5 7 - 10 8 - 11
1) Minimum recommended intake

2) EU-SCF AR: Average Requirement
3) EU-SCF PRI: Population Reference Intake
4) D-A-CH: Reference Values for Germany, Austria and Switzerland
5) USA-RDA: Recommended Dietary Allowance
6) USA-AI: Adequate Intakes

Micronutrient Supply with Supportan® DRINK

Supportan
EU-SCF (1993)
DRINK D-A-CH (2000) USA (1997 – 2001)
Per 400 ml = 600
kcal
1)
Vitamin A mg 0.6 0.4 – 0.5 0.6 – 0.7 0.8 – 1.0 0.7 – 0.9
Vitamin E mg 15 Not defined ≥3–4 11 – 15 15
Vitamin K mg 84 Not defined 70 60 – 80 90 - 120
Vitamin D mg 10 Not defined 0 – 10 5 – 10 5 - 15
Vitamin B1 mg 1.2 0.6 – 0.8 0.9 – 1.1 1.0 - 1.3 1.1 – 1.2
Vitamin B2 mg 1.6 1.1 – 1.3 1.3 – 1.6 1.2. – 1.5 1.1 -.1.3
Vitamin B6 mg 1.7 1 – 1.3 1.1 – 1.5 1.2. – 1.5 14 – 16
Niacin mg 15 11 – 15 14 – 18 13 – 17 1.3 – 1.7
Vitamin B12 mg 3 1.0 1.4 3 2.4
Pantothenic
mg 6 3 – 12 6 5
acid
Biotin mg 37.5 15 – 100 30 - 60 30
Folic Acid mg 250 0.14 0.2 0.4 0.4
Vitamin C mg 75 30 45 100 75 - 90
®
Micronutrient Supply with Supportan DRINK

Supportan® DRINK EU-SCF (1993) D-A-CH (2000) USA (1997 – 2001)

Per 400 ml = 600 kcal1)
Na mg 190 575 – 3000 ≥ 550 -
K mg 512 3100 ≥ 2000 -
Cl mg 200 ≥ 830 -
Ca mg 812 550 700 100 1000 – 1200
P mg 480 400 550 700 700
Mg mg 104 150 – 500 300 – 400 310 – 420
Fe mg 10 7 9 – 16 10 – 15 8 – 18
Zn mg 8 5.5 –7.5 7 – 9.5 7 - 10 8 - 11
7) Minimum recommended intake

8) EU-SCF AR: Average Requirement
9) EU-SCF PRI: Population Reference Intake
10) D-A-CH: Reference Values for Germany, Austria and Switzerland
11) USA-RDA: Recommended Dietary Allowance
12) USA-AI: Adequate Intakes

07.1 Scientific Rationale

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7 Scientific Rationale

KIC/MSA-EN/Dr. Christina Schneid Status 20/06/07 page 1 of 50

1 Main product features and intended use ............................................................. 6

2 Scientific Rationale for disease adapted feeds in cancer patients ................... 7

3 Nutritional strategies in cancer related weight loss and cancer cachexia..... 13

4 The key nutrient in Supportan® - EPA................................................................ 15

5 Product concept and nutrient composition....................................................... 24

KIC/MSA-EN/Dr. Christina Schneid Status 20/06/07 page 2 of 50

6 Instructions for use ............................................................................................. 34

7 Selected publications on clinical evidence for EPA supplementation in cancer

KIC/MSA-EN/Dr. Christina Schneid Status 20/06/07 page 3 of 50

Figure 2: Differentiation of malnutrition, cachexia and sarcopenia ........................................... 10

Figure 3: Eicosanoids derived from EPA and AA ..................................................................... 16

Figure 6: Example for the use of Supportan tube feed ........................................................... 26

Figure 7: The “two Tetras” concept of the Supportan DRINK ................................................. 27

Table 3: Resulting derangements of metabolism include ......................................................... 12

Table 4: Beneficial effects of enteral nutrition support in cancer patients ................................. 13

Table 5: Patients benefiting from disease adapted enteral nutritional support.......................... 13

Table 6: Nutritional strategies in cancer patients...................................................................... 14

Table 8: Physiological advantages of MCT .............................................................................. 29

Table 9: Selected publications ................................................................................................. 39

KIC/MSA-EN/Dr. Christina Schneid Status 20/06/07 page 4 of 50

KIC/MSA-EN/Dr. Christina Schneid Status 20/06/07 page 5 of 50

Available as tube and sip feed

KIC/MSA-EN/Dr. Christina Schneid Status 20/06/07 page 6 of 50

2.1 Prevalence and pathogenesis of cancer

Main patient groups herein are:

• Lung (1.3 million deaths/year)

• Physical carcinogens such as ultraviolet (UV) and ionising radiation

• Chemical carcinogens such as asbestos and tobacco smoke

• Biological carcinogens such as infections by virus and bacteria or contamination of food

KIC/MSA-EN/Dr. Christina Schneid Status 20/06/07 page 7 of 50

Food -borne- Expression in Neoplasms

2.2 Cancer related weight loss

2.2.1 Malnutrition in cancer patients

KIC/MSA-EN/Dr. Christina Schneid Status 20/06/07 page 8 of 50

• physical abnormalities associated with a tumour

2.2.2 Cancer cachexia

KIC/MSA-EN/Dr. Christina Schneid Status 20/06/07 page 9 of 50

Cachexia or cancer anorexia-cachexia syndrome is characterised by decreased appe-

2.2.3 Cachexia is not simply malnutrition

Malnutrition Cachexia Sarcopenia

Does reverse Does not reverse Does not reverse

Pure caloric deficiency Inflammatory or neo- Body composition

Figure 2: Differentiation of malnutrition, cachexia and sarcopenia

KIC/MSA-EN/Dr. Christina Schneid Status 20/06/07 page 10 of 50

2.3 Metabolic changes in cancer and cancer cachexia related to nu-

Bedridden patients: 25-30 kcal/kg b.w./d

Table 3: Resulting derangements of metabolism include:(1;2;4;8;9;15;19-21)

Hyperlipidaemia and loss of adipose tissues

Muscle wasting and loss of muscle protein

Increased hepatic production of acute phase proteins

KIC/MSA-EN/Dr. Christina Schneid Status 20/06/07 page 12 of 50

Table 4: Beneficial effects of enteral nutrition support in cancer patients (1;10)

• increases body weight and prevention of weight loss

Table 5: Patients benefiting from disease adapted enteral nutritional support

KIC/MSA-EN/Dr. Christina Schneid Status 20/06/07 page 13 of 50

3.2 Goal directed nutritional strategies of cancer patients

Table 6: Nutritional strategies in cancer patients:

• Impaired glucose tolerance as well as the alterations in lipid metabolism as seen

KIC/MSA-EN/Dr. Christina Schneid Status 20/06/07 page 14 of 50

4 The key nutrient in Supportan® - EPA

4.1 Metabolism of n-3 and n-6 fatty acids

Leukotrienes of the Prostanoids of the