Scientific Product Rationale

Scientific Product Rationale Supportan & Supportan DRINK Enteral Nutrition Formula Adapted to the Special Needs of Cancer Patients Tube & Sip Feed for Supplemental or Complete Nutrition Food for Special Medical Purposes Daniela Scheiner & Dr. Christina Schneid Medical Scientific Managers Enteral Nutrition Global Business Center Clinical Nutrition and Pharmaceuticals Fresenius Kabi Deutschland GmbH Revision 04, 04 October 2011

Contents Abbreviations... 4 1. Main product features & 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 a current definition... 11 2.3 Metabolic changes in cancer and cancer cachexia related to nutrition. 13 3. Nutritional strategies in cancer related weight loss & cachexia... 15 3.1 Nutrition recommendations of ESPEN & ASPEN for cancer patients... 15 3.2 Goal directed nutritional strategies in cancer patients adaption to the patients` metabolism... 18 4. The key nutrient in Supportan & Supportan DRINK - EPA... 20 4.1 Metabolism of n-3 and n-6 fatty acids... 21 4.2 Rationale for and effective dose of EPA in cancer cachexia... 22 4.3 Clinical evidence of EPA & DHA in cancer patients Current data... 26 4.4 Safety of EPA + DHA Intake recommendations... 31 4.4.1 Nutrition and supplementation including fish oil in general... 31 4.4.2 Clinical nutrition including fish oil in cancer patients & side effects 33 4.4.3 Conclusion for the use of fish oil in long-term clinical nutrition... 34 5. Product concept and nutrient composition... 35 5.1 Product concept for supplemental use... 37 5.2 Product concept for complete nutrition... 38 BCEN/ MSA & E: CSc, DSc revision 04, 04 October 2011 2 of 67

5.3 Usage guide... 38 5.4 Product composition adapted to the patients metabolic needs... 40 5.4.1 Energy content... 41 5.4.2 Macronutrients... 41 5.4.3 Micronutrients... 48 6. Instructions for use... 51 6.1 Indications, contraindications, important notes and warnings... 51 6.1.1 Indications... 52 6.1.2 Contraindications... 52 6.1.3 Important notes and warnings... 53 6.2 Dosage and storage recommendations... 54 6.2.1 Dosage... 54 6.2.2 Storage recommendations... 56 7. References... 57 8. History... 66 9. Annex... 67 BCEN/ MSA & E: CSc, DSc revision 04, 04 October 2011 3 of 67

Abbreviations AA = Arachidonic Acid AI = Adequate Intake APP = Acute Phase Protein APPR = Acute Phase Protein Response AR = Average Requirement Aug = August BCAA = Branched Chain Amino Acids b.w. = Body Weight CRP = C-Reactive Protein CT = Chemotherapy D A CH = Nutrition Reference Values for Germany Austria - Switzerland DHA = Docosahexaenoic Acid DNA = Desoxyribonucleic Acid DRI = Dietary Reference Intake EAR = Estimated Average Requirement e.g. = exempli gratia EN = Enteral Nutrition EPA = Eicosapentaenoic Acid EU = European Union FDA = Food and Drug Administration Feb = February FSMP = Food for Special Medical Purposes GI = Gastrointestinal GRAS = Generally Recognised As Safe IL = Interleukin LBM = Lean Body Mass LCT = Long Chain Triglycerides MCT = Medium Chain Triglycerides ONS = Oral Nutritional Supplement PBMC = Peripheral Blood Mononuclear Cells PIF = Proteolysis Inducing Factor PN = Parenteral Nutrition PRI = (European) Population Reference Intake BCEN/ MSA & E: CSc, DSc revision 04, 04 October 2011 4 of 67

PUFA = Polyunsaturated Fatty Acids QoL = Quality of Life RCT = Randomised Controlled Trial RDA = Recommended Daily Allowance RDD = Recommended Daily Dosage RDI = Recommended Daily Intake REE = Resting Energy Expenditure RT = Radiation Therapy SCF = (European Commission's) Scientific Committee on Food SCFA = Short Chain Fatty Acids TNF-α = Tumour Necrosis Factor α USA = United States of America UV = Ultraviolet WHO = World Health Organisation BCEN/ MSA & E: CSc, DSc revision 04, 04 October 2011 5 of 67

1. Main product features & intended use Supportan and Supportan DRINK are indicated for tube and sip feeding of patients with cancer, chronic catabolic disease and/ or cachexia, at risk of malnutrition and with high energy & protein needs. Hence, Supportan and Supportan DRINK are designed to meet the specific metabolic substrate requirements of cancer patients. Key features are the following High in fish oil providing eicosapentatenoic acid (EPA) 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 (31 energy %) to provide energy for the patient, not for the tumour; With medium chain triglycerides (MCT) to ensure good intestinal tolerance and absorption for improved energy supply; High in protein (27 energy %) to counteract loss of muscle mass; High energy density (1.5 kcal/ ml) to ensure a tolerable volume and high long-term compliance; Covering requirements for most vitamins & trace elements Available as tube & sip feed to provide optimal supply according to the patients condition; Available in three flavours: Cappuccino, Tropical Fruits, Pineapple-Coconut to ensure high compliance; (not launched yet) Crucial aim is to assure the uptake of the effective dose of the key component EPA, in a low daily volume. Consequently, tube as well as sip feed are primarily designed for supplementary nutrition. This concept assures the uptake of 2 g EPA/ day within 1 x 500 ml EasyBag of Supportan tube feed or 2 x 200 ml EasyBottles of Supportan DRINK. Further caloric needs can be supplied according to the patients individual requirements and abilities by standard feeds or normal nutrition. If the dose is reduced appropriately, the formula can also be given to children > 1 year. Under the condition of special medical advice and monitoring Supportan and Supportan DRINK are also suitable for complete nutrition. BCEN/ MSA & E: CSc, DSc revision 04, 04 October 2011 6 of 67

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 (QoL). [1] Furthermore, accounting for 7.4 million deaths in 2004, which corresponds to about 13 % of all deaths, cancer is a leading cause of death worldwide. Worldwide cancer deaths are even projected to continue rising with an estimated 12 million people dying from cancer in 2030. The types of cancer causing most cancer deaths each year are the following: [World Health Organisation (WHO), February 2009] Lung cancer (1.3 million deaths/ year) Stomach cancer (803 000 million deaths/ year) Colorectal cancer (639 000 deaths/ year Liver cancer (610 000 deaths/ year) Breast cancer (519 000 deaths/ year) The most frequent types of cancer worldwide and corresponding statistics for their incidence and mortality, calculated for both sexes, are as follows: [GLOBOCAN project providing data on cancer incidence and mortality worldwide, 2008] Lung cancer (incidence: 12.7 %, mortality from cancer: 18.2 %) Breast cancer (incidence: 10.9 %, mortality from cancer: 6.1 %) Colorectal cancer (incidence: 9.7 %, mortality from cancer: 8.0 %) Stomach cancer (incidence: 7.8 %, mortality from cancer: 9.7 %) Prostate cancer (incidence: 7.2 %, mortality from cancer: 3.4 %) Cancer occurs because of changes of genes responsible for cell growth and repair. These changes are the result of the interaction between genetic host factors and carcinogenic external agents which can be categorised as either/ or: Physical carcinogens, such as ultraviolet (UV) and ionising radiation. KIC/ BU EN/ MSA: CSc, DSc revision 01, 05 August 2010 7 of 67

Chemical carcinogens, such as asbestos and tobacco smoke. Biological carcinogens, such as infections by virus and bacteria or contamination of food by mycotoxins. The induction of a tumour is a multi-event process occurring over time, divided into three separate 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 food borne carcinogen carcinogen electrophilic electrophilic reactant or free reactant or free radical radical expression in expression in altered cellular altered cellular information information neoplasm neoplasm binding of binding of carcinogen to carcinogen to DNA/ protein DNA/ protein alterations in alterations in DNA/ proteins/ DNA/ proteins/ carcinogen/ carcinogen/ damaged cell damaged cell growth of growth of altered cells by altered cells by proliferation proliferation promoter promoter metastasis metastasis 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 disease and appears to be a prominent feature. [3] Depending on site and stage of the tumour, as many as 31 87 % of patients have been reported to lose weight already prior to diagnosis; Thereby highest frequencies have been seen in patients with pancreatic cancer (85 %), BCEN/ MSA & E: CSc, DSc revision 04, 04 October 2011 8 of 67

gastrointestinal cancer (80 %), lung cancer (69 %) or in those with more advanced cancer disease. [4-7] Nutritional intake and nutritional status of cancer patients can be impaired by a multitude of reasons (table 1). Table 1: Exemplary factors influencing nutritional intake and nutritional status in cancer patients: [2;5;8-10] Decreased nutritional intake - variations in taste and smell sensations - host response to the tumour causing anorexia - early satiety - reduced appetite Physical abnormalities associated with the tumour - altered metabolism and increased catabolism (see also table 2) Treatment related effects - nausea, constipation, diarrhoea - extensive resection with loss of functional capacity - mucositis, stomatitis - dysphagia Emotional effects - physiological problems such as depression, grief or anxiety - pain 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 which might become so severe that some patients even appear to die of wasting. The syndrome of cachexia has been considered to be synonymous with severe weight loss. However, it is impor- BCEN/ MSA & E: CSc, DSc revision 04, 04 October 2011 9 of 67

tant 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 lays the problem of progressive tumour growth and the catabolic side-effects of conventional anti-neoplastic therapy. These two phenomena subsequently 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 factors. [8] This systemic inflammatory response again is presumably associated with loss of appetite and body weight (b.w.) and may also facilitate tumour progression. [4] In turn, these mediators cause either a reduction in food intake (=anorexia), abnormalities in metabolism (including hypermetabolism) or a combination of both. Anorexia is a major contributing factor in the development of the cachectic state. It is characterised by a marked decrease of appetite which is caused by the systemic inflammatory reaction associated with many types of cancer, leading to weight loss in up to 50 % of newly diagnosed 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 appetite, weight loss, cytokine-induced metabolic alterations and a proinflammatory state, apparently blocking anabolism and, thus, preventing cachectic patients from regaining body cell mass during nutritional support. [4] BCEN/ MSA & E: CSc, DSc revision 04, 04 October 2011 10 of 67

2.2.3 Cachexia is not simply malnutrition a current definition Starvation and cachexia are the two major paradigms of weight loss. However, there is also the condition of sarcopenia. These 3 paradigms and their major differences are summarised in figure 2. Starvation is characterised by a pure caloric deficiency (= malnutrition). The organism adapts metabolically to conserve lean body mass (LBM) and increase fat metabolism. [12] The changes can be reversed by appropriate feeding. In contrast, cachexia is associated with inflammatory or neoplastic conditions leading to an acute phase response associated with muscle wasting. Feeding alone 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, patients with growth deficiency and patients with limited physical activity. Starvation Starvation Cachexia Cachexia Sarcopenia Sarcopenia does reverse does reverse does not reverse does not reverse does not reverse does not reverse Inadequate caloric intake Inadequate caloric intake metabolic changes metabolic changes to maintain LBM to maintain LBM increase fat metabolism increase fat metabolism Inflammation Inflammation & neoplastic progression neoplastic progression acute phase response acute phase response with loss of LBM with loss of LBM Aging Aging changes in body composition changes in body composition loss of skeletal muscle mass loss of skeletal muscle mass no weight loss no weight loss F E E D I N G F E E D I N G Figure 2: Differentiation of malnutrition, cachexia and sarcopenia: Whereas feeding does reverse starvation, it does not reverse cachexia and sarcopenia (adapted from [14]) The change of body composition in cachexia markedly differs from that found in anorexia or uncomplicated starvation: During starvation, there is an adaptation to conserve protein and reduce 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 BCEN/ MSA & E: CSc, DSc revision 04, 04 October 2011 11 of 67

continuing breakdown of body stores equally affecting skeletal muscle mass and fat. [3;7;9] Cachexia is not reversible by the provision of standard nutrition alone, dietary counselling or nutritional supplementation cannot halt the wasting process. [4;8;9;15] Due to its unwanted side effects, cancer cachexia severely impairs QoL and the patient s survival (table 2). It is the most common reason of death in cancer patients causing over 20 % of deaths from malignancies. [1;3;4;8;10] Table 2: Side effects associated with malnutrition and cachexia in cancer patients [1-3;5;6;8;16;17] Poor prognosis Increased risk of complications in surgery and radiation therapy (RT) Impaired response to chemotherapy (CT) Fatigue Decreased performance status Diminished ability to tolerate treatment Diminished QoL and sense of well-being As cancer cachexia is worsening the patients prognosis, its diagnosis and treatment is very important. However, as mentioned above, the cachectic syndrome is multifactorial and the underlying mechanisms are not fully understood, yet. Consequently, there has been a lack of a universally agreed definition, so far. Using this as an opportunity, in 2006, several well-known scientists and clinicians met to reach a consensus definition. The resulting new definition of cachexia is the following: Cachexia is a complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass. The prominent clinical feature of cachexia is weight loss in adults (corrected for fluid retention) or growth failure in children (excluding endocrine disorders). Anorexia, inflammation, BCEN/ MSA & E: CSc, DSc revision 04, 04 October 2011 12 of 67

insulin resistance and increased muscle protein breakdown are frequently associated with cachexia. Cachexia is distinct from starvation, age-related loss of muscle mass, primary depression, malabsorption and hyperthyroidism and is associated with increased morbidity. [18] The concept of this definition is presented in figure 3 below. Chronic Chronic Illness Illness e.g. e.g. cancer cancer Anorexia Anorexia Inflammation Inflammation Insulin resistance Insulin resistance Hypogonadism Hypogonadism Anemia Anemia Fat Loss Fat Loss Muscle Wasting Muscle Wasting Weight Loss Weight Loss Weakness & Fatigue Weakness & Fatigue Weight loss < 5 Weight loss < 5 % in in 12 12 months months or or less less or or BMI BMI < < 20 20 kg/ kg/ m 2 2 CACHEXIA CACHEXIA DIAGNOSIS DIAGNOSIS & Decreased Decreased muscle muscle strength strength Fatigue Fatigue Anorexia Anorexia Low fat free mass index Low fat free mass index Abnormal biochemistry Abnormal biochemistry Figure 3: Concept of the new definition of cachexia as defined by Evans et al. in 2006 [18] 2.3 Metabolic changes in cancer and cancer cachexia related to nutrition 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 and ranges from < 60 % up to > 150 % of the predicted value, depending on the tumour site. [2;8;15;19] This variability is caused by the BCEN/ MSA & E: CSc, DSc revision 04, 04 October 2011 13 of 67

inherent heterogeneity of cancer and the host response to tumours. [5] For nonobese patients, total energy expenditure can be estimated using the following equations: [4] Ambulant patients: Bedridden patients: 35-40 kcal/ kg b.w./ day 25-30 kcal/ kg b.w./ day 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). [20] To give an overview of possible metabolic changes in cancer cachexia, the underlying pathogenesis is depicted in figure 4. Malignant Tumour Cells Malignant Tumour Cells Pro-inflammatory Cytokine Production Pro-inflammatory Cytokine Production IL-1, IL-6, TNF-α IL-1, IL-6, TNF-α Proteolysis Inducing Proteolysis Inducing Factor (PIF) Factor (PIF) Appetite Appetite Initiated Acute Phase Initiated Acute Phase Response (e.g. CRP ) Response (e.g. CRP ) Food Intake Food Intake Resting Energy Resting Energy Expenditure (REE) Expenditure (REE) Affected Metabolism of Affected Metabolism of Macronutrients Macronutrients Lean Body Lean Body Mass (LBM) Mass (LBM) Cancer Associated Weight Loss Cancer Associated Weight Loss Figure 4: Metabolic pathogenesis of cancer cachexia [21] A selection of metabolic derangements in cachectic cancer patients is further summarised in table 3: BCEN/ MSA & E: CSc, DSc revision 04, 04 October 2011 14 of 67

Table 3: Resulting derangements of metabolism include: [1;2;4;8;9;17;22-24] Insulin resistance Impaired glucose tolerance has been observed in more than 60 % neoplastic patients. This is due to insulin resistance and increased rates of glucose turnover, gluconeogenesis, and glucose recycling via lactate (Cori cycle). Hyperlipidaemia & loss of adipose tissues Increased lipolysis while its suppression by glucose administration is impaired in combination with nearly undisturbed lipid oxidation. Muscle wasting & 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 (APPR). Increased hepatic production of acute phase proteins (APP) IL-6 is the possible principal regulator of the hepatic APPR. Importantly, an elevated level of C-reactive protein (CRP), an inflammatory marker, has been considered to be a predictor of poor survival in pancreatic cancer. 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 reserves of the body are exhausted. [8;10;15] Importantly, the pro-inflammatory milieu, and thus, the metabolic mechanisms ultimately leading to the development of the cachectic 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 nutrition intervention. [4] 3. Nutritional strategies in cancer related weight loss & cachexia 3.1 Nutrition recommendations of ESPEN & ASPEN for cancer patients Important therapeutic goal in cancer patients is the improvement of function and outcome by prevention and treatment of undernutrition and maintenance of physi- BCEN/ MSA & E: CSc, DSc revision 04, 04 October 2011 15 of 67

cal capacities. [4] Therefore the goals of nutritional intervention in cancer patients can be summarised as follows (see table 4): Table 4: Goals of nutritional intervention therapy in cancer patients [25] Improvement of nutritional status/ prevention of malnutrition Reversal of protein-calorie malnutrition Better tolerance to treatment Decrease of morbidity Improvement of QoL Improvement of survival Specialised nutritional support by means of enteral nutrition (EN) and/ or parenteral nutrition (PN) is recommended when nutritional status cannot be maintained by means of normal nutrition. Thereby nutritional support should start as early as the first signs of reduced nutritional intake are apparent, in order to prevent metabolic derangements and the transition to the catabolic state. In the face of extensive malnutrition and pronounced cachexia, nutritional therapy gains utmost importance in order to prevent further decline of the patient. The ideal nutritional intervention starts with the evaluation of the patient s nutritional status and, may include the following regimens (table 5): [26] Table 5: Possible types of clinical nutrition support Dietary counselling Oral nutritional supplementation (ONS) with sip feeds EN with tube feeds PN BCEN/ MSA & E: CSc, DSc revision 04, 04 October 2011 16 of 67

The ESPEN [4] and the ASPEN [27] guidelines for clinical nutrition support in cancer patients recommend the following Cancer patients are nutritionally at risk and nutritional assessments should be done frequently [4;27] EN should be started, if undernutrition already exists or if food intake is anticipated to be inadequate for > 7 10 days [4] Thereby the enteral route should be preferred wherever feasible [4] Tube feeding should be used if an obstructive head-neck or oesophageal cancer interferes with swallowing or if severe local mucositis is expected [4] Nutrition support is appropriate in malnourished patients receiving active anti-cancer treatment who are anticipated to be unable to ingest and/ or absorb adequate nutrients for a prolonged period of time [27] During RT and/ or CT intensive dietary advice and ONS are recommended to increase dietary intake and to prevent therapy-associated weight loss and interruption of RT [4] Perioperative nutrition support may be beneficial in malnourished patients, if administered 7 14 days prior to major surgery [4;27] Immune-enhancing enteral formulae including essential fatty acids may be beneficial in (malnourished) patients undergoing major cancer surgery [4;27] In cachectic patients n-3 fatty acid supplementation may help to improve nutrition status and stabilize weight [4;27] The provision of EN support gives the patient an opportunity to marshal host defences in support of healing and convalescence and may improve QoL (table 6). Table 6: Beneficial effects of EN support in cancer patients [10;26] Improvement of tolerance to treatment by attenuating side effects Reduction of postoperative complications and infection rate Shortening length of the hospital stay Improvement of survival [28] Improvement of QoL Increase of body weight and prevention of weight loss Improvement of nitrogen balance Suppression of protein catabolism Better control of cancer-related symptoms Enhancement of immuno-metabolic host response BCEN/ MSA & E: CSc, DSc revision 04, 04 October 2011 17 of 67

In a number of studies it has been suggested, that specially designed disease adapted enteral formulations might augment immune competence and beneficially modulate metabolic alterations associated with neoplastic disease (table 7). [4;5;16;29] Table 7: Patients benefiting from disease adapted EN 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-neck cancer Patients with therapeutic interventions promoting gastrointestinal dysfunction (extensive surgery, stomatotoxic CT) Patients with intensive RT and/ or CT due to the concomitant mucositis [30] In these patients, EN should be provided to improve or maintain nutritional status, thus contributing to the maintenance of patients QoL. [4] 3.2 Goal directed nutritional strategies in cancer patients adaption to the patients` metabolism Carefully directed nutritional support should be started as early as the first signs of reduced nutritional 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 integrated care of patients. [8] Goal directed nutrition interventions adapted to the metabolism of cancer patients aim to beneficially influence the nutrition status of the host, without supporting tumour growths. [31] 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 systemic 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 BCEN/ MSA & E: CSc, DSc revision 04, 04 October 2011 18 of 67

the host. [4;32;33] 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] A summary of possible interventions is given in table 8. Table 8: Nutritional strategies in cancer patients adapted to their metabolism: Use of fish oil providing 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] (for further details, please see chapter 4) Use of diets/ formulae high in fat, low in carbohydrates Impaired glucose tolerance as well as the alterations in lipid metabolism as seen in cancer patients support the recommendation to deliver higher amounts of fat as source of energy and increase the fat: carbohydrate ratio in feeding cancer patients. [4] Glucose utilisation in cancer patient is impaired and fat is the preferred fuel of energy. [31] Importantly, while in host tissues fat can be used normally for energy production, fat utilisation in tumour cells is poor as these cells lack key enzymes for free fatty acid and ketone body degradation. So, tumour tissues mainly utilise glucose as metabolic substrate while the host mainly favours fat as source of energy. [1;2;17;24;34] Therefore it is recommended to provide > 50 % of non-protein calories from fat. [31] Provision of high amounts of protein For the compensation of increased gluconeogenesis and increased skeletal muscle proteolysis, an increased supply of protein is recommended in cancer patients. Recommendations for optimum nitrogen supply are as follows: [4] Minimum supply: 1 g/ kg b.w./ day [35] Target supply: 1.2-2 g/ kg b.w./ day [36] Provision of high amounts of energy If patients refuse to consume the full volume of normocaloric EN, highenergy, high protein enteral formulations are to be preferred. Provision of adequate amounts of antioxidants Electrolytes, trace elements and vitamins must be supplied with EN and corresponding recommendations are based on recommended daily allowance (RDA) levels. [29] Since markers of oxidative stress have been shown to be elevated and levels of antioxidants are decreased in cancer, inclusion of adequate amounts (1-3 x RDA) of antioxidants (vitamins A, C, E, β-carotene, selenium and zinc) are suggested. [4;37] Inclusion of prebiotic, soluble fibres Due to known intestinal perturbations as a consequence of CT and/ or RT, cancer patients could profit from prebiotic, soluble fibres, such as inulin (personal communication Prof. A. Giacosa). BCEN/ MSA & E: CSc, DSc revision 04, 04 October 2011 19 of 67

4. The key nutrient in Supportan & Supportan DRINK - EPA 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 CT, it failed to improve weight, anthropometric measures, response rate, survival, or QoL. [15] 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. [20;23] Consequently, effective treatment of cancer cachexia requires correction of the underlying metabolic abnormalities. [20] 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 [15] and also the approach of delivering n-3 polyunsaturated fatty acids (PUFA) from fish for nutrition intervention seems to be promising. Being incorporated into cell membranes n-3 PUFA not just modify the formation of pro- and anti-inflammatory lipid mediators, but are also able to e.g. alter cell membrane properties, modulate membrane-linked enzyme systems and receptor functions or influence signal transduction. [38] Consequently, the provision of n-3 PU- FA from fish in cancer patients may have various effects on cancer metabolism as well as on cancer therapy. Providing EPA seems to affect a number of potential mediators of cachexia, thus beneficially modulating the cachectic process. [8;23;39]. Furthermore, besides influencing the patient s cachectic state by helping to prevent cancer associated weight loss and modulating immune response, the n-3 PUFA EPA and docosahexaenoic acid (DHA) may also improve cancer therapy efficiency and alleviate corresponding side effects. BCEN/ MSA & E: CSc, DSc revision 04, 04 October 2011 20 of 67

4.1 Metabolism of n-3 and n-6 fatty acids As mentioned above, 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 A 2 in the course of inflammatory activation is, thus, lowered. As a consequence, less AA is available for further metabolism to prostaglandins and leukotriens by cyclooxygenase and lipoxygenase in platelets and vascular cells. This means, dietary fish oil providing high amounts of n-3 fatty acids reduces formation of the n-6 PUFA derived pro-inflammatory prostaglandins and leukotriens, and increases the formation of n-3 PUFA derived anti-inflammatory homologues of these eicosanoids. [40] Further details are shown in figure 5. Pro-inflammatory Pro-inflammatory mediators mediators Leukotrienes, 4 series: Leukotrienes, Leukotrienes, 4 4 series: series: LTB 4 LTB LTB 4 LTC 4 4 LTC LTC 4 LTD 4 4 LTD LTD 4 4 Leukotrienes 5 series: Leukotrienes 5 series: Leukotrienes 5 series: LTB LTB 5 LTB 5 LTC 5 5 LTC LTC 5 LTD 5 LTD 5 LTD 5 5 AA AA C20:4 n-6 C20:4 n-6 Lipoxygenase Lipoxygenase EPA EPA 20:5 20:5 n-3 n-3 Cyclooxygenase Cyclooxygenase Prostanoids 2 series: Prostanoids Prostanoids 2 2 series: series: PGE 2 PGE PGE 2 PGF 2 2α PGF PGF 2α 2α TXA 2α 2 TXA TXA 2 2 Prostanoids 3 series: Prostanoids Prostanoids 3 3 series: series: PGE 3 PGE PGE 3 PGI 3 3 PGI PGI 3 TXA 3 TXA 3 TXA 3 3 Anti-inflammatory Anti-inflammatory mediators mediators Figure 5: Pro-inflammatory eicosanoids derived from AA and anti-inflammatory eicosanoids derived from EPA (adopted from [41]) BCEN/ MSA & E: CSc, DSc revision 04, 04 October 2011 21 of 67

4.2 Rationale for 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 CT and RT [42-45]. EPA inhibits fat and protein breakdown in animal models of cancer cachexia, [42] as well as in clinical studies. [20;43;44] 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;45] In patients with pancreatic cancer, Wigmore and colleagues demonstrated a reduced production of IL-6 and TNF- α following 4 weeks of supplementation with escalating doses of EPA (1-6 g/ day). Administration of EPA also down-regulated pro-inflammatory cytokine release and produced a fall in the CRP level, a marker of the APPR. [22] Indeed, the APPR may be stabilized in pancreatic cancer patients by means of a fish-oil enriched nutritional supplement, suggesting a profound modulation of the cachectic process. [15;43] The proportion of patients excreting PIF, a factor 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 effects 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. [46] 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 unresectable pancreatic cancer patients. The EPA containing ONS increased weight significantly after 7 weeks of treatment (figure 6) and patients tolerated the supplement well. Body composition analysis using bio-impedance analysis sug- BCEN/ MSA & E: CSc, DSc revision 04, 04 October 2011 22 of 67

gested no change in fat mass but a significant gain in LBM. 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 QoL were improved or stabilised. [47] Figure 6: Weight change of patients with advanced pancreatic cancer receiving a fish oil enriched nutritional supplement after 3 and 7 weeks. Weight gain at 3 weeks was +1 kg and at 7 weeks + 2 kg (p<0.05); From Barber et al. 1999 [47]; In order to define an effective dose of EPA, a number of studies were conducted using prescribed doses at 2 and 6 g EPA/ day [22;23;39;44;47] without any difference in the effects between these two concentrations. Therefore, 2 g EPA/ day could be considered as effective dosage. Yet, there seems to be a minimum effective dose of EPA required to achieve these beneficial 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. This is also confirmed by a current systematic review of Colomer et al. recommending an administration of > 1.5 g EPA/ d. [48] BCEN/ MSA & E: CSc, DSc revision 04, 04 October 2011 23 of 67

In a large, randomised controlled trial in 200 patients with unresectable pancreatic cancer, Fearon and colleagues compared the advantage of an ONS rich in EPA with an identical ONS without EPA. Before the intervention trial, patients were loosing weight at a median rate 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. There was no corresponding correlation in the control group. Due to the suboptimal compliance, the daily EPA dose was as low as 1.5 g/ day. [20] Above that, measurements of plasma EPA revealed that fish oil capsules had been taken also by the patients 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 enriched energy and protein dense supplement results in net gain of weight, LBM and improved QoL. This effect was confirmed by a sub-group analysis stratifying patients according to their plasma EPA levels. [49] Bruera and colleagues studied 60 weight losing 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. [50] The results indicate that 2 weeks may be too short, to induce clinically measurable effects. [4] Consequently, as demonstrated by the studies of Barber, Fearon, Wigmore and colleagues, [22;23;39;44;47] 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 7. BCEN/ MSA & E: CSc, DSc revision 04, 04 October 2011 24 of 67

Figure 7: Change in body weight of patients before and after EPA supplementation (2 g/ day; from Wigmore, 2000 [23]) Wigmore and colleagues evaluated in 26 weight losing patients with advanced pancreatic cancer 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 6 g/ 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 supplementation. 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 [23]. BCEN/ MSA & E: CSc, DSc revision 04, 04 October 2011 25 of 67

One primary goal of the nutritional supplementation with Supportan is to assure the provision of the effective dose of the key nutrient EPA, respectively 2 g/ 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 nutritional support. 4.3 Clinical evidence of EPA & DHA in cancer patients Current data 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 nutritional and functional status of the patient and thereby increasing their QoL as well as their tolerance towards therapeutic interventions. EN support of cancer patients with n-3 fatty acids containing energy and protein rich formulae, such as Supportan, intends to modulate immune response, reduce cancer associated weight loss/ cachexia, ameliorate nutritional status & dietary intake, and improve tolerance towards different cancer therapy regimens. An updated selection of various publications on the beneficial effects of EPA and/ or DHA (containing EN formulae) in cancer patients is depicted in table 9. The shown effects are also summarised below: Clinical evidence: beneficial effects of n-3 PUFA supplementation from fish Beneficial modulation of stress response and APPR Reduced proteolysis by counteracting the production of pro-inflammatory cytokines and PIF Improved nutritional status (weight gain, increase in LBM) Improved nutrition intake & appetite Improved performance status & overall condition BCEN/ MSA & E: CSc, DSc revision 04, 04 October 2011 26 of 67

Table 9: A list of selected publications on involving n-3 PUFA from fish in the dietary management of cancer patients (update August 2010); Publication Bayram et al., 2009 [51] Ryan et al., 2009 [52] Guarcello et al., 2007 [53] Fearon et al., 2006 [54] Moses et al., 2004 [55] Clinical study/ Patient population Prospective, openlabelled RCT in paediatric cancer patients receiving CT (n = 52); Double-blinded RCT in oesophageal cancer surgery (n = 53); Blinded RCT in malnourished lung cancer patients undergoing CT (n = 46); Multicentre, doubleblinded, placebo controlled RCT in advanced GI or lung cancer (n = 518); Advanced pancreatic caner patients, also included in [20] (n = 24); Enteral n-3 fatty acid application tested EPA containing ONS providing ~ 2 g EPA/ d, over 3 months; Perioperative EN regimen delivering 2.2 g EPA/ d, 5 days before surgery orally and 21 days post surgery jejunally; EPA containing ONS providing ~ 2 g EPA/ d, over 60 days; Pure EPA-diester at a dose of 2 g/ d vs. 4 g/ d, over 8 weeks; EPA enriched ONS providing 2 g EPA/ d, over 8 weeks; Effects observed at 3 months: Loss of weight * Remission rate * EPA containing ONS was safe & well tolerated; EPA levels (cells, plasma) Maintenance of LBM Stress response Good tolerance; Body weight * Energy intake * Protein intake * Appetite QoL * CRP * Promising trends for 2 g EPA/ d: Weight (in GI cancer) LBM Karnofsky Weakness However no significant benefits on survival; Remarks: This study used synthetic EPA-diester, and no marine fish oil. The compliance of lung cancer patients might have been bad, worsening the results; PAL QoL ; BCEN/ MSA & E: CSc, DSc revision 04, 04 October 2011 27 of 67

Publication Clinical study/ Patient population Multicentre RCT in advanced pancreatic caner (n = 200); Enteral n-3 fatty acid application tested EPA & AOX containing ONS providing 2 g EPA/ d vs. isocaloric/ isonitrogenous control ONS without EPA, over 8 weeks; Effects observed Fearon et al., 2003 [20] (post hoc analysis by Bauer et al. [49]) Low compliance 1.5 g EPA/ d no superiority of EPA containing ONS seen But correlations: EPA & weight EPA & LBM EPA & QoL Good tolerance; after 3 weeks: IL-6 production (by PBMC) PIF excretion Weight Good tolerance; EPA levels * Weight loss * Good tolerance; Barber et al., 2001 [56] Clinical trial in unresectable pancreatic cancer (n = 20); EPA enriched ONS providing 2 g EPA/ d; Wigmore et al., 2000 [23] Clinical trial in weight losing pancreatic cancer patients (n = 26); Escalating dose of 1-6 g EPA/ d, over 4 weeks continued as 6 g EPA/ d over 8 weeks, orally by capsules; EPA enriched ONS providing 2 g EPA/ d, over 3 weeks; Barber et al., 2000 [44] Clinical trial in weight loosing pancreatic cancer patients (n = 16) vs. healthy controls (n = 6); Clinical trial in pancreatic cancer (n = 36) vs. healthy controls (n = 6); Clinical trial in unresectable pancreatic cancer (n = 20); Weight LBM * Metabolic normalisation (fat oxidation ) Good tolerance; after 3 week: Stabilisation of APPR Weight *; Barber et al., 1999 b [43] ONS providing 2 g EPA & 1 g DHA/ d for 3 weeks; Barber et al., 1999 a [47] ONS providing 2 g EPA/ d; EPA levels (plasma phospholipids) Dietary intake * Weight * Appetite * Karnofsky status ; Karnofsky status * Survival ; Gogos et al., 1998 [46] RCT in mixed cancer patients (n = 60); 18 g fish oil capsules providing ~ 3 g EPA & ~ 2 g DHA & 200 mg Vitamin E/ d vs. placebo; Escalating dose of 1-6 g EPA/ d, over 4 weeks, orally by capsules; Wigmore et al., 1997 [22] Clinical study in unresectable pancreatic cancer (n = 6); after 4 weeks: Serum CRP * IL-6 production * (by PBMC) reduction of APPR; BCEN/ MSA & E: CSc, DSc revision 04, 04 October 2011 28 of 67

Publication Clinical study/ Patient population Clinical study in unresectable pancreatic cancer (n = 18); Enteral n-3 fatty acid application tested Escalating dose of 2-12 g fish oil/ d (< 2.16 g EPA & 1.44 g DHA/ d), over 8 weeks, orally by capsules; Effects observed Wigmore et al., 1996 [39] (reviewed in [48]) after 1 month: Serum CRP * after 3 months: Weight * EPA in plasma phospholipids No serious AE; Reduction Increase * significant Beside their beneficial effects on cancer metabolism, n-3 PUFA may also improve efficacy and toxicity of different cancer therapy regimens. Referring to the question how n-3 PUFA may modulate the tumour cell response to chemotherapeutic drugs, various mechanisms are discussed: Being incorporated in tumour cell membranes n-3 PUFA may e.g. affect membrane-associated signalling proteins or, due to their susceptibility to oxidation, cause irreversible tumour cell damage through increased lipid peroxidation. Some studies also suggest increased drug uptake by membrane alterations or even enhanced drug activation. [57] Bougnoux et al. for example, conducted an open-labelled single-arm study in 25 breast cancer patients with rapidly progressing visceral metastases to investigate the effect of 1.8 g/ day DHA in addition to an anthracycline-based CT regimen. DHA was given orally 7 10 days before initiation of CT and for further 5 months during CT. DHA supplementation was well tolerated and the outcome of CT was improved by chemosensitisation of the tumour. Thereby the authors elucidated, that patients survival was associated with the extent of DHA incorporation into plasma phospholipids. [58] However, although in cachectic patients EPA is discussed as a metabolic modulator possibly helping to improve nutritional status and although general recommendations for EN in cancer patients are given, in 2006 the authors of the ESPEN Guidelines on Enteral Nutrition: Non-Surgical Oncology state that clinical trial evidence on BCEN/ MSA & E: CSc, DSc revision 04, 04 October 2011 29 of 67

EPA supplementation is controversial and it is not possible to reach any firm conclusion with regard to improved nutritional status/ physical function [4]. Beside the new convincing data integrated in table 9, this statement might be also 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 in the studies included in the EPSEN analyses. 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 influence muscle metabolism (compare 3.2.5). The outcome of the large multi-centre trial conducted by Fearon and colleagues [20], where the ESPEN recommendations are partly based on, was invalidated by low compliance and/ or the uncontrolled consumption of fish oil capsules by the patients in the control group (compare 3.1). As stated by the authors of the ESPEN guidelines it is of utmost importance to enhance the 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, by Supportan and Supportan DRINK is given has been reduced as much as possible. Furthermore, in contrast to the ESPEN guidelines of 2006, the recently published ASPEN guidelines on nutrition support therapy during adult anticancer treatment and in hematopoietic stem cell transplantation recommend to use immunemodulating enteral formulations supplemented with agents such as [ ] n- 3 fatty acids and antioxidants for appropriate patient populations such as e.g. head-neck cancer. [27] BCEN/ MSA & E: CSc, DSc revision 04, 04 October 2011 30 of 67

4.4 Safety of EPA + DHA Intake recommendations 4.4.1 Nutrition and supplementation including fish oil in general There is some concern with regard to the use of nutrients such as n-3 fatty acids 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 Disease. [59] Based upon this review of safety, the FDA declares that: Consumption of EPA & DHA as dietary supplements is safe, provided that total daily intakes do not exceed 3 g. Gastrointestinal disturbances and nausea are the most commonly reported side effects for concentrations above this FDA determined safety limit. Decreased platelet aggregation and modest prolongation of bleeding times are reported, as well. Some evidence indicates that fish oil supplementation may enhance fibrolysis. Side effects depend on dosage, duration of supply and route of administration. 4.4.1.1 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 appear 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 BCEN/ MSA & E: CSc, DSc revision 04, 04 October 2011 31 of 67

on fish oil supplements. [60;61] 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 resulting in hemorrhagic stroke and causing oxidative damage to various tissues. [62-64] Up to now these results have not been confirmed in humans. 4.4.1.2 Impact of long-term n-3 fatty acid consumption on bleeding time 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. [65;66] Excessive cutaneous bleeding time and reduced in vitro platelet aggregation have been reported in those who ingest an average 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 Inuit 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. [67] Until today there are no sufficient data to support establishing an obligatory upper limit for EPA & DHA. Nevertheless, the proposed FDA limit of 3 g EPA & DHA per day should be taken into consideration for longterm application of fish-oil. Although excessively prolonged bleeding times and increased incidence of bleeding have been observed in Greenland Inuit, whose diet is rich in EPA and DHA, information is lacking to conclude that EPA and DHA were the sole reason for these observations. BCEN/ MSA & E: CSc, DSc revision 04, 04 October 2011 32 of 67

4.4.2 Clinical nutrition including fish oil in cancer patients & side effects 4.4.2.1 Parenteral nutrition PN with fish oil after major abdominal cancer surgery over an observation period of 5 days did not result in an alteration of coagulation and platelet function. [68] Fish oil administration up to 0.2 g/ kg b.w. per day was shown to be safe in terms of intrinsic and extrinsic coagulation and did not influence platelet aggregation. Calculated for a 70 kg patient these doses delivered up to 2 4 g EPA and 2 4 g DHA per day. However, concerning the cited study on parenteral administration of fish oil, it has to be taken into account that the application is of short term, not aiming for anti-cachectic effects. Nonetheless, it should be mentioned, that PN products such as Omegaven providing similarly high levels of EPA & DHA (up to ~ 8 g EPA & DHA in a 70 kg patient) are approved to be given over 4 weeks and considered to be safe. 4.4.2.2 Enteral nutrition No increased bleeding times or influence on vessels were reported in supplemental studies conducted with EN supplements delivering up to 2 g EPA over several weeks. No effects were also observed during the supplementation of 2 g EPA as fish oil capsules. [15;20;23;43;44;47;55] Referring to other clinical conditions, in which evidence is available that fish oil has beneficial effects on the patient s process of recovery, acute lung injury and acute respiratory deficiency can be mentioned. And also in these patient populations enteral supplementation with a fish oil containing tube feed formula delivering up to 5 g EPA and 2 g DHA per day were given without raising any safety concerns. However, also here, in most data the nutrition intervention was given only short-term. [69] BCEN/ MSA & E: CSc, DSc revision 04, 04 October 2011 33 of 67

Up to date no relevant side effects occurred concerning the use of fish oil in the clinical nutrition setting. 4.4.3 Conclusion for the use of fish oil in long-term clinical nutrition For the time being there are no sufficient data to establish a tolerable upper intake level for EPA & DHA. However, following the first n-3 fatty acid advisory board, the FDA has ruled out the intakes of up to 3 g/ day 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. [70] FDA reviewed 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 g of EPA & DHA per day. This refers to the general population and also implies long term intake. Main adverse side effects of fish oil supplements, although generally well tolerated, could be a mild gastrointestinal discomfort, appearing as a fishy aftertaste, eructation, nausea, flatulence or loose stools (table 10). Table 10: Risk evaluation of potential side effects due to n-3 fatty acid consumptions in relation to the dose administered: Gastrointestinal upset Clinical bleeding Fishy aftertaste Worsening glycaemia Rise in LDL cholesterol < 1 g/ day Very low Very low Low Very low Very low 1 to 3 g/ day Moderate Very low Moderate Low Moderate > 3g/ day 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. BCEN/ MSA & E: CSc, DSc revision 04, 04 October 2011 34 of 67

As cancer patients are receiving multiple drug treatments, side effects and the risk of interactions should be minimised. We thus postulate that the intake of 3 g EPA & DHA per day, corresponding roughly with the RDD for supplemental nutrition with Supportan and as also suggested by the FDA for general nutrition, given as long term treatment for > 8 weeks, is without any risk. Hence, the primary concept of Supportan is to provide 2 g EPA/ d for > 8 weeks for supplemental nutrition. In case Supportan is used for complete nutrition higher doses of EPA & DHA are given: < 1000 ml of Supportan tube feed provide up to 4 g EPA and 1.7 g DHA resulting in a total of 5.7 g EPA & DHA and < 1000 ml of Supportan DRINK provide up to 5 g EPA and 2.1 g DHA resulting in a total of 7.1 g EPA & DHA. As this exceeds the amounts of EPA & DHA recommended to be safe by the FDA, we recommend, that in case of complete nutrition, particularly for long term use, special medical advice and monitoring referring to high fish oil intake is performed. Nonetheless, it should be mentioned, that PN products such as Omegaven providing similarly high levels of EPA & DHA (up to ~ 8 g EPA & DHA in a 70 kg patient) are approved to be given over 4 weeks and considered to be safe. 5. Product concept and nutrient composition Nutritional therapy is an essential component of cancer management. Nutrition status has an important effect on the QoL and sense of well-being in cancer patients and weight loss in cancer patients is of prognostic significance. [29] In summary, primary goals of nutrition management in cancer patients should be (see table 11): BCEN/ MSA & E: CSc, DSc revision 04, 04 October 2011 35 of 67

Table 11: Goals of nutritional intervention therapy in cancer patients [25] Improvement of nutritional status/ prevention of malnutrition Reversal of protein-calorie malnutrition Better tolerance to treatment Decrease of morbidity Improvement of QoL Improvement of survival Specialised nutrition support is clearly indicated in cancer patients. Yet, providing EN to cancer patients, the fear might arise that, with the provision of nutrients, tumour growth and metastasis might be stimulated. [29] It is thus, of utmost importance to optimally feed the patient and at the same time to minimise the growth of tumour tissue. [71] Importantly, up to date there are no reliable data in humans showing any effect of EN on the promotion of tumour growth. [4] An insufficient nutrient supply is always more harmful for the patient than it is for the tumour [72] The nutritional goal is to prevent starvation of the patient; any attempt to starve the tumour would certainly be unrealistic. Supportan tube feed and Supportan DRINK are designed to meet the specific metabolic substrate requirements of cancer patients. Therefore the formula is: High in energy High in fat - high in fish oil (providing EPA & DHA) - with MCT Low in carbohydrates -with fibres High in protein With sufficient amounts of antioxidants BCEN/ MSA & E: CSc, DSc revision 04, 04 October 2011 36 of 67

5.1 Product concept for supplemental use The prominent feature of the product concept for Supportan tube feed and Supportan DRINK is to provide 2 g EPA per day. Consequently, Supportan was designed as a supplemental EN formula, available for both, tube feeding as well as sip feeding. This concept will ensure that patients receive the effective dose of 2 g of EPA as a one-shot pharmacological dose, which is safe and effective and enables the patient to adopt its nutrition regimes to its specific needs and wishes. Supportan tube feed is available in 500 ml EasyBags and the sip feed Supportan DRINK is packed in 200 ml EasyBottles and available in 3 flavours: cappuccino, tropical fruit and pineapple-coconut (latter flavour not launched yet). Consequently, the sip as well as the tube feed is primarily designed for supplemental nutrition by reducing as much as possible the daily volume in which 2 g EPA is given. The uptake of the effective dose of 2 g of EPA is assured within 500 ml (1 EasyBag) tube feed or 2 x 200ml (2 EasyBottles) sip feed, respectively, independently of the patients individual energy requirements. In summary, the main features of the Supportan concept are the following Providing EN supplements to ensure provision of the effective dose of the key nutrient EPA - 2 g per day Meeting the specific metabolic needs of cancer patients Low dosage volume to assure optimum tolerability and compliance The overall nutrient composition, along with the European Population Reference Intake (PRI) [73], the US Dietary Reference Intakes (DRI) [74;75] and the European legal limits are given in the annex. BCEN/ MSA & E: CSc, DSc revision 04, 04 October 2011 37 of 67

5.2 Product concept for complete nutrition Supportan tube feed and Supportan DRINK can also be used for short term complete nutrition providing high amounts of energy, protein and fish oil. For complete nutrition a thorough medical follow-up is recommended due to the high amounts of protein given per daily dosage and the low sodium concentration of Supportan. In some cases additional salt administration might be advisable. 5.3 Usage guide As mentioned above the Supportan concept was planned as a concept for mainly long term supplemental nutrition assuring the uptake of the effective dose of 2 g EPA/ day with 500 ml (1 EasyBag) of Supportan tube feed or 2 x 200 ml (2 EasyBottles) of Supportan DRINK. Additional calories should be provided according to the patients individual requirements by a standard tube feed not containing high amounts of n-3 fatty acids (e.g. Fresubin energy fibre), a standard ONS (e.g. Fresubin protein energy DRINK), PN or normal food. Examples for nutrition combinations are given in figures 8 and 9. Thereby, it is taken into respect that for long-term uptake 3 g EPA & DHA per day should not be exceeded. BCEN/ MSA & E: CSc, DSc revision 04, 04 October 2011 38 of 67

Figure 8: Example for using 2 g EPA containing 500 ml of Supportan for supplemental tube feeding in combination with a standard tube feed not providing further amounts of EPA: e.g. Fresubin energy Figure 9: Example for using 2 g EPA containing 2 x 200 ml of Supportan DRINK for supplemental sip feeding in combination with standard ONS such as e.g. Fresubin protein energy DRINK or normal food BCEN/ MSA & E: CSc, DSc revision 04, 04 October 2011 39 of 67