The inadequate nutritional status and cancer anorexia-cachexia syndrome related to it are clinically relevant since the response to antineoplastic measures, such as radiation and chemotherapy, may be diminished, their side effects aggravated and patient QoL and prognosis negatively affected. Therefore, supportive nutritional care of oncological patients is of central importance (17). An impaired nutritional status is associated with reduced QoL, lower activity level, increased treatment-related adverse reactions, reduced tumor response to treatment and reduced survival. However, a cause-effect relationship is yet to be established (18).

A link between QoL and nutritional status is supported by evidence that an insufficient nutritional status is frequently related to reduced QoL (19,20). Similarly, food intake – one of the major determinants of nutritional status – appears to influence QoL, as a correlation between them exists (21). Moreover, a low QoL is associated with nutrition-related symptoms and weight loss (22).

In curative oncology treatment, nutritional intervention aims to reduce the number of complications and to shorten the recovery phase. The probability of developing malnutrition is increased after curative treatment as aggressive therapeutic strategies are frequently used. A prolonged therapy based on patient response may further aggravate the risk for impaired nutritional status, although it should be acknowledged that tumor site and inherent nutritional risk of the treatment also contribute to the deterioration of the nutritional status. Nevertheless, alleviation of nutrition-related symptoms and signs may contribute to the well being of the patient (23,24).

In palliative oncology treatment, the aim of nutritional intervention is to sustain or enhance recovery of patient performance in everyday life, their well-being and their QoL. Palliative cancer treatment is also a system of care that strives to relieve the suffering of patients with progressive cancer. Given the intractable symptoms with which certain malignancies manifest, palliative care offers a practical approach towards improving patient QoL. However, there is an array of ethical issues associated with this treatment strategy, such as particular methods of pain relief, a reliable assessment of suffering, autonomy and multi-specialist care (25). The development of palliative care in terms of recognizing the needs of the dying has becoming a nursing and medical speciality. The involvement of the World Health Organization (WHO) in palliative care and the continuous development of treatment modalities available to cancer patients creates the expectation that outcomes for the patient should also be positively influenced (26,27). Palliative care is focused on maintaining adequate hydration, alleviating or controlling symptoms (e.g., nausea and vomiting) and maintaining body weight and composition. When selecting the type of nutritional intervention, for instance oral nutritional supplementation (ONS), enteral nutrition or parenteral nutrition, the wishes of the patient and their family must be considered (28).

Enteral nutrition (EN) by means of ONS and tube feeding (TF) offers the possibility of increasing or ensuring nutrient intake in cases where normal food intake is inadequate. There are no data from controlled studies to suggest a cancer-specific enteral formula. Standard formulas are recommended for EN of cancer patients. General information about enteral nutrition in shown in Table I (30).

The therapeutic goal for cancer patients is the improvement of function and outcome by i) preventing and treating undernutrition; ii) enhancing antitumor treatment effects; iii) reducing adverse effects of antitumor therapies; and iv) improving QoL (30).

Nutritional therapy should be initiated when undernutrition already exists or when it is anticipated that the patient may be unable to eat for more than 7 days. EN should also be initiated when an inadequate food intake (<60% of estimated energy expenditure) is anticipated for more than 10 days. It should substitute the difference between actual intake and calculated requirements.

According to recent guidelines, initiating EN in patients is indicated upon decreased oral intake (31,32). When nutritional intake is chronically reduced, then a corresponding weight loss and a worsening of prognosis are anticipated. To determine a reduced intake of normal food, a simple 24 h recall is usually adequate. If this proves difficult in individual cases, it may be appropriate to ask the patient whether his/her nutritional intake is less than 50% (low intake) or less than 25% (minimal intake) of their usual intake before the onset of the disease. In patients who are losing weight due to insufficient nutritional intake, EN should be provided to improve or maintain nutritional status (31). This may also contribute to the maintenance of QoL (30).

Omega-3 (n-3) FAs are long-chain polyunsaturated FAs with a final carbon-carbon double bond in the n-3 position, the third bond, from the methyl end of the chain. Omega-6 (n-6) FAs have a similar structure with the first double bond 6 carbons from the methyl end of the chain. Humans are unable to desaturate the n-3 or n-6 double bond and as such this makes both compounds ‘essential FAs’ which can only be obtained from dietary sources. Omega-6 fatty acid is consumed as linoleic acid or arachidonic acid found in meats and vegetable oils (safflower, corn and soybean oil). The principal dietary source of n-3 FAs is from oily cold-water fish namely eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). General interest has focused on the properties of n-3 FAs. Both omega-3 and omega-6 FAs are used as substrates for the production of eicosanoids which are a class of compounds, including prostaglandins (PGs), thromboxanes and leukotrienes intimately involved in immunomodulation, inflammation and tumor formation. Eicosanoids produced using n-6 FAs (arachidonic acid) as a substrate stimulate inflammation and tumor angiogenesis, whereas eicosanoids produced from n-3 FAs, EPA and DHA are anti-inflammatory and do not stimulate angiogenesis (33,34). The administration of fish oil reduces production of cytokines, such as IL-6, TNF and IL-1, in healthy subjects (35).

The potential benefit of n-3 FA supplementation is the effect of these fats on cachexia. Anti-inflammatory agents, such as fish oil, in combination with nutritional supplementation may reverse features of cachexia (36). Pancreatic cancer patients often develop debilitating cachexia. Certain studies have shown weight gain and improved QoL after daily supplementation of the diet with an energy- and protein-dense (610 kcal, 32.2 g protein) liquid supplement containing 2.2 g EPA and 0.96 g DHA for 8 weeks (37). Patients who consumed a supplement that contained energy and protein, but did not contain the n-3 FAs, did not gain weight.

The effects of omega-3 FAs on improvement in appetite and body weight have been studied in cancer patients (30). Takatsuka et al (38) studied 16 consecutive patients, 7 of whom received 1.8 g/day EPA orally from 30 days before until 180 days after allogeneic HSCT. EPA was found to lower the levels of prostanoids and cytokines. In addition, complications of HSCT were less and the survival rate was significantly higher in the group treated with EPA. In a short-term (2-week) placebo-controlled trial, Bruera et al (39) studied 60 weight-losing cancer patients and found no effect of 1.8 g EPA/day on appetite, tiredness, nausea, well-being, caloric intake and nutritional status or function. However, it was indicated that ingested EPA accumulates in tissues over time, and 2 weeks may be too short to induce clinically measurable effects. In a clinical study, a group of 18 weight-losing patients with advanced pancreatic cancer received oral fish-oil preparations providing approximately 2.2 g of EPA and 1.4 g of the related docosahexanoic acid daily. Before treatment, all patients experienced weight loss at a median rate of 2.9 kg/month. After 3 months of supplementation, the patients' weights stabilized, with less than half of the patients continuing to lose weight. There was no change in the percentage of total body water during the study, suggesting that patients were not simply retaining fluid (40).

The use of EPA-containing protein- and energy-dense ONS (EPA-ONS) was shown to reduce weight loss, increase lean body mass (LBM), improve functional capacity, nutritional status and QoL, however not to any greater degree than conventional supplements (41). Intention to treat patients indicated that, at the mean dose taken, enrichment with n-3 FAs did not provide a therapeutic advantage and that both supplements were equally effective in arresting weight loss. Post hoc dose-response analysis suggests that if taken in sufficient quantity, only the n-3 FA-enriched energy- and protein-dense supplement results in net gain of weight, lean tissue and improved QoL. (42). Read et al (43) indicated that after an average amount of 408 ml/day EPA for 3 weeks, a significant increase was noted in mean patient weight (2.5 kg) (p=0.03), and LBM was maintained. In the summary of this study, it was stated that dietary counseling by suitably qualified dietitians and the administration of EPA in patients with advanced colerectal cancers receiving chemotherapy, help to maintain weight and possibly improve symptom control, nutritional status and QoL.

In summary, multiple mechanisms play a role in the suppression of tumor growth by n-3 FAs. Some of the mechanisms may play a more dominant role in particular tumor types, i.e., alteration of estrogen is likely to be more important for suppression of breast than of esophageal cancer. Pre-clinical studies indicate that n-3 FAs should be beneficial for cancer treatment. Mechanistic studies indicate feasible mechanisms for the influence of n-3 FAs on tumor growth, survival and response to chemotherapy. A limited number of clinical studies indicate that n-3 FAs may be beneficial when consumed before chemotherapy. It seems important to commence human trials using an (n-3) fatty acid as a supplement to standard chemotherapy (2,44,45).

Glutamine is a non-essential amino acid with a special role in metabolism and nutrition. A number of key functions of glutamine in metabolism are shown in Table II (46). Being a precursor for nucleotide synthesis, glutamine availability is a key factor in cell growth. In the human body, glutamine availability is crucial for intestinal mucosal cells and also for immune-competent cells. When glutamine is used as an energy source, a high metabolic flow rate is present; furthermore a small fraction of that flux will be sufficient to dramatically increase the nucleotide synthesis rate. Therefore, many cells use glutamine as an energy substrate. It has been demonstrated that stressed cells have a particular preference for glutamine as an energy source. The role of glutamine for inter-organ transport is also well established (47).

An increasing number of clinical investigations have focused on the supplementation of specialized enteral and parenteral nutrition with the amino acid glutamine to improve the efficacy of nutritional support (48,49).

Endogenous production of glutamine may become insufficient during critical illness. The shortage of glutamine is reflected as a decrease in plasma concentration, which is a prognostic factor for poor outcome in sepsis. Since glutamine is a precursor for nucleotide synthesis, rapidly dividing cells are most likely to suffer from a shortage. Therefore, exogenous glutamine supplementation is necessary (50). In particular, when i.v. nutrition is administered, extra glutamine supplementation becomes critical, as most current formulations for i.v. use do not contain any glutamine for technical reasons. The major portion of endogenously produced glutamine comes from skeletal muscle. For patients who must remain for a long time in the intensive care unit (ICU), the muscle mass decreases rapidly, which leaves a tissue of diminishing size to maintain the export of glutamine. The metabolic and nutritional adaptation in long-staying ICU patients has been poorly studied and is one of the fields that requires more scientific evidence for clinical recommendations (47). To date, there is evidence to support the clinical use of glutamine supplementation in critically ill, in hematology and in oncology patients. Strong evidence is presently available for i.v. glutamine supplementation to critically ill patients on parenteral nutrition (51). This must be regarded as the standard of care. For patients on enteral nutrition, more evidence is required. Concerning the administration of glutamine, there are good arguments to use the measurement of plasma glutamine concentration for guidance. This may provide an indication for treatment as well as proper dosing. Most patients will have a normalized plasma glutamine concentration by adding 20–25 g/24 h. Furthermore, there are no reported adverse or negative effects attributable to glutamine supplementation (52).

Glutamine behaves as an essential amino acid in clinical settings where there is marked metabolic stress, such as that which occurs after HSCT (53). Glutamine supplementation in animals was found to reduce bacterial translocation and mucosal damage after chemotherapy or radiotherapy, making supplementation an attractive option for reducing post-transplant complications (54,55). There has also been a lack of an objective tool for measuring mucosal barrier injury (MBI), not only of the mouth, but also of the digestive tract as a whole, despite the fact that MBI is the most frequent cause of morbidity associated with the myeloablative-conditioning treatment to prepare for an HSCT (56). Oral mucositis is relatively easy to recognize, whereas the detection of intestinal mucosal injury has relied essentially on non-specific symptoms, such as nausea, vomiting, diarrhea and abdominal cramps, which affect almost every HSCT recipient and do not necessary reflect MBI (57).

Oral and i.v. glutamine appear to have differing effects. There is no apparent reason why this should be the case. Glutamine (i.v.), when administered with TPN, produces improvement in gut function and less gut atrophy, suggesting that i.v. glutamine has local effects on the gut mucosa. Oral glutamine appears to have no effect on mortality, infections, time to neutrophil recovery or relapses. Oral glutamine may reduce mucositis (decreased average score and fewer days of opioids and trends for less days of mucositis and less severe mucositis) and Graft-vs.-host-disease (GVHD) (which may be due to mucositis being a risk factor for GVHD) (58,59).

The administration of enteral or parenteral glutamine at doses of up to 40 g/day appears safe according to studies of patients receiving BMT and high-dose chemotherapy published to date (60). It is possible that glutamine is utilized as a growth factor in interactions between malignant tumors and chemotherapeutic drugs (61). Thus, carefully planned pharmacological studies may be required when large doses of glutamine are administered to patients receiving cytotoxic drugs. However, the available clinical data in cancer patients does not suggest that glutamine-supplemented nutrition enhances or induces tumor growth or worsens clinical outcomes. However, further study of long-term outcomes with other novel forms of therapy, is indicated to complement primarily short-term safety data available to date. Glutamine deserves further study to elucidate its interactions with methotrexate and to investigate its effects on autologous HSCT patients. Supplementation of glutamine should be considered in the design of future randomized, controlled clinical trials and in the metabolic support of individuals undergoing marrow transplantation and cancer (60,62).

Diarrhea is a common complication of enteral nutrition in cancer patients. For many years, fiber was extensively investigated for its role in preventing diarrhea; however, a more recent focus has been the investigation of specific fiber blends, including soluble fibers and prebiotics, for which there is now considerable quality evidence. Enteral nutrition may result in deleterious effects on gastrointestinal microbiota, including reductions in bifidobacteria and key butyrate producers. Their modulation by prebiotics has been confirmed in studies on healthy individuals, but convincing evidence in acutely ill patients is required (63).

The pathogenesis of diarrhea involves antibiotic prescription, enteropathogenic colonization and abnormal colonic responses, all of which involve an interaction with colonic microbiota. Alterations in the colonic microbiota have been identified in patients receiving enteral tube feeding, and these changes may be associated with the incidence of diarrhea. Preventing negative alterations in the colonic microbiota has therefore been investigated as a method of reducing the incidence of diarrhea. Probiotics and prebiotics may be effective because of their functions in modulating both the structure and composition as well as activities of both mucosa and microflora suppression of enteropathogenic colonization (stimulation of immune function and modulation of colonic metabolism) (2,64). Randomized controlled trials of probiotics have produced contrasting results, although Saccharomyces boulardii has been shown to reduce the incidence of diarrhea in patients in the ICU receiving enteral tube feeding. Prebiotic fructo-oligosaccharides have been shown to increase the concentration of fecal bifidobacteria in healthy subjects consuming an enteral formula, although this finding has not yet been confirmed in patients receiving enteral TF. Furthermore, there are no clinical trials investigating the effect of a prebiotic alone on the incidence of diarrhea. Further trials of the efficacy of probiotics and prebiotics, alone and in combination, in preventing diarrhea in this patient group are warranted (64).

Probiotics and prebiotics may beneficially affect a series of GI functions by modulating both the structure and composition, as well as activities of both mucosa and microflora (64). Potential targets and expected benefits have been identified as reduced risk for metabolic syndrome and prevention of colorectal cancer (65).

The potential effects of probiotics and prebiotics in cancer are as follows (64,66–68). i) Reversing the disruption of micro-biota and improving resistance to colonization by pathogens: Gut microflora themselves act as barriers against invasion by pathogens. Chemotherapy profoundly disturbs floral balance in a manner that potentiates colonization by pathogens, and an efficient probiotic or prebiotic may favorably modify these changes, inhibiting overgrowth of potential pathogens that cause secondary infectious diarrhea following chemotherapy. ii) Beneficially modulating the immune system: Probiotics extensively influence intestinal innate/adaptive immunity and barrier function. Probiotics and prebiotics may also directly or indirectly modulate the inflammatory cytokine network. These probiotics and prebiotics appear to enhance the gut barrier and reduce inflammatory injury by rebalancing the proinflammatory/anti-inflammatory cytokine network. iii) Enhancing production of short-chain FAs (SCFAs): Fermentation of oligofructose and insulin increases production of SCFAs, primarily acetate, butyrate and propionate, in the gut. SCFAs, the main energy source for colonic mucosal enterocytes, play a central metabolic role in maintaining the epithelial cell barrier and in repairing mechanisms that are likely important for the prevention or resolution of inflammation. iv) Drug metabolism by intestinal microflora contributes to the pharmacological profile of various drugs: Probiotics and prebiotics may modulate the pharmacokinetics of anticancer drugs by altering the composition and metabolic activity of the microflora. More research is required to determine probiotic and prebiotic modulation of bacterial enzyme activity during chemotherapy.

During the last few years, the importance of the correct nutritional assessment as a part of the therapeutic process of human pathologies has a greatly increased relevance. Still more in oncology, such a relationship between nutritional assessment and a beneficial result of the therapeutic treatment has a fundamental importance (69). There is a clear correlation between the degree of malnutrition and increased risk of perioperative complications in cancer patients undergoing surgery. It is known from various studies that the value of a variety of nutrition status parameters for predicting risk of surgical complications is important (70). Nutrition support therapy should not be used routinely in patients undergoing major cancer operations (71). For surgical patients, practical information, such as weight loss or subjective global assessment, would provide a better basis for deciding whether or not to delay surgery. At least 10 days of nutritional support is recommended in severely malnourished patients before major digestive surgery. In non-severely malnourished patients, pre-operative oral immunonutrition is associated with a 50% decrease in post-operative complications. The benefit of immune-enhancing diets in severely malnourished patients remains to be proven. For patients undergoing radiochemotherapy, dietary counseling is proposed. In cases of severely malnourished patients or if dietary counseling suffers a setback, EN should be recommended (72).

The maintenance or improvement of QoL, and the increase in the effectiveness of antitumor therapy and a reduction in side effects are further objectives in regards to cancer patients. Indications for TPN in tumor patients are essentially identical to those in patients with benign illnesses, with preference given to oral or enteral nutrition when feasible. A combined nutritional concept is preferred when oral or enteral nutrition, particularly exclusive artificial nutrition, is administered. The use of TPN as a general accompaniment to radiotherapy or chemotherapy is not indicated, but TPN is indicated in chronic severe radiogenic enteritis or after allogenic transplantation with pronounced mucositis or GVHD (73). General information regarding TPN application in oncology patients is shown in Table III (4).

The treatment aims for TPN in cancer patients (73) are as follows. i) TPN should stabilize the nutritional state and prevent or reduce progressive weight loss; ii) TPN should maintain or improve the QoL; iii) TPN may increase the effectivity and reduce the side effects of anticancer therapies.

The majority of cancer patients requiring long-term TPN are cachectic and hypophagic because of (subacute) intestinal obstruction due to peritoneal carcinomatosis. This condition is often associated with expansion of extracellular water volume, and an overzealous administration of glucose may easily precipitate a peritoneal effusion which consequently forces withdrawal of the intravenous nutrition (74).

In patients who are losing weight mainly because of an insufficient nutritional intake, artificial nutritional support should be provided to maintain nutritional status or at least prevent further nutritional deterioration. This may also contribute to the maintenance of QoL. Any such improvement in the nutritional status is usually modest and is most expected when weight loss is mainly due to hypophagia. In the presence of systemic inflammation, however, it appears to be extremely difficult to achieve whole body protein anabolism in cancer patients. In this situation, in addition to nutritional interventions, pharmacological efforts are recommended to modulate the inflammatory response (75). Patients who received the planned amounts of energy and nitrogen (given by vein when necessary) were found to exibit improved energy balance, increased body fat and greater maximum exercise capacity, in addition to prolonged survival when compared to patients randomized to support without TPN (76).

Enteral and parenteral nutrition confer a number of risks, including the physiologic stress and discomfort associated with the placement of a feeding tube or central line and complications involved in the placement or in nutrition. Infection is the most common complication of both types of nutritional support and occurs frequently with parenteral nutrition because of the high nutrient value of the infusion. Although usually easily treated, these infections often require hospitalization and insertion of a new catheter, and may lead to complications, such as subacute bacterial endocarditis. Other common complications of enteral and parenteral nutrition include metabolic problems, such as hyperglycemia and fluid, and electrolyte imbalances, diarrhea from enteral feeding and hepatic abnormalities from parenteral feeding. In the terminally ill, both types of nutrition cause fluid overload, worsening edema or shortness of breath (77).