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Nutritional support of the oncology patient

Critical Reviews in Oncology/Hematology, 2, 87, pages 172 - 200

Abstract

This review focuses on the nutritional support of the non-surgical cancer patient. The following topics are reviewed: cancer cachexia (definition and staging, prevalence and impact on clinical outcome); nutritional screening to identify potential candidates for nutritional support; nutritional requirements in terms of macro-and micro-nutrients of the advanced cancer patient.

Finally, the indications and results of nutritional support are presented with a special focus on the following issues: routes of delivering nutritional support, the use of standard or n−3 fatty acids-enriched oral nutritional supplements during radiation therapy and/or chemotherapy, tube feeding during RT (with/without chemotherapy), parenteral nutrition during chemotherapy, nutritional support during hematopoietic stem cell transplantation, (home) enteral or total and supplemental parenteral nutrition in the incurable patient.

Lastly, the bioethical aspects of feeding patients with incurable disease are briefly reviewed.

Keywords: Nutritional support, Cancer cachexia, Nutritional requirements of cancer patients, Nutritional screening, Oral nutritional supplements, Tube feeding, Home enteral nutrition, Home parenteral nutrition.

1. Background

Nutritional support should be considered for all cancer patients who are malnourished, or for those who are receiving treatment which potentially may impair their ability to eat and cause clinically significant malnutrition.

For clinical practitioners, malnutrition can be defined as an abnormal body composition with functional impairment of different organs, due to an acute or chronic imbalance between energy and protein availability and body requirements. This imbalance may be due to a reduced intake of nutrients (poor administration of food, anorexia, dysphagia, vomiting, etc.), to an excessive loss of nutrients from the gut (malabsorption, fistulas, etc.), to an alteration of the metabolic utilization of the substrates or to different combinations of these factors.

For many years, the terms “malnutrition”, “weight loss” and “cachexia” have been used interchangeably in the scientific literature. However, when referring to cancer patients we prefer to use the term “cachexia”, mainly for two reasons. Firstly, the term “malnutrition” in a broad sense would also include conditions of overweight and obesity and, second and more importantly, it suggests that the cause of weight loss is mainly a reduced intake of food, whereas in cancer patients quite often there is a combination of poor intake and metabolic alterations. Furthermore, the term “malnutrition” would imply that an adequate nutritional support is able to fully reverse the state of weight loss or emaciation, whereas in cancer cachexia the effect of a standard optimized nutritional support can only prevent a further deterioration of the general status of the patients and, for a successful outcome, nutritional support needs to be combined, at an early stage, with anabolic/anticatabolic agents.

2. Cancer cachexia

2.1. Definition and staging

A recent, consensus-based definition of cancer cachexia, published in the Guidelines for Parenteral Nutrition on behalf the European Society for Clinical Nutrition and Metabolism (ESPEN) [1] is the following:

  • - From the clinical point of view cancer cachexia is a complex syndrome characterized by a chronic, progressive, involuntary weight loss which is poorly or only partially responsive to the common nutritional support and it is often associated with anorexia, early satiation and asthenia. It is usually amenable to two main components: a decreased nutrient intake (which may be simply due a crucial involvement of the gastrointestinal tract by the tumour or by cytokines or similar anorexia-inducing mediators) and metabolic alterations due to the activation of systemic proinflammatory processes.
  • - Resulting metabolic derangements include insulin resistance, increased lipolysis and normal or increased lipid oxidation with loss of body fat, increased protein turnover with loss of muscle mass and an increase in production of acute phase proteins. The systemic inflammatory reaction that develops with many cancers is an important cause of loss of appetite (anorexia) and weight. The syndrome of decreased appetite, weight loss, metabolic alterations and inflammatory state is therefore referred to as cancer cachexia or cancer anorexia–cachexia syndrome. These cytokine-induced metabolic alterations appear to prevent cachectic patients from regaining body cell mass during nutritional support, and are associated with a reduced life expectancy, and are not relieved by exogenous nutrients alone.

Whereas this definition is a quite comprehensive consideration of the main clinical and metabolic features of cancer cachexia, it is not fit for routine use in clinical practice.

For this purpose, Fearon et al. [2] have defined cancer cachexia as characterized by three main factors: body weight loss ≥10%, nutrient intake ≤1500 kcal/day and level of C-reactive protein ≥10 mg/L. This definition is supported by a strong clinical and pathophysiological rationale, it is prognostically validated, and represents the first true attempt to define cachexia according to objective criteria.

Still it has some limitations: firstly, it defines cachexia but it does not classify it in different stages of severity; second, there is an objective difficulty in assessing the energy content of the diet of cancer patients in a non-specialist setting and without the help of a dietician, and third, this definition requires a blood test and, consequently, the need to assess the patient twice. Finally, this definition was validated in a population of patients with pancreatic cancer and not in a wide spectrum of cancer patients.

More recently, Bozzetti and Mariani [3] have defined cancer cachexia as: a complex syndrome characterized by a severe, chronic, unintentional and progressive weight loss, which is poorly responsive to the conventional nutritional support, and may be associated with anorexia, asthenia and early satiation.

At variance with previous definitions, this pragmatic statement mainly focuses on clinically self-evident features and emphasizes some specific aspects of the condition (chronic, unintentional and progressive weight loss, unresponsive to conventional nutritional support). Furthermore it includes anorexia, early satiety or fatigue, not only for their high prevalence in weight-losing cancer patients but also because their pathogenesis is closely related to the same underlying factors (interleukin-6, TNF-α, etc.) that are responsible for the derangement of metabolism and for the weight loss. Hence their presence might reflect the role of some common specific mechanisms underlying both the clinical appearance and the metabolic picture of cancer cachexia.

Depending on the degree of the weight loss and the presence/absence of one/all these symptoms, it is possible to stratify patients into 4 different classes ( Fig. 1 ).

gr1

Fig. 1 Proposed definition and classification of cancer cachexia by Bozzetti and Mariani (2009) [3] .

These classes (from 1 to 4) represent stages of progressive severity of cachexia.

Considering different groups from “asymptomatic precachexia” (class 1) to “symptomatic cachexia” (class 4), there were statistically significant trends (p < 0.0001) in the percentage of gastrointestinal vs nongastrointestinal tumours, severity of cancer stage, percentage of weight loss, number of symptoms per patient, ECOG performance status, and nutritional risk score.

In 2011, a consensus of experts [4] proposed a new classification where the cut-off between precachexia and cachexia was set at < or >5% weight loss. This classification has not been validated so far.

As mentioned previously, in many studies weight loss – which is the key marker of cachexia was often used instead of cachexia and hence many studies investigated the relationship between weight loss and many other clinical variables.

It should be pointed out that the proposed definitions have yet to be widely adopted in the scientific literature and publications dealing with cancer-related wasting often refer to such a condition as cachexia, weight loss or malnutrition.

2.2. Prevalence

As already mentioned, in many studies weight loss, which is the key marker of cachexia, was often used instead of cachexia and hence many studies investigated the relationship between weight loss and many other clinical variables.

The prevalence of weight loss ranges from 8% to 84% and it mainly depends on the cancer site and stage [5] . From a review of the more recent studies, which used a variety of different methodologies, including weight loss as sole parameter, estimates of the prevalence of malnutrition in specific groups of cancer patients are: up to 9% in urological cancer patients, up to 15% in gynaecological cancers, up to 33% in patients with colorectal cancer, up to 46% in lung cancer patients, up to 67% in head and neck cancer patients, up to 57–80% in patients with oesophageal or gastrointestinal cancers, and up to 85% in pancreatic cancer patients [6] .

2.3. Impact on clinical outcome

Longitudinal studies have demonstrated that the prognosis for cancer patients with weight loss is worse than that for weight-stable patients.

Even though tumour stage and unresponsiveness to the oncological therapy are major prognostic factors for survival, a large body of literature has shown that weight loss is a significant and often independent predictor of decreased survival in non-surgical cancer patients [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], and [28]. Undernutrition (defined as low serum albumin level), BMI < 18 kg/m2, and WHO performance index > 2, are predictive of early mortality after palliative self-expanding metal stent insertion in patients with inoperable or recurrent oesophageal cancer [29] .

A recent review by Gupta and Lis [30] of 29 papers reported that in 90% of them there was a statistical correlation between high serum albumin and survival.

Phase angle is a measure that characterizes the distribution of water between the extracellular and the intracellular spaces and is one of the most sensitive indicators of malnutrition [31] . Depletion of body proteins [36] or a bioelectrical impedance phase angle lower than the 5° percentile of the standard Refs. [32], [33], [34], [35], and [36] are also associated with a poorer survival.

Sarcopenia was found to be an independent predictor of worse recurrence-free and overall survival in metastatic colorectal cancer [37] and decreased psoas muscle density and area, and increased intra-abdominal fat, suggested decreased survival in adrenocortical cancer patients [38] .

Murphy et al. [39] reported that accelerated loss of adipose tissue begins at 7 months reaching an average loss of 29% of total adipose tissue 2 months before death and loss of adipose tissue and phospholipid fatty acids occur in tandem and are predictive of survival.

Several composite scores of the nutritional status (usually including biochemical and anthropometric parameters) showed a correlation with prognosis.

In patients with cancer of the oesophagus, Nozoe et al. [40] observed that the Prognostic Nutritional Index was a factor independently associated with long-term survival and Pedersen et al. [22] recommended that the degree of weight loss be incorporated in the conventional classification. In patients with gastric cancer, the Prognostic Nutritional Index also proved to be an independent prognostic factor [41] . Crumley et al. [42] demonstrated that the Glasgow Prognostic Score, an index ranging from 0 to 2, depending on the low level of serum albumin (<3.5 mg/dl) or a high level of CRP (>10 mg/dl), was able to predict on multivariate analysis cancer survival of patients with inoperable gastro-oesophageal cancer.

Recent experience in patients with metastatic lung cancer [43] has shown that mininutritional assessment has a higher predictive and prognostic power than simple 5% weight loss.

Malnourished cancer patients also have a poor response to chemotherapy (rate and duration) [7], [11], [21], [24], [44], [45], [46], [47], and [48]. Hadjibabaie et al. [49] observed a significant negative relationship between patient's body mass index and the time taken for engraftment in bone marrow transplantation.

There is emerging evidence that malnourished cancer patients are at higher risk for chemotherapy toxicity. Weight loss and hypoalbuminemia are associated with an increased toxicity from chemotherapy [50] .

Total body nitrogen was found to be the most powerful predictor of neutropenia after chemotherapy in breast cancer patients [51] .

Assuming that fat-free mass represents the volume of distribution of many cytotoxic chemotherapy drugs, Prado et al. [52] estimated that individual variation in fat-free mass could account for an up to three-times variation in effective volume of distribution per unit body-surface area for chemotherapy administered to cancer patients. They concluded that sarcopenia is a significant predictor of toxicity and time-to-progression in metastatic breast cancer patients treated with capecitabine. In a subsequent prospective study of colon cancer patients treated with 5-FU and leucovorin, Prado et al. [53] , showed that women who had a low proportion of skeletal muscle in relation to their body surface area had a higher incidence of dose-limiting toxicity. In this study a cut off point of 20 mg 5-FU/kg of lean body mass was a predictor of 5-FU toxicity.

Similarly, a BMI < 25 kg/m2 with diminished muscle mass is a significant predictor of toxicity in metastatic renal cell carcinoma patients treated with sorafenib [54] .

Not only was a low BMI associated with toxicity from sorafenib but there was an association of skeletal muscle wasting with treatment with sorafenib in patients with advanced renal cell carcinoma [55] . Treatment with cisplatin was also associated with adverse effects, including cachexia and anorexia, thereby perpetuating a vicious circle [56] .

Quite recently, Awad et al. [57] reported that neoadjuvant chemotherapy in patients with oesophagogastric junction cancer was associated with reductions in fat-free mass and an increase in the proportion of patients becoming sarcopenic.

Ravasco et al. [58] showed that 20–30% of quality of life performance was accounted for by nutrient intake and nutritional status, respectively, and Nourissat et al. [59] reported a significant association of weight loss with the main dimensions of the quality of life: physical, functional, cognitive, social, fatigue, nausea, pain, loss of appetite, constipation and diarrhoea in 907 cancer patients. In head-neck cancer patients, weight loss was associated with a poor quality of life [60] .

Finally, Lis et al. [61] in a recent systematic review of 26 studies on the relation between nutritional status and quality of life reported that nutritional status was found to be an independent predictor of quality of life in over 90% of patients.

Malnourished cancer patients have higher rates of hospital readmissions, longer hospital stays [23] and [62], increased symptom distress [63] and reduced quality of life [44], [45], [64], [65], and [66].

Recently, Norman et al. [67] reported that malnutrition is a disease independent risk factor for reduced muscle strength and functional status in cancer patients.

Finally, between 4 and 23% of terminal cancer patients ultimately die because of cachexia [68], [69], [70], and [71].

As a consequence, some oncologists [72], [73], and [74] recently started to incorporate maintenance of body weight as a parameter in the concept of clinical benefit.

3. Nutritional requirements

Recommendations about a “cancer-specific” nutritional regimen are especially valid in three conditions: when cachectic status is full-blown; when PN or EN are exclusive (which means that the contribution of spontaneous oral feeding is quite small) and when nutritional support is expected to last for at least several weeks. In other conditions (perioperative state, supplemental enteral or parenteral nutrition, use of oral supplements, etc.) there is less evidence that patients need a “specific” nutritional support.

3.1. Energy

Resting energy expenditure (REE) can be unchanged, increased or decreased in relation to predicted energy expenditure. The energy requirements of cancer patients should be assumed to be normal or slightly increased unless there are specific data showing otherwise. In about 25% of patients with active cancer, REE measured by the gold standard method – indirect calorimetry – is more than 10% higher, and in another 25% it is more than 10% lower than predicted energy expenditure. The extent or direction of the error cannot be predicted for individual cases [75] and [76]. In the extensive experience from the group of Lundholm [77] approximately 50% of all weight-losing cancer patients were hypermetabolic when compared with appropriate controls – allowing for similarities in physical activity, body composition and age; weight loss and hypermetabolism were not compensated for by an increase in spontaneous food intake. Even in those studies that reported no significant differences among controls and cancer patients, there were a higher ratio of measured REE/fat-free mass and measured REE/predicted REE in cancer patients [78] . There is some variability in REE depending on the different types of tumour; some authors reported normal REE in patients with gastric or colorectal cancers [78], [79], and [80] and higher than expected REE in subjects with pancreatic or lung cancers [80], [81], and [82].

The increase in REE in lung cancer patients is related to the presence of a systemic inflammatory response [83] . Gambardella et al. [84] were successful in administering propanolol and Intralipid® (Fresenius Kabi) to weight-losing cancer patients since they found a significant decrease in REE and a better adequacy of nutritional support to meet the calorific needs.

However, if we consider the total energy expenditure (TEE) which includes the resting energy expenditure plus the physical activity energy expenditure, this value may appear decreased in advanced cancer patients when compared with predicted values for healthy individuals [81] and [82] mainly because of a reduction in physical activity.

Recent data [85] and [86] reporting the use of a wearable device, the Sense-Wear ARMBAND (Sensormedics, Italia Srl) would indicate that TEE of weight-stable leukemic patients and of weight-losing bedridden patients with gastrointestinal tumours is about 24 and 28 kcal/kg/day, respectively.

There are few and inconsistent data regarding effects of cancer treatments on energy expenditure. Hansell et al. [79] studied 15 patients with colorectal cancer and did not observe any effects of curative surgery or of hepatic metastases on REE. Fredrix et al. [80] compared REE in healthy controls and 104 patients with gastric or colorectal cancer and 40 patients with non-small cell lung cancer before and 1 year after surgery. Subjects with gastrointestinal cancer had normal REE, which rose slightly after surgery, while lung cancer patients had elevated REE which fell after curative resection, although not if there was tumour recurrence. Chemotherapy treatment in twelve patients with newly diagnosed small-cell lung cancer reduced both circulating inflammatory mediators and REE [83] .

For practical purposes, and if not measured individually, total daily energy expenditure in cancer patients may be assumed to be rather similar to healthy subjects and ranging between 25 and 30 kcal/kg/day.

3.2. Choice of nutrients

3.2.1. Fat

The majority of studies addressing the metabolic utilization of substrates have been performed after/during intravenous administration to avoid any interference from an unpredictable variation in intestinal absorption following enteral administration.

In 1971, Waterhouse and Kemperman [87] showed that fat was efficiently mobilized and utilized as a fuel source in cancer patients. The rationale for the use of lipid emulsions stems from several sophisticated metabolic studies [88], [89], [90], [91], [92], [93], and [94] and relies on the following observations:

  • (a) many authors [88], [89], [90], [91], [93], and [94] have demonstrated a very efficient mobilization and oxidation of endogenous fat in postabsorptive state, which ranged from 0.7 to 1.9 g/kg/day (that is about 6.3–17 kcal/kg/day – approximately 60–78% of the resting metabolic expenditure) both in weight-stable and weight-losing cancer patients.
  • (b) subsequent investigations focused on the effect of different fat emulsions, long-chain triglycerides (LCT) and medium-chain triglycerides (MCT). After the administration of LCT or mixed LCT/MCT emulsions, the clearance of lipid was reported to be 1.4 vs 2.3 vs 3.5 or 1.2 vs 1.6 vs 2.1 g/kg/day in healthy subjects vs weight-stable vs weight-losing cancer patients, respectively [94] .
  • (c) the oxidation rate after intravenous administration of LCT or mixed LCT/MCT emulsions in weight-losing cancer patients was reported to be 1.3–1.6 or 0.62 g/kg, respectively [92] and [94].

There is, however, some concern about the potential toxicity of long-term parenteral administration of lipids. Previous studies [95] showed that the adverse effects reported with LCT emulsions occur when lipid infusion rate are greater than 2.6 g/day (that is about 20–24 kcal/kg/day), but now many authors suggest not to exceed a dose of 1 g/kg/day if parenteral nutrition is administered for some weeks.

It is important to point out that these recommendations mainly refer to the experience with soybean oil emulsions administered for periods usually exceeding 1 month; data with mixed LCT/MCT emulsions and with olive oil emulsion seem more promising.

Carpentier et al. [96] have reported 20 patients on home parenteral nutrition receiving mixed emulsions LCT/MCT for 3–6 months and with optimal liver tolerance. Rubin et al. [97] investigated, in a double-blind randomized cross-over study, the metabolic effects of a standard 20% soybean oil emulsion vs a structured triacylglycerol emulsion containing both medium- and long-chain fatty acids. No alteration of liver function occurred in any of the patients treated for one month with the structured lipid emulsion, whereas 10% of those receiving LCT emulsion developed abnormal liver function which resolved after switching to the structural emulsion. Interestingly, the lipid emulsion provided 30–50% of the daily total energy intake and was infused at a dose of 1.0–2.0 g fat/kg/day.

More recently, Simoens et al. [98] compared plasma triacylglycerol clearance of a lipid emulsion (5:4:1) made of 50% MCT, 40% LCT, and 10% fish oil (wt:wt:wt) with a control (5:5) emulsion including 50% MCT and 50% LCT. They showed that the addition of 10% fish oil in mixed emulsion particles enhanced plasma clearance of infused triacylglycerols (18%, p < 0.0001). The faster elimination of the 5:4:1 emulsion appeared related to an enhanced uptake of remnant particles rather than to faster intravascular lipolysis. Furthermore, each infusion of 5:4:1 emulsion raised the eicosapentaenoic acid (EPA) concentration in blood cell phospholipids to reach a 7-fold enrichment in platelets and a >2-fold enrichment in the white blood cells after 4 infusions.

With regard to the long-term effects of mixed soybean and olive oil emulsions [1], [2], [3], and [4], there are favourable data in the literature [99], [100], and [101] showing that administration of 0.6–1.23 g/kg/day for 3 months are well tolerated with no or minimal derangement of some liver function tests, comparing favourably with MCT/LCT emulsions.

Concerning the effects of fat infusion on protein metabolism of cancer patients, data from literature are scanty: Shaw and Holdaway [102] showed that the administration of Intralipid, a soybean-based emulsion, at about 29 kcal/kg/day, was able to significantly decrease net protein catabolism in patients with lower gastrointestinal tumours but not in those with upper gastrointestinal disease.

While there is a general agreement that glucose should not account for the overall energy load, the type of fat emulsion to be used is also matter of investigation because of the concern that excess of n−6 polyunsaturated fatty acids (PUFA), present in the classic soyabean or safflower-based lipid emulsions, might be immunosuppressive and proinflammatory.

This has led to development of alternative lipid emulsions.

Lipid emulsions based on mixtures of LCT and MCT were formulated in order to reduce the n−6 PUFA content. The n−6/n−3 PUFA ratio is similar in soyabean and mixed LCT/MCT emulsions but the content of essential fatty acids (linoleic and α-linolenic acid) of LCT/MCT emulsions is half of that soyabean-based formulations.

Another approach is the use of olive oil-based emulsions which contain about 20% n−6 PUFA (enough to supply the essential fatty acid requirements), 65% oleic acid and are rich in α-tocopherol.

In this way there is a potentiation of the anti-inflammatory action of the admixture through a down-regulation of PGE2 production, activation of peroxisomal proliferator-activated receptors [103] , and suppression of the activation of genes involved in the inflammatory process [104] .

Since chemotherapy and radiation therapy are associated with increased formation of reactive oxygen species and depletion of critical plasma and tissue antioxidants [105] , a potential benefit of olive oil emulsion could be the protective effect of α-tocopherol on lipid peroxidation.

More recently, n−3 enriched fatty emulsions have become available. There has as yet been no specific experience with such emulsions in cancer patients and their potential role will be discussed in the section devoted to the use of n−3 fatty acid enriched oral nutritional supplements.

3.2.2. Glucose

There are additional advantages to replacing glucose with lipid in the PN regimen.

Firstly, it appears wise to try to limit the infectious risk associated with hyperglycemia, which, although mainly reported in the non-oncology setting, may also be expected in cancer patients with a poor utilization of both endogenous and exogenous glucose. Furthermore, in a clinical setting it was shown that in patients undergoing allogeneic bone marrow transplantation for haematologic malignancies there were reduced rates of lethal acute graft-vs-host diseases when receiving high-LCT parenteral nutrition regimens [106] .

Finally, glucose administration tends to cause a deleterious positive water balance which is discussed in the following section.

3.2.3. Water

A restriction in water administration is advised for several reasons.

Cachexia is often associated with the expansion of the extracellular fluid volume.

If patients have peritoneal carcinomatosis an overzealous administration of water, glucose and sodium can precipitate ascites.

Gamble [107] first demonstrated that glucose reduces renal sodium excretion and, for the same reasons, the loss of extracellular fluid. Bloom [108] suggested that this effect was mediated by insulin, a potent antinatriuretic and antidiuretic hormone [109] , through an increased sympathetic activity.

The effects of a glucose-based PN on positive water and sodium balance have been demonstrated by Rudman et al. [110] and subsequently described in oncology patients by Fan et al. [111] , Bozzetti et al. [112] and Gray and Meguid [113] .

In cancer patients there may be excessive production of antidiuretic hormone (ADH) due to the tumour [114] , to the presence of nausea, which frequently occurs in advanced stages of disease, or due to the administration of morphine. Furthermore, cachexia is associated with loss of intracellular water and solutes which affect the hypothalamic osmoreceptor cells to stimulate the ADH release at levels which maintain serum osmolality and sodium levels at subnormal levels [115] . As a consequence, the clearance of free water is decreased, also because the urea load presented to the kidney is reduced secondary to protein undernutrition, whereas the synthesis of endogenous water is maintained by the oxidation of carbohydrates and fats [116] and insensible water loss drops due to reduced physical activity [117] .

According to expert opinion, the ESPEN Guidelines (European Society for Clinical Nutrition and Metabolism) [1] and [118] suggest that the total volume of fluid and sodium should be ≤30 mL and 1 mmol per kg per day. However, clinicians should be aware that no formula for estimating the water requirement is scientifically validated and that, in general, use of a weight-based formula results in a significant higher estimate of water needs than does use of an energy-based formula [119] .

3.2.4. Protein

The optimal nitrogen supply for cancer patients cannot be determined at present.

Recommendations (expert opinion) range between a minimum protein supply of 1 g/kg/day [120] and a target supply of 1.2–2 g/kg/day [121] and [122].

There are reports in the literature of an average Resting metabolic expenditure/Nitrogen ratio of 130/1 in conditions of postabsorbitive status [92], [123], [124], and [125]. Since the net protein utilization of the infused aminoacids is less than 100%, the kcal/N ratio of the nutritional admixture should decrease accordingly (kcal/N ≤ 100 ratio).

According to a recent review of the literature [126] , the dose of amino acid capable of supporting a positive protein balance should be close to 2 g/kg/day. This is in agreement with the recent investigation by Winter et al. [127] who showed that lung cancer patients with moderate cachexia had considerable insulin resistance and altered whole-body protein anabolism, but their anabolic protein response was stimulated normally by hyperaminoacidemia.

Considering the quality of proteins, Tayek et al. [128] and Hunter et al. [129] in a prospective, randomized, crossover trial involving patients with advanced intra-abdominal adenocarcinoma, concluded that branched chain amino acid-enriched total parenteral nutrition resulted in an improved protein accretion and albumin synthesis when compared with standard amino acid solutions. This approach was not subsequently explored further.

The role of a supplementation with glutamine is still controversial despite some biological rationale for its use. A recent narrative review by Kuhn et al. [130] has shown that in 24 studies evaluating the effects of oral glutamine on chemotherapy toxicity only 8 reported a clinical benefit, and in 12 studies with parenteral glutamine supplementation only six reported a reduced clinical toxicity.

According to the ESPEN Guidelines [1] there is a general consensus that “the vast majority of ambulatory or hospitalised cancer patients requiring nutritional support for only a short period of time (surgical patients, patients requiring a bowel rest for severe GI adverse effects from chemotherapy or radiation, etc.) do not need any specific formulation.”

However, special attention should be paid to patients with overt cachexia requiring nutritional support for several weeks because of the well-known abnormalities in energy and substrate metabolism in these conditions.

4. Clinical approach

4.1. Role of the oncologist

Oncologists do not feel comfortable, confident, or adequately prepared in providing nutrition counselling. This may be related to suboptimal knowledge of basic nutrition science facts and understanding of potential nutritional interventions.

A recent ad hoc survey in UK [131] has shown that 80% of specialist oncological trainees expressed uncertainty or a lack of confidence in their ability to identify malnutrition and a similar study of US radiology oncologists [132] reported that only approximately 9% of them used body weight plus other assessment tools.

Furthermore a report [133] showed that assessments of weight loss and anorexia led to interventions only 60% of the time and when interventions were recommended, only 44% were evaluated for effectiveness.

Nevertheless the proper time to start nutritional support and the best way of providing nutrients are important tasks for the oncologist. The oncologist should be familiar with the main indications for nutritional support, the choice of the more common formulations and the routes of administration, in the same way as they prescribe antiemetic drugs, antibiotic therapy or pain killers, etc. for their patients [134] .

There are several reasons for this:

  • - Cachexia (and precachexia!) are so common in both hospitalised and ambulatory patients [3], [6], [135], and [136] that it would be unrealistic, especially in Europe, to expect that dietitians or the nutrition support teams are always available for all potentially malnourished patients, rather than concentrating their efforts on patients with major nutritional problems.
  • - Only the oncologist knows the natural history of the disease of his/her patients as well as the severity and duration of toxicity of an oncological treatment, and he/she can know better than anyone if and when there may be a role for nutritional support. It is a common experience that while the best results are achieved through the nutritional support of mildly malnourished patients (precachexia), the vast majority of patients referred to the specialized units for nutritional support have an advanced state of cachexia which is often unresponsive to any treatment.
  • - Weight loss, if detected early and properly treated, may be reversed and this may translate into a better disease outcome. As first shown by Shaw and Wolfe [137] in early non-weight-losing gastrointestinal cancer patients and in normal volunteers, the basal rate of net protein catabolism, whole-body protein catabolism and whole-body synthesis were quite similar and, in both groups of subjects, glucose infusion (∼22 kcal/kg/day) resulted in a significant decrease in whole-body protein catabolism. In contrast, in advanced weight-losing gastrointestinal cancer patients, the rate of net protein catabolism was significantly higher than in either volunteers or early non weight-losing gastrointestinal cancer patients, and glucose infusion did not yield a decrease of net protein catabolism.
  • - More recently, RCTs with oral/enteral nutritional support [138], [139], [140], and [141] showed that better nutrient intake improved body weight maintenance, compliance with radiation therapy wit or without chemotherapy, and better quality of life scores were achieved in patients with minimal disease or mild malnutrition by the SCRINIO cancer cachexia classification [3] .
  • - The patients must comply with nutritional support as they comply with the oncological therapy, and this is more easily accomplished if the nutritional support is prescribed and supervised by the oncologist – whereas it is often deemed as a less important treatment if only nutritionists or dieticians are in charge of it.
  • - Finally, the modern approach to cancer is often multimodal and this combined modality is unavoidably associated with iatrogenic gastrointestinal toxicity: hence the nutritional support should be planned as a part of the combined approach.

4.2. Nutritional screening

There is a worldwide consensus that nutrition support should not be used routinely as an adjunct to chemotherapy or irradiation but only if there is a state of malnutrition or evidence of some nutritional risk. Hence it is extremely important that the oncologist be familiar with some method of nutritional screening.

Several screening tools which have validated sensitivity and specificity in cancer patients, have been the subjects of prospective clinical investigations. They are: the patient generated subjective global assessment (PG-SGA) [142], [143], [144], [145], and [146], and the nutrition risk index [145] .

The European Society for Parenteral and Enteral Nutrition suggests that the nutritional risk of cancer patients potentially candidate to nutritional support be evaluated according to the ESPEN NRS 2002. This screening system was validated against over 100 randomized clinical trials comparing nutritional support versus spontaneous intake [147] and [148] and proved highly effective in prospective clinical investigations since patients identified “at nutritional risk” had better outcome if supported nutritionally. In a recent comparison of the evidence of the main nutrition screening tools [149] , the NRS 2002 obtained the highest score and is probably one of the more suitable for cancer patients [135] . It should be also stressed that NRS 2002 has been validated for its accuracy to detect patients likely to be benefited from any means of nutritional support and not as a screening tool for malnutrition per se.

Briefly, if the patients at the initial screening have a BMI < 20.5 or they have lost weight in the last 3 months or they have a reduced dietary intake in the last week or they are severely ill, then they move to the final screening where a quantification of the previous parameters is completed and it summed with the severity of the disease. The final scoring ranges from 0 to 7, being 0 = no risk, 1–2 = low risk, 3–4 = medium risk and >5 = high risk. For age ≥ 70 years, 1 additional score is added. A score ≥ 3 is considered worth requiring a further deeper nutritional assessment for a potential nutritional intervention.

Another practical and simple way to evaluate a potential indication for nutritional support is to classify the patients according to the SCRINIO staging system [3] : patients in Stage I and II probably require oral supplements and/or antianorectic and/or anticachectic agents, especially if the oncologist foresees that the condition is going to last several weeks and progressively worsen. In Stage III and IV tube feeding (TF) or parenteral nutrition (PN) are the only ways, combined with anticachectic agents, to attempt to reverse a state of cachexia.

5. Planning nutritional support

5.1. Routes of delivering nutritional support

There are three ways of providing nutritional support: through dietary advice and counselling or oral supplementation, through enteral (tube feeding via a direct gastric or jejunal route) or through parenteral nutrition (PN) when oral and enteral routes are, for any reason, unavailable.

In some way these three approaches parallel the clinical condition of the patients.

Oral nutritional supplements are probably the commonest and less invasive way for supporting outpatients when the primary cause of weight loss is anorexia. The major indication is when patients are mildly malnourished, or they are in good condition but they are candidates for a toxic oncological therapy which will cause nausea and vomiting and upper gastrointestinal mucositis. The patients should be able to swallow and their gut should be working normally, at least during the interval between the cycles of the oncological treatment.

Tube feeding (TF) is primarily recommended when patients are malnourished (any grade), but oral feeding is not possible (upper gastrointestinal tumours, severe oral/pharyngeal/oesophageal mucositis, etc.). TF can be administered through a nasogastric tube or a gastrostomy, usually a percutaneous endoscopic gastrostomy (PEG). A recent study [150] compared TF via nasogastric tube to a PEG: weight gain at 6 weeks was better in patients with a PEG but patient self-assessed general physical condition and overall quality of life scores were similar in both groups. Similarly Sobani et al. [151] reported on a small retrospective series of patients and showed that those receiving enteral feeding via a gastrostomy had a better preservation of body weight as compared to patients fed through nasogastric tubes. A small RCT [152] showed that there were no significant differences in overall complication rates, chest infection rates or in patients’ assessment of their overall quality of life. The duration of use of PEG tubes was significantly longer, a median 139 days compared with a median 66 days for nasogastric tube and the authors concluded that there was no evidence to support the routine use of PEG tubes over nasogastric tubes in patients undergoing radiation (chemo)therapy for head-neck cancer. These findings were recently confirmed by the recent Cochrane review [153] .

In patients candidate to oesophagectomy and reconstruction through a gastric conduit, it was initially considered obligatory to avoid positioning the PEG in the greater curvature to minimize the risk of an injury to the gastroepiploic vessels. However cancer has been found to be a strong predictor for postoperative complications [154] . Despite some preliminary conflicting reports, the recent American and European experience has shown that preoperative PEG is safe and does not compromise the stomach or the oesophagogastric anastomosis [155] and [156] in patients with oesophageal cancer.

Recently Locher et al. [157] , on the basis of a comprehensive review of the literature, stated that systematic evidence assessing both the benefits and harm associated with prophylactic PEG tube placement in patients undergoing treatment for head and neck cancer is weak, and benefits and harm have not been established.

Lastly, PN is sometimes used in severely compromised patients, sometimes the very patients who would require TF, but with the difference being that their gut is not working effectively (peritoneal carcinomatosis, radiation enteritis or chemotherapy- or radiation-induced diarrhoea, etc.) or more simply because patients refuse the tube.

The recommendations which follow are in keeping with those of European Society for Parenteral and Enteral Nutrition ESPEN [1] and [118] and those of the American Society for Parenteral and Enteral Nutrition (ASPEN) [158] and [159].

5.2. Standard oral nutritional supplements (SONS) during radiation therapy (RT) and/or chemotherapy

SONS are generally used when patients are not severely compromised and maintain some ability to continue oral feeding. This explains why RCTs assessing the effects of SONS are more common than those in patients receiving TF or PN, who are aphagic and hence unsuitable for a randomization to two arms, one with nutritional support and the other without nutritional support.

The literature about the use of SONS has been recently reviewed in large meta-analyses [160], [161], and [162]. The messages from these studies were that: (1) dietary counselling alone was not able to ameliorate the quality of life of the patients. (2) Malnourished cancer patients receiving dietary counselling plus nutritional supplements (when required), gained more weight than patients receiving dietary counselling alone and both gained more weight than those who received the simple usual care, although no difference was observed after removing the studies responsible for heterogeneity. (3) Some aspects of the quality of life including emotional functioning, dyspnoea, loss of appetite, and global quality of life were improved and in this context the contribution of the works by Isenring et al. [139] and by Ravasco et al. [140] and [141] were significant. (4) Nutritional intervention had no effect on mortality.

The nutritional and clinical effects of SONS also depend on the compliance of patients with oral nutritional supplements. A recent comprehensive systematic review by Hubbard et al. [163] including 46 studies (most of them in cancer patients) has shown: (1) mean compliance was 77% and was probably better with liquid SONS which are less satiating and easier to take than solids when individual are ill, have poor appetite or are without dentition. (2) The greater compliance with higher energy density products (91% for SONS ≥ 2 kcal/ml) was likely due to the smaller volume needing to be consumed by the patient. (3) SONS had little suppressive effect on appetite and food intakes, the majority of SONS energy was additive to food, resulting in significant increase in total energy and nutritional intake. (4) Clinical benefits occurred when the intake was in the range of 250–600 kcal/day (mean pooled value 433 kcal/day).

A major contribution in this area was provided by the studies of Wallengren et al. [164] and [165]: they showed that dietary energy density was positively associated with energy balance in a large cohort of patients with advanced cancer and that survival was positively, and systemic inflammation negatively, associated with energy balance.

Regarding taste preferences, a RCT [166] has demonstrated that patients with pelvic malignancy and healthy controls rated elemental nutritional supplements as highly as polymeric supplements and significantly better than peptide supplements.

No study has demonstrated a better protection of the gastrointestinal toxicity from pelvic irradiation with the use of elemental diets as partial substitutes of the normal oral diet.

RCTs in patients receiving SONS during chemotherapy are extremely scanty partly because gastrointestinal toxicity from chemotherapy can be a major problem in patients who are candidates for SONS. A RCT in gastrointestinal cancer patients was not conclusive [167] ; an underpowered RCT investigated the role of dietary advice and/or SONS in malnourished patients receiving chemotherapy: no differences in survival, weight or quality of life between the groups were seen [168] . Similarly, 3 non-randomized trials, in breast cancer patients [169] , in colorectal and non-small cell lung cancer patients [13] and in patients with acute leukaemia did not show any benefit from oral supplementation in non malnourished patients, apart from a better preservation of the albumin serum level [170] .

Hence there is no evidence that oral nutritional supplementation is effective as an adjunct to chemotherapy.

Caloric supplementation should be given between meals to have an optimal effect [171] and the available evidence suggests that aminoacid supplements are more efficacious if given in pulse form 2 to 3 times a day.

A preclinical study by Dillon et al. [172] reported that in patients with advanced ovarian cancer, amino acids (40 g in 3 h) were capable of acutely stimulating muscle protein synthesis despite ongoing chemotherapy and an enhanced inflammatory burden.

5.3. N−3 fatty acid enriched oral nutritional supplements (n−3ONS)

In comparison with N−6 fatty acids, N−3 fatty acids (n−3FA) favour production of 3-series prostaglandins (PGE3) and 5-series leukotrienes (which are associated with improved immunocompetence and reduced inflammatory responses) and reduced levels of the PGE2 and 4-series leukotrienes (immunosuppressive and proinflammatory). In addition to the effects on prostaglandin synthesis and COX-2 inhibition, n−3 fatty acids also seem to be effective in reducing the proinflammatory cytokines involved in cancer cachexia. It has been demonstrated that administration of n−3FA-enriched diets leads to increased incorporation of (EPA) and docosohexaenoic acid (DHA) not only in liver and gut mucosa tissue, but also in tumour tissue in patients with solid gastrointestinal tumours [173] .

Although the effects of n−3FA have been studied extensively in the laboratory, in experimental tumours and in clinical practice, RCTs are relatively few. Most of them have used enriched supplements [174], [175], [176], [81], [177], [178], [179], [180], and [181] and three n−3FA capsules [182], [183], [184], and [185]. Recently, Taylor et al. [185] tested marine phospholipids (1.5 g/day) as softgel capsules for a period of 6 weeks in 31 tumour patients with various tumour types suffering from severe weight loss and reported body weight stabilization and improvement of appetite and quality of life.

Generally it was patients with advanced disease who were no longer undergoing active oncological treatment who were investigated.

There are 5 meta-analyses [186], [187], [188], [189], and [190] assessing the effects of oral n−3FA. Three of them reported that no effect was observed on weight change, quality of life or survival. It should be noted that these RCT were compromised by the poor compliance to ingest the n−3ONS preparations (unpleasant taste or too many capsules to take), the too short duration of treatment, the selection of symptomatic gastrointestinal cancer patients and the failure to combine n−3FA with adequate nutritional support.

However since these meta-analyses, further investigations have been published: Weed et al. [191] in a prospective study reported that n−3FA-containing protein- and energy-dense nutritional supplement may help increase perioperative lean body mass in patients with head and neck cancer-related weight loss. van der Meij et al. [192] recently showed, in an RCT, that n−3FA enriched supplements were able to improve the quality of life in lung cancer patients on multimodality therapy.

The more recent ASPEN Guidelines [159] state that n−3FA supplementation may help to stabilize weight in cancer patients on oral diets experiencing progressive unintentional weight loss.

Another poorly explored potential effect of n−3FA is its potentiation of antineoplastic therapy. Bougnoux et al. [193] reported a positive correlation between DHA level in breast adipose tissue of breast cancer patients and response to chemotherapy. Baronzio et al. [194] noted a longer survival and a reduction of late radionecrosis in patients receiving a mixture of bioflavonoids and n−3FA. Recent experiences from an important Canadian group [195] and [196] have shown that the daily administration of 2.5 g EPA + DHA as 4 1-g gelatin capsules per day containing 2.2 g EPA and 240 mg DHA or 7.5 mL liquid fish oil per day (containing 2.2 g EPA and 500 mg DHA) to non-small cell lung cancer patients on chemotherapy was associated with a better response to chemotherapy and a gain in muscle mass and a maintenance of body weight. Patients included in this trial were in ECOG 0–1 stage and with 4–6% weight loss.

In 2012 Miyata et al. [197] showed in a RCT of patients on neoadjuvant chemotherapy for oesophageal cancer that grade 3 or 4 leukopenia and neutropenia were significantly less frequent in patients receiving n−3ONS (600 kcal) comparing with those receiving isocaloric supplemental standard PN.

However, perhaps the more interesting contribution is that of Bayram et al. [180] who reported that feeding paediatric patients on intensive chemotherapy with a protein and energy dense nutrition supplement containing n−3FA decreased the cancer-induced weight loss and was associated with a higher remission rate at 3 months.

The use of n−3FA enriched oral supplements remains one of the most promising approaches to be further investigated combined with a proper nutritional support.

5.4. Branched chain amino acids (BCAA)-enriched oral nutritional supplements

The use of BCAA was proposed some years ago based on the rationale that increased hypothalamic serotinergic activity could play a role in the development of anorexia. BCAA might slow down the entry of the precursor of serotonin – tryptophan – into the brain by competing for the same transport system across the blood–brain barrier. Encouraging results have been reported in a pilot study where anorectic patients received oral supplementation of BCAA for a few days [198] . Poon et al. [199] investigated in a randomized fashion the benefit of a supplementation with BCAA (11 g/day) for 1 year in patients undergoing chemoembolisation for hepatocellular carcinoma. They reported lower morbidity, higher serum albumin and better quality of life than the control group. In a recent small RCT Ichikawa et al. [200] reported that the recurrence rate at 30 months after surgery was significantly lower in the in patients receiving BCAA supplementations in comparison with the control group.

Nowadays, however, there is evidence that certain BCAAs (especially leucine) can act as nutrient signals themselves to modulate cellular processes leading to an acceleration of protein synthesis through augmented initiation of mRNA translation.

The effect of an oral supplementation with a combination of β-hydroxy-β-methylbutyrate (3 g/day), arginine (14 g/day), and glutamine (14 g/day) for six months was evaluated in a double-blind fashion. Patients receiving the supplementation had a significant gain in body mass and fat-free mass whereas the isonitrogenous control group had progressive weight loss [201] .

However a subsequent larger RCT on 472 patients by Berk et al. [202] was unable to adequately test the ability of beta-hydroxy beta-methylbutyrate, glutamine, and arginine to reverse or prevent lean body mass wasting among cancer patients. Possible contributing factors beyond the efficacy of the intervention were the inability of patients to complete an 8-week course of treatment.

The use of fish oil and leucine-enriched supplements appears promising according to the recent experience of Deutz et al. [203] .

5.5. Arginine-enriched supplements

Arginine supplementation is believed to augment specific and nonspecific antitumour mechanisms, such as retarding tumour growth and prolonging survival, because arginine is essential for a normal T lymphocyte function [204] . In contrast with the appearance of arginase, decreased T cell proliferation, low expression of specific T cell receptors, and decreased production of cytokines have been observed [205] .

In a very small RCT Buijs et al. [206] showed that patients receiving arginine-enriched nutrition had a significantly better overall survival, disease-specific survival and locoregional recurrence-free survival. However it should be considered that this study included a small subgroup of patients originally enrolled in a perioperative nutrition trial and lacked any preliminary formal estimate of the statistical power of the analysis.

5.6. Tube feeding during RT (with/without chemotherapy)

At variance with studies on SONS and n−3ONS, which can be performed in a randomized fashion because the patients are not severely dysphagic and malnourished, the patient population suitable for tube feeding is quite often dysphagic because of the site of the tumour and/or the therapy-related mucositis. This often hampered a randomized comparison with a control group of patients not receiving TF. A multivariate analysis performed by Mangar et al. [207] showed that the most significant categorical predictive parameters for reactive enteral feeding in patients with head-neck cancer were stage III-IV disease, PS 2–3, and smoking >20 cigarettes/day. Combined modality treatment (induction chemotherapy and chemoradiation) results in a higher proportion of patients requiring enteral feeding (66–71% compared to 12% for radiotherapy) [163] and [208].

Silander et al. [209] showed that prophylactic PEG was associated with significantly earlier start and longer use of enteral nutrition, fewer malnourished patients over time, and improved the quality of life at 6 months posttreatment start. Additionally, Osborne et al. [210] reported that most patients with a PEG had a positive or neutral experience and would recommend PEG to patients in similar situations.

Recently Salas et al. [211] reported that mildly malnourished patients with unresectable head-neck squamous cell carcinoma (III–IV stage) undergoing radio-chemotherapy and receiving a prophylactic gastrostomy, had significantly higher quality of life comparing with patients randomized to no prophylactic gastrostomy at 6 months. However the sample size was small (n = 40) and no differences were found at 6 months for mortality, locoregional control or change in BMI.

In one prospective [212] and several retrospective [213], [214], [215], and [216] studies TF was shown to significantly reduce weight loss compared with normal oral alimentation; this was also seen when RT was combined with chemotherapy [217] . As a consequence, quality of life could be maintained [218] , interruptions of treatment could be prevented [215], [218], [219], and [220] and frequency of hospital admissions could be reduced [220] and [221]. Paccagnella et al. [222] reported that early nutritional intervention in patients with head-neck cancer receiving chemoradiotherapy resulted in an improved treatment tolerance and fewer admissions to hospital. A recent study [223] has shown a correlation between the level of Il-6 and Il-8, the severity of mucositis and the further need of a PEG.

Jenkinson et al. [224] reported a retrospective review of their protocol to place a feeding jejunostomy at the time of a laparoscopic staging in the preoperative period, with the mean time between placement and surgery of 10.4 weeks. Patients who received jejunostomy feedings were more likely to maintain or increase their weight (70%) comparing with patients who did not receive nutritional support via the jejunal route (35%).

In conclusion, the routine use of TF during radiotherapy or a combined therapy is not recommended but there is some evidence that TF is beneficial in malnourished dysphagic (mainly head and neck) cancer patients undergoing RT alone or combined with chemotherapy.

Nutritional status can be better preserved (or restored) and compliance with oncological therapy is improved.

5.7. Parenteral nutrition during chemotherapy

A systematic review of the RCTs assessing nutritional interventions accompanying chemotherapy published in 2001 [225] showed not only no benefit but possible harm when PN was given as an adjunct to chemotherapy in patients who were neither uniformly malnourished nor hypophagic.

If the few studies [226], [227], [228], and [229] that have included some malnourished patients are considered, benefits on body weight gain, on the level of prealbumin and on the drop in serum albumin level were observed.

Sikora et al. [230] performed a retrospective review of 30 oesophageal cancer patients, that were unable to maintain oral diets but received TPN during neoadjuvant therapy. The TPN patients tolerated a higher total dose of chemotherapy and had surgical outcomes similar to those who were able to maintain oral diets. A very small retrospective study on cancer patients receiving chemotherapy by Richter et al. [231] reported that a timely onset of PN with sufficient calories leads to an improved nutritional status evaluated through bioimpedenzometry (phase angle, body cell mass, extracellular mass, etc.). PN enhanced the quality of life and the administration of anti-tumour therapy without interruption. For late-stage tumour patients they reported some improvement in the quality of life.

A recent small RCT of glutamine supplementation (30 g/day) in patients receiving chemotherapy for acute leukaemia [232] showed that parenteral supplementation enhanced neutrophil phagocytic function, maintained nutritional status and was cost effective.

In conclusion, both the ESPEN [1] and [118] and the ASPEN [159] Guidelines state that “the routine use of PN during chemotherapy is not recommended. However, if patients are malnourished or they are facing a period of longer than a week of starvation and where enteral nutritional support is not feasible, PN is recommended.

Where patients develop gastrointestinal toxicity from chemotherapy or radiation therapy, there was a general consensus that “short-term PN is usually better tolerated (and efficient) than EN to restore the intestinal function and to prevent a nutritional deterioration”.

The effects of long-term home parenteral nutrition (HPN) in outpatients receiving chemotherapy are discussed in the following sections.

5.8. Nutritional support in hematopoietic stem cell transplantation (HSCT)

After autologous transplantation patients are generally not in need of nutritional support because nutritional intake is restricted for only a short time.

However, patients undergoing allogeneic HSCT are prone to develop malnutrition because of the underlying disease, the conditioning regimen and other treatment-associated toxicities to the GI tract [233], [234], [235], and [236]. Malnourished patients receiving HSCT have excessive morbidity and mortality [233], [234], [235], and [236]. Moreover alterations in nutritional state may persist several months after transplantation and about 50% of patients are still below their usual body weight at 1 year [235] .

According to a review of this issue, Mesejo Arizmendi et al. [237] reported that when the prevalence of malnutrition was considered as the only indication for PN administration, up to 37% of autologous transplant recipients who did not receive irradiation, up to 50% of autologous transplant recipients undergoing full intensity conditioning, up to 58% of allogeneic transplant recipients undergoing full intensity conditioning and up to 92% of allogeneic transplant recipients with irradiation and HLA-non compatible donors may have an indication for PN.

According to the ASPEN Guidelines [159] nutritional support is considered appropriate in patients undergoing HSCT who are malnourished and who are expected to be unable to absorb adequate nutrients for a period of 1–2 weeks (General consensus)

Evaluating the risks and benefits of PN in HSCT patients is difficult because of patient and treatment heterogeneity.

There are 7 RCTs where PN was compared with EN [238], [239], and [240], with a standard oral diet (SOD) [241] or with intravenous fluid alone (IVF) [242], [243], and [244].

The use of peri-transplant enteral feeding (usually a TF) after conditioning regimens has been investigated in 3 RCTs [238], [239], and [240] and compared with PN or a combination of PN and EN. In general, less hyperglycemia and less diarrhoea were reported [238] and [245] with EN and no other effects were observed. However, the enteral approach and the delivering of EN poses formidable problems [233] owing to coagulopathy, the risk of aspiration pneumonia, sinusitis, delayed gastric emptying and vomiting, diarrhoea, ileus, and/or abdominal pain.

According to many authors [244], [246], and [247] PN is the preferred way of nutritional support. EN is a safer approach as a transition step from PN to an oral diet once GI function has recovered or in patients suffering from late complications such as graft vs host disease.

ESPEN guidelines [1] suggest that, “especially in allogeneic HSCT PN may be preferred to EN”.

A study of PN vs SOD [241] in non-malnourished breast cancer patients undergoing autologous HSCT showed an improved nutrition state and preservation of lean body mass in the PN group with no other clinically important differences.

Comparisons of PN with intravenous feeding (IVF) [242], [243], and [244] demonstrated earlier resumption of oral intake with IVF and less weight loss in PN group [242] but no difference in morbidity [244] . No differences were reported by Jonas et al. [243] . Weisdorf et al. [244] reported a positive effect on mortality in patients on PN receiving allogeneic (but not autologous) HSCT comparing with those infused with IVF. There was no difference in GVHD between groups but HSCT patients had higher prevalence and earlier onset of bacteremia.

In conclusion, ESPEN Guidelines [118] recommend that “standard PN should be reserved for those with severe mucositis, ileus or intractable vomiting (General consensus)”.

Finally, the effects of PN composition on outcome has been investigated: there was no benefit with the use of high amino acid infusion (2 g/kg/day) [248] , while the use of PN regimen with 80% of non-protein energy from fat might reduce the graft vs host disease compared with a glucose-based formula [106] .

The addition of glutamine to the PN formula [249], [250], [251], [252], [253], [254], [255], [256], and [257] or as an oral preparation [258], [259], [260], [261], and [262] has been extensively investigated in RCT.

The results suggest that that there was a decreased frequency of severe mucositis in patients receiving glutamine-supplemented PN, a finding not seen with oral glutamine. In a recent Cochrane review, Murray and Pindoria [263] concluded that PN may be not associated with a shorter hospital stay, but with a benefit of fewer bloodstream infections.

According to the ESPEN Guidelines [1] HSCT patients “may benefit from glutamine-supplemented PN”.

Whether neutropenic HSCT patients should avoid foods associated with an increased risk of infections has been investigated through a few RCT [264], [265], [266], and [267]. There is no convincing evidence of a benefit, nevertheless ASPEN [159] suggests “that it seems prudent to continue to provide dietary restrictions on high-risk foods, during the period of neutropenia, while paying attention to the palatability of food in this population of anorectic subjects”.

As regards the GVHD there are no data on the impact of the nutritional support on the resolution of this condition, whereas its occurrence has been positively associated with a glucose-based regimen of PN [106] and decreased by enteral nutrition [240] and [244].

ASPEN [159] suggests that “nutritional support be used to maintain/improve the nutritional status during prolonged nutritional deterioration resulting from GVHD”.

5.9. Comparing EN with PN

Only a few studies that are randomized [268], [269], and [270] or prospective and controlled [270] , have compared short-term EN with PN ( Table 1 ). They showed that PN was more effective than EN in promoting weight gain [270] even though this gain may be simply due to accrual of fat or water. PN, however, was able to maintain a better nitrogen balance and plasma amino acid level [268], [269], and [270] and a positive balance of K, Na, Cl, P and Mg [271] .

Table 1 Prospective studies on the metabolic effects of EN vs TPN.

Nutritional parameter EN TPN p
Balance of      
 N pos pos  
 P pos more pos 0.05
 K neg pos 0.05
 Na neg pos 0.05
 Cl neg pos 0.05
 Ca pos neg  
 Mg neg pos 0.05
Δ H2O pos pos  
Δ Albumin no change pos  
Δ CHI pos pos  
Δ TSF pos pos  
Δ MMA pos pos  
 
N balance pos after 7 days pos after 1 day  
Weight ↑ 1% after 30 days ↑ 6% after 30 days  
Albumin ↑ 7.4% ↑ 6.3%  
 
Glucose turnover rate ↑ × 4 ↑ × 4  
Gluconeogenesis from alanine suppressed suppressed  
Plasma amino acid level maintained increased  
 
Weight no change 0.05
N balance no change 0.03
Albumin no change  
Transferrin no change no change  
Ceruloplasmim no change no change  
TBK no change no change  
3 Met-His no change no change  

Nixon (1981): EN vs TPN (kg/day): 38 kcal and 0.9–1.2 vs 1.2–1.8 g AA.

Lim (1981): EN vs TPN (kg/day): 63 vs 62 kcal and 2.1 vs 1.5 g AA.

Burt (1983): EN vs TPN (kg/day): 49 vs 49 kcal and 1.5–2 vs 2.5 g AA.

CHI, creatinine/height index; TSF, triceps skinfold; MMA, muscle mass area; TBK, total body potassium; 3 Met-His, 3 methylhistidine.

Burt et al.’s study [270] did not find any difference between PN and EN as far as whole body flux, protein synthesis and catabolism were concerned. During the control (basal) period, whole-body protein catabolism was uniformly and significantly higher than synthesis and during the period of nutritional repletion through EN or PN the rate of whole-body synthesis tended to be greater than that of catabolism. Furthermore, during the administration of nutritional support, the percentage of nitrogen entering the metabolic pool that was derived from catabolism of protein was significantly decreased in both EN and PN groups.

A study by Dresler et al. [272] has shown that before nutritional repletion, the flux of nitrogen entering the metabolic pool originated only from the breakdown of body protein and about 75% of this flux was utilized in protein synthesis. However, when an exogenous supply of aminoacids was introduced in cancer patients, utilization efficiency decreased to 58% during EN, and to 39–43% in cancer patients during PN. Therefore, there appeared to be an advantage of the enteral route in terms of utilization of nitrogen for synthesis of body proteins.

Overall, both EN and PN tend to stabilize the nutritional status and whole-body protein economics and there appears to be no clear general advantage of one mode over the other.

5.10. (Home) enteral nutrition in the incurable patient

Some advanced cancer patients, especially those with an incurable upper aero-digestive tumours which precludes oral alimentation may die from progressive starvation, that is, they will die with the tumour but not because the tumour. Long-term nutritional support may be provided enterally at home (HEN), usually through a gastrostomy.

In patients undergoing long-term nutiritional support, usually at home, both length of survival and quality of life are important.

Survival rates in series of patients receiving HEN is reported in Table 2 [273], [274], and [275]. It is noteworthy that in some of them survival at 1-year is around 30%. Moreover data from the British Artificial Nutrition Survey show that in patients with upper gastrointestinal cancer the 1-year survival is 70–80% [276] , and in the series of the Nice Group [277] and [278] the 1-year and the 4–5-year survival rates were 38.8 and 21.7–23.8%, respectively. The disparity in the composition of the series and indications for home artificial nutrition (some series mix together patients with incurable cancer and patients with irreversible sequelae to the upper digestive system from surgery and/or radiotherapy) can account for different survival rates in reports on patients receiving HEN or HPN.

Table 2 Survival of cancer patients on HEN.

Author Year Patient number Survival
Howard (1993) [273] 1985–1990 1296 32% at 1 year; mean/median 6 months
Howard et al. (1995) [274] 1989–1992 1644 41% at 1 year
Gaggiotti et al. (2001) [275] 1992–1999 3690  
Mean survival (months) Type of tumour
18.3 Head and neck
13.5 Oesophagus-stomach
21.8 Colon-rectum
16.8 Biliary
10.7 Lung

The studies on quality of life provide data that are somewhat discouraging.

It has been estimated that 10% of head and neck cancer patients finally require permanent enteral nutrition [279] because of the site of the tumour and also the long-term effects of chemoradiation therapy which severely interfere not only with chewing, swallowing and oral intake of nutrients but also with quality of life in general [280] .

Ravasco et al. [281] , in a recently published well-documented review on cancer wasting, quality of life and response to nutritional support, emphasize that reduced energy/protein intake and weight loss are independent determinants of quality of life.

There are specific difficulties in assessing quality of life in cancer patients: first, individuals may be at different time points of the trajectory of their illness and expectations are likely to change over time [282] and [283]. Secondly, a prospective study [284] in terminally ill cancer patients demonstrated a limited concordance in quality of life assessments between patients and their primary family caregivers.

Although initial studies in patients with PEG feeding [285] reported an improvement in quality of life, Rogers et al. [286] reported interesting research where they compared the quality of life of three groups of patients operated on for head-neck cancer: patients who never had a PEG as part of their treatment; patients who had their PEG removed after a while and patients who still had a PEG (median 34 months). Patients harbouring a PEG had significant deficits in all quality of life domains in comparison with non-PEG or PEG-removed patients and they also had a much poorer quality of life. Interestingly, the major PEG-related problems were not those of discomfort, leakage or blockage, but the daily interference with family life, intimate relationships, social activities, and hobbies.

Paccagnella et al. [287] prospectively investigated the effects of HEN in on quality of life of patients and in their primary caregivers after a mean period of 19.2 months. They used a questionnaire comprising 27 items (The Satisfaction Profile) measuring satisfaction of psychological functioning, physical functioning, social functioning and sleep/eating/leisure. In addition, all subjects were asked to list the 5 main advantages and 5 main disadvantages of EN.

They reported that the Satisfaction Profile Score of females was similar to the normative standard scores but, by contrasts, males showed depressed scores for physical functioning and sleep/eating/leisure. When they looked at main advantages of the EN, less than one third of patients reported an improvement in some physical feelings and in the management of eating functioning but almost half of them complained of a severe limitation in autonomy and one quarter complained the loss of oral function.

Generally, it could be concluded that in this group of patients, disadvantages outweighed the advantages. Quality of life in males was moderately depressed as compared with the ‘reference’ standard. These findings are in agreement with the previous studies of Roberge et al. [288] who demonstrated in a prospective study that functional scores and symptoms were unchanged or slightly improved after 28 days of tube feeding.

In contrast, only the female caregivers showed lesser scores for psychological and physical functioning and sleep/eating/leisure, while males were comparable to standard values. The main advantages recognized by caregivers were the benefit in physical feelings of their patients (44%) and in management of eating functioning (33%); less disadvantages were noted in limitation of autonomy (27%) and in complications of therapy (23%).

It clearly appears that not only is there a dissociation between patients and respective caregivers regarding the appreciation of advantages and disadvantages of home EN on quality of life, but also that quality of life of both patients and caregivers should deserve attention.

On the whole, the data show that patients while recognizing that PEG had been life-saving, found that the tube feeding finally came to dominate their lives and was associated with an appreciable burden of treatment [289] .

The ESPEN Guidelines [118] suggest that “EN should be provided in order to minimize weight loss, as long as the patient consents and the dying phase has not started (General consensus)”.

5.11. (Home) parenteral nutrition in the incurable patient

Early experiences on home nutrition date back to the early 1990s [159], [290], and [291]. The recommendations concerning whether an aphagic, (sub)obstructed incurable cancer patient should be supported through HPN is an extremely controversial topic. Clinicians know well that patients with benign intestinal failure may survive several years thanks to HPN, whereas incurable cancer patients always will die after weeks or months despite HPN. Hence, in a period of financial constraints for the Public Health System and the consequent need of rationing resources, some countries, especially in North Europe, do not accept incurable cancer patients for in HPN programmes.

However, there are at least two facts that, besides the cultural/religious discrepancies among different countries, represent a continuous stimulus for a further assessment and refining of the potential indications for HPN. Firstly, in our western society there is a growing number of cancer patients who survive in a chronic condition of starvation and cachexia. Second, there is an open debate [292] and [293] as to whether artificial nutrition has to be considered as therapy (and hence strictly regulated according to the existing medical indications/contraindications) or whether it should considered a basic support that needs to be in some way, always guaranteed [294] – even if scientific evidence of efficacy on the basis of RCTs does not exist and cannot exist for ethical reasons.

5.12. Natural history of the incurable cancer patient and prevalence of HPN

Cancer cachexia occurs during the terminal course of disease in approximately 70% of patients with cancer and it is recognized as the cause of death in 5–23% [68], [69], [70], and [71] of terminal cancer patients.

Anorexia, hypophagia and continuing negative energy balance are prominent features of cachexia. Hypermetabolism and weight loss are significant predictors of decreased survival [77] . These factors may explain why cancer patients account for a high percentage – sometimes even the majority – of the subjects enrolled in HPN programmes.

Registers of HPN patients in various countries report the following figures for cancer patients: Italy 57% (De Francesco 1995), Japan 55% [295] , USA 46% [274] and [296], and France 18% [297] . In a European survey of 500 patients receiving HPN in 1997 [298] , it was found that cancer patients accounted for 60%, 39%, 27%, 23%, 8% and 5% in The Netherlands, Spain, France, Belgium, Denmark and United Kingdom, respectively.

In Italy the prevalence of HPN in adults is 22.3 per million inhabitants and cancer patients account for 60.9% (13 per million inhabitants) [299] .

5.13. Clinical outcome

The main series reporting outcome of HPN are summarized in Table 3, Table 4, and Table 5.

Table 3 HPN survival: retrospective selected series.

Author No. patients Outcome and median survival
Weiss et al. (1982) [300] 9 67% ≥6 months (15–578 days)
Hurley et al. (1990) [301] 9 13.6 months (mean)
August et al. a (1991) [302] 17 53 days (5–208), 88% felt HPN beneficial
King et al. b (1993) [303] 61 60 days 82–780), 23% ≥30 days
Mercadante (1995) [304] 13 3–121 days (23% ≥30 days)
Cozzaglio et al. (1997) [305] 75 121 days (30–456)
Pasanisi et al. (2001) [306] 76 74 days (6–301), 85% ≥30 days
Duersken et al. (2004) [307] 9 26–433 (2 > 1 year)
Hoda et al. (2005) [308] 52 152 days (30–4620), 31% ≥1 year
Brard et al. (2006) [309] 28 72 days
Santarpia et al. (2006) [310] 152 45 days (6–1269), 11%≥90 days
Chermesh et al. (2011) [311] 38 140 days (20–783)

a 33% fistulas, 22% radiation enteropathy.

b 18% small bowel syndrome/radiation enteropathy.

Table 4 HPN survival: prospective studies.

Author No. patients Outcome and survival
Pironi et al. (1997) [299] 29 85 days (mean), acceptable compliance in 90%
Bozzetti et al. (2002) [312] 69 122 days (median) (30–426)
Violante et al. (2006) [313] 140 81 (mean)

Table 5 Database and registry data on HPN.

AUTHOR No. patients OUTCOME and SURVIVAL
Howard et al. (1991) [296] 777 50% at 6 months,25% at 1 year
Howard (1992) [314] 1362 50% at 6–9 months, 25% at 1 year
Howard et al. (1995) [274] 2122 37% at 1 year
Messing et al. (1998) [297] 524 19% at 6 months
Bakker et al. (1999) [315] and Van Gossum et al. (1999) [298] 200 26% at 6–12 months
SINPE Register (2004) [316] 1103 20% at 1 year, median 6 months

The literature shows that:

  • (a) in large series from national databases or registries on long-term PN in cancer, 19–50% of patients survive at 6 months, even if we cannot be sure that these figures apply to incurable cancer patients ( Table 5 ).
  • (b) in retrospective analyses of more limited series – which however include probably incurable patients – the mean survival is about 82 days, but there are long survivors ( Table 3 ).
  • (c) in the few prospective studies that have been published, again the mean survival was 85–122 days ( Table 4 ).

The recent experience of Fan [317] in 115 patients with malignant obstruction admitted to a palliative care unit, showed the median time from initiation of PN to death was 6.5 months.

Since the data from the literature have also shown that cancer patients with malignant obstruction have a median survival of 41 days if unsupported with PN [318] and only 19 days if they are at home [319] , regardless of their stay in a surgical unit or a palliative care unit ( Table 6 ), it would appear that HPN might benefit some of these patients. The major challenge is how to select patients with a tumour stage/spread which would allow them to survive at least 3 months. In fact, it is known that healthy people on total protein-energy deprivation barely survive 2–3 months [330], [331], and [332]. Any benefit from HPN cannot be expected if a patient's life expectancy is only a few weeks because of the cancer, that is this patient is more likely to die from the disease than from progressive starvation. Prognostic factors for survival include: Karnofsky Performance Status (KPS) [299], [305], [312], and [333]; serum level of albumin at initiation [306] ; presence of pain; vomiting and low serum level of cholinesterase [334] .

Table 6 Survival of patients with inoperable malignant obstruction.

AUTHOR No. patients Survival (mean), days
Tunca et al. b (1981) [320] 27 33
Piver et al. b (1982) [318] 11 60
Krebs and Goplerud b (1983) [321] 14 <30
Baines et al. (1985) [322] 40 87
Gemlo et al. (1986) [323] 27 60
Rubin et al. b (1989) [324] 11 54
Hardy et al. a (1998) [325] 39 75
Laval et al. a (2000) [326] 58 41
Ripamonti et al. a (2000) [327] 17 11
Mercadante et al. a (2000) [328] 18 2–37
Mystakidou et al. a (2002) [329] 68 7–61

a In palliative care units receiving symptomatic agents.

b Patients with ovarian cancer.

Predictions of length of survival in general, have proven to be poor in several studies [117], [335], [336], [337], [338], [339], [340], [341], and [342] with just a few exceptions [343], [344], and [345]. Caraceni et al. [344] have shown that patients with a favourable palliative score (<5.5) have >70% probability of surviving 2 or 3 months depending on the presence or absence of delirium. However, in a prospective investigation [346] in which 343 physicians were asked to estimate the length of survival of 468 patients there was an overestimation of the survival by a factor of 5.3. Overall, the patients had a median survival of 24 days. Only 20% of the predictions were accurate, i.e. within 33% of the number of days that the patient actually survived; 63% were optimistic and 17% were pessimistic.

This tendency to overestimate the survival time has long been recognized [347], [348], [349], and [350]. It is interesting to note that physicians in the upper quartile of practical experience were the most accurate, which lends weight to the supposition that the senior director of care may be best placed to make these judgements [346] .

Unfortunately, accuracy is generally higher when predicting a short-term survival, Delirium is a strong indicator of short-term survival [345] and [351]; prediction is definitely worse when considering patients who are not imminently dying.

However it may be difficult to apply these scores to patients who are potential candidates for HPN, because some of these indices include variables such as dysphagia or weight loss that are per se responsible for nutritional deterioration – apart from reflecting the severity of the disease – and that could be partially reversed through nutritional support. Therefore, a judicious use of HPN in this setting requires careful clinical assessment on a patient-by-patient basis [352] .

5.14. Quality of life

HPN should not be provided with the presumption that it will prevent hunger or thirst. These symptoms are rarely experienced by terminally ill cancer patients [353] and even in less advanced conditions patients are usually anorectic.

Thirst, if present, is not always a consequence of dehydration and may be managed with assiduous mouth care. These points should be explained to the patient and to the family.

Two studies have investigated the quality of life of these patients retrospectively [303] and [305] and one prospectively [312] . King et al. [303] reported that HPN produced an overall improvement in quality of life compared with the pre-HPN period. Morale and social interactions improved as did gastrointestinal discomfort, nausea, vomiting and fatigue. Sixteen percent of patients worked outside the home and 6.6% were able to undertake recreational travel. However, this study has some flaws because the quality of life assessment was based on the impressions of clinicians who undertook a retrospective review of patient case notes using an arbitrary scoring system. Cozzaglio et al. [305] also reported improved quality of life for patients who survived for more than 3 months on HPN. Again this was based on clinicians’ judgement rather than patient participation. Bozzetti et al. [312] studied prospectively 69 Italian patients and measured quality of life using the Rotterdam Symptom Checklist, a validated cancer-specific tool at the start of HPN, then repeated this at monthly intervals. Fifty percent patients complained of worries, tension and desperate feelings about the future. Anorexia, tiredness, lack of energy and decreased sexual interest were also present. Most patients were unable to do housekeeping, climb stairs, do odd jobs, walk outside and go to work or they needed help to do these activities. Yet, when asked ‘how are you today’, 58% answered ‘well’. After one month on HPN around half the patients deteriorated; 40% improved and the rest remained the same in terms of physical, psychological and activity assessments. Both the Italian studies [305] and [312] demonstrated improved or stabilized quality of life for patients surviving longer than 3 months although this deteriorated during the last two months of life. This indicates that for HPN to impact positively on quality of life a patient needs to survive for at least 3 months. Both studies used the KPS to follow the course of a patient's illness. Those with the highest score at the time of tumour diagnosis tended to have the best survival and quality of life over the course of their illness

In conclusion, HPN may be recommended in incurable cancer patients who cannot be fed orally or enterally (a) if it is estimated that they will die from starvation prior to dying from tumour progression, mainly because of (sub)obstruction and aphagia, (b) if their performance status and quality of life are acceptable, and (c) if there is a strong patient and family motivation for a demanding procedure which has not yet been fully validated as to outcome [354] and [355].

The ESPEN Guidelines [1] recommend “that in case of intestinal failure long-term PN should be offered, if (1) oral/enteral nutrition is insufficient, (2) expected survival due to the tumour spread is longer than 2–3 months, (3) it is expected that PN can stabilize or improve performance status and quality of life, and (4) the patient desires this mode of nutritional support (Expert opinion)”.

5.15. Supplemental parenteral nutrition

Supplemental parenteral nutrition refers to a partial parenteral nutritional support to patients who are not fully aphagic and maintain some capability to nourish orally by themselves. Consequently, in this patient population it is possible to perform an RCT, however, there are few studies on this specific topic [259], [355], [356], [357], [358], and [359]. Lundholm et al. [356] and [357] tested a “supplemental” PN in 309 weight-losing patients with solid tumours (primarily gastrointestinal lesions) and with an expected survival of at least 6–12 months or longer, using a multimodal palliation which included COX inhibitors (usually indomethacin, 50 mg twice daily), erythropoietin (15–40,000 units per week) and insulin (0.11 units/kg/day). They showed that on an intention-to-treat basis patients randomized to receive supplemental nocturnal home PN (20–25 kcal/kg/day; 0.10–0.15 g nitrogen/kg/day) had an improvement in energy balance (p < 0.03) and the as-treated analysis demonstrated a prolonged survival (p < 0.01), improved energy balance (p < 0.001), increased body fat (p < 0.05) and a greater maximum exercise capacity (p < 0.04 in those patients receiving parenteral nutrition).

Pelzer et al. [359] showed that supplemental, nighty PN for a about 4 months was able to improve the phase angle and to achieve at least a temporary benefit or stabilization of the nutritional status in the majority of the patients investigated.

Finocchiaro et al. [259] reported on severely malnourished and very advanced patients who were aphagic (36%) or hypophagic (<500 kcal/day, 64% of the series) and often receiving palliative chemotherapy, in an uncontrolled study. The median survival was 2 months or less. Orreval et al. [358] reported experience of the palliative homecare services in the Stockholm region in 68 patients and they noted that PN was more common than TF because of the frequency of gastrointestinal symptoms, e.g. early satiety, nausea, and vomiting which make the use of TF difficult. These findings are in keeping with previous prospective investigations on the preferences of cancer patients for the type of nutritional support, intravenous vs TF reported by Scolapio et al. [360] .

In conclusion, early long-term intravenous nutritional support in less-advanced cancer patients with mild hypophagia and mild malnutrition could protect integrated metabolism and metabolic function in these subjects. This would also support the concept that nutrition is a limiting factor influencing survival when the disease is advanced but the final outcome is not imminent. The current availability of commercial all-in-one admixtures (<1 L) able to cover more than half the energy requirement of the average advanced cancer patient simplifies enormously the nutritional approach to weight-losing hypophagic cancer patients.

6. Feeding the incurable cancer patient: bioethical aspects

Indications for HPN in incurable cancer patients represent a continuous source of debate and controversy not only among different specialists but even among physicians belonging to the same specialty.

There are two main points to consider: on the one hand there is the clear awareness of clinicians that current medical care has evolved to such an extent – by transforming previously lethal diseases into chronic conditions – that malnutrition and inability to feed may finally represent in some patients the main determinant for the length of survival (even in malignant diseases). On the other hand, all physicians involved in HPN practice are perfectly aware that patients with benign intestinal failure survive “thanks” to HPN whereas cancer patients finally die “despite” nutritional support.

Besides these two pivotal points, there are a number of psychological, cultural and economical factors which can affect the options of the caregiver, patient and his/her relatives. The decision whether or not to start and whether or not to withdraw an incurable cancer patient from a PN programme is always difficult [300] .

6.1. Areas of controversy

6.1.1. The incurable vs the terminal cancer patient

When discussing with different specialists (surgeons, oncologists, palliativists, nutritionists, etc.) involved in the care of cancer patients generically defined as “terminal” and who are potential candidates for an HPN programme, it is important to be sure that conversations refer to the same type of patient.

It should be clear that while all terminal cancer patients are “oncologically” incurable, not all incurable cancer patients are “biologically” terminal. The oncological definition of “terminal” often means that no oncological therapy is available for the patient whose survival may range from a few days to several months [361] . In common language “terminal” refers to patients in a state of agony or preagony where palliation of symptoms and not nutritional support is the absolute priority.

In order to avoid any ambiguity in defining the severity of the state of the patients and potential candidacy for HPN, it is better to adopt the term “incurable” to focus on cancer patients who have exhausted all available oncological therapies and might sometimes require a nutritional support if aphagic and not imminently dying [292] .

6.1.2. Nutritional support: therapy vs basic care

The question of the benfits of nutritional support vs basic care is not merely academic. Many US state laws and professional groups consider artificial nutrition as a form of medical therapy [362], [363], [364], and [365] – a point of view which is not universally shared [366] and [367].

A therapy needs to be validated through randomized clinical trials in order to be accepted as an evidence-based medicine and in such a trial one arm may receive no treatment, or merely the standard treatment. However, in aphagic/obstructed cancer patients it would be impermissible to have a randomized no-treatment arm, which means progressive undernutrition until death, as the standard treatment simply does not exist.

Miles [368] , emphasizing the cultural and symbolic value of nourishment, which is traditionally viewed as an expression of love and care for both the living and the dying, made the important distinction that while physicians tend to see “nourishment” as a medical treatment aimed at achieving physiological objectives, families see feeding “as an act of community”.

It is common experience that the anorexia and hypophagia of a dying cancer patient represent a major concern for both the patient and their family members [353], [369], and [370].

A specific study on the nutritional situation prior to the introduction of HPN from the perspective of patients with advanced cancer and their family members, in order to understand factors contributing to the decision to accept HPN has been published a few years ago [353] . Patients reported wanting and trying to eat, but being unable to do so; family members experienced powerlessness and frustration, as they could not enable the patient to eat. This desperate and chaotic nutritional situation in the family influenced the patient's willingness to accept HPN. A further study of the same group reported that the interviewed patients with advanced cancer and their family members experienced physical, social, and psychological benefits from HPN treatment [354] .

The point that nutrition cannot be completely equated to a therapy was clearly recognized in the ASPEN Guidelines for the Use of Parenteral and Enteral Nutrition in Adult and Paediatric Patients [371] where the Board of Directors writes “… A major distinction between therapeutic trial of efficacy of a drug or a procedure and the feeding of nutrients known to be essential to maintenance of human health and survival must be made. Withholding a drug or invasive procedure will not produce disease in otherwise healthy humans, whereas essential nutrients must be provided to both healthy and ill people…

The above-mentioned considerations led to the final conclusion that the value of HPN in incurable cancer patients has to be assessed regardless of the absence of randomized clinical trials and keeping in mind that absence of evidence is not evidence of absence [372] .

In this context, it is appropriate to report the position of the Roman Catholic Church [373] on the use of artificial nutrition and hydration near the end of life: “there should be a presumption in favour of providing nutrition and hydration to all patients who require medically-assisted nutrition and hydration” and this approach should be warranted as long as “there is sufficient benefit to outweigh the burdens involved in the patient.”

6.1.3. Differentiating effects and benefits

The goals to be attained through an HPN approach in the incurable patient should be realistically discussed with the patient and the family.

The metabolic effects of short-term PN [374] and HPN [9] in cancer patients are reported in the literature.

Do these effects translate into a clinical benefit for the patient?

If the goal of HPN is simply to blunt progressive nutritional deterioration and to ensure a longer survival for the patient while he/she remains within the family home, the answer is probably “yes”, at least for a certain number of patients who are considered good candidates.

If the goal of HPN is to improve the patient's quality of life, the answer is quite uncertain. This is because the quality of life of the patient is not only a strictly individual matter, but may be related more to the symptoms of the primary disease and the previous oncological treatment than to intestinal failure or malnutrition.

A predefinition of the goals of HPN and the chances of success is essential not only to avoid overoptimistic expectations such as “my husband was condemned to die because he could not eat… now HPN will avoid it!” but also because if HPN is not be able to attain those endpoints, withdrawing it will be less traumatic for the family and ethically acceptable for the physician.

6.1.4. The trial-and-error method

Since the discrimination between good candidates and bad candidates will select/exclude only a small percentage of patients, for the majority of them the benefit of HPN is unpredictable and its indication very uncertain.

In this group of patients especially it is worthwhile to adopt the trial-and-error method. That is, one can initiate HPN and withdraw it if it is found to be inappropriate or not beneficial on a subsequent reassessment. This was also the final conclusion of the Consensus Meeting launched by the European Association for Palliative Care in 1996 [375] .

Conflict of interest

Author has no conflict of interest to be disclosed.

Reviewers

Amina Jatoi, M.D., Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905, USA.

Nathalie Jacquelin-Ravel, MD, Clinique de Genolier, 1 route du Muids, CH-1272 Genolier, Switzerland.

Christine Baldwin, PhD, RD, Division of Diabetes and Nutritional Sciences, School of Medicine, King's College London, Franklin Wilkins Bldg, London SE1 9NH, UK.

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Dr F Bozzetti has worked many years at the NCI of Milan (Italy) as surgeon oncologist, finally reaching the position of Director of the GI Surgical Unit and Chief of the Nutrition Support Team. His interests mainly focused on surgical treatment of GI cancer and metabolic care of surgical patients and cancer patients. He was recently coordinator of the Guidelines for Parenteral Nutrition (on behalf of the European Society for Clinical Nutrition and Metabolism, ESPEN) and of the Scientific Basis for the Definition of the Clinical Practice Guidelines for the Treatment of Gastric Cancer (on behalf of the Italian Alliance against Cancer). He is a faculty member of ESPEN and Chairman of the Task Force on Nutritional Support of the Elderly Cancer Patient within the International Society of Geriatric Oncology. Presently, he works as private surgeon and has an academic appointment at the Faculty of Medicine of the University of Milan.

Footnotes

Faculty of Medicine, University of Milan, via Festa del Perdono 9, Milan, Italy


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