malignant disease: nutritional implications of disease and treatment

Cancer and IVletastasis Review~ 6:357-381 (1987) © Martinus Nijhoff Publishcrs, Boston - Printed in the Netherlands.

Malignant disease: nutritional implications of disease and treatment

Susan Holmes ~ and John W.T. Dickerson=' 1 Division of Nursing Studies, z Division of Nutrition and Food Science, Department of Biochemistl 3' Univer- sit), of Surrey, Guildford, U.K.

Key words: protein-energy malnutrition (PEM), anorexia, cachexia, surge~', radiotherapy, chemothcrapy, quality of life

Abstract

Protein-energy malnutrition (PEM) is common in cancer patients and may dcvclop into the syndrome known as 'cancer cachexia'. This is characteriscd by complcx disturbances in carbohydrate, lipid, protein, and electrolyte metabolism. The aetiology is equally complex, with host and therapeutic factors contributing to the reduced food intake and effects on host tissues. Anorexia is of primc importancc, differing in its cause from one patient to another and often presenting a barrier to successful nutritional support. Furthcr research is necessary to elucidate the interaction of central and peripheral factors that may bc involved in the aetiology of anorexia. Because of the interplay of biochemical, physiological, and psychological consequences of cancer, the nutritional support of thc patient presents a considerable challenge to the caring professions.

Introduction

Protein energy malnutrition (PEM) frequently ac- companies malignant disease [1-3] affecting about 40% of all patients hospitalised for the treatment of cancer [4]. PEM is associated with a poor prognosis, reduced response to anti-neoplastic therapy, prolonged, or enhanced, morbidity of therapeutic side effects, and a reduced quality of life [5, 6]. Such malnutrition varies in onset, occurring at different stages in the progress of the disease. It is not directly correlated with food intake, with the stage, histological type, or site of the tumour, duration of disease, or the site or number of metastases. Weight loss is not always associated with a large tumour burden, and may occur with a small primary tumour even preceding diagnosis [6]. Shils [7] reported that 45% of newly hospitalised adult cancer patients had lost at least 10% of their body weight and 25% had lost 20% or more. Such weight loss is accompanied by a marked reduction in body fat and a loss of muscle mass.

This 'starvation' is now well recognised and has come to be known as "cancer cachexia', a syndrome characterised clinically by emaciation~ debilitation, and inanition associated with anorexia, early satiety. anaemia, and marked asthenia. Profound abnormalities of host metabolism accompany cachexia including disturbances of carbohydrate [8, 9], protein [10.11]. and fat [12-14] metabolism. These changes are believed to be responsible for the nutritional problems in the cancer bearing host, since weight loss can be observed even when the food intake is apparently adequate. Yet it has been ar- gued [15] that much of this weight loss can be attributed to an inadequate food intake resulting from anorexia; alternatively, it has been suggested [16] that "normal" individuals will compensate for any increase in body energy requirements bv increasing their food intake. Clcarly cancer patients fail to compensate in this way and nutrient intake fails to kcep pace with nutrient requirements. Yet some patients fail to gain wcight or maintain their current weight on energy intakes of 3-4,000 kcal/

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day [15]. In thc absence of obvious causative factors, such as coexistent endocrine disordcrs (or other anatomical lesions) or sepsis, it appears that malignant diseasc per se induces profound nutritional problems. It is difficult to imagine, howcver, that even a small tumour can create such marked nutrient deficits; this places great importance on the metabolic disturbances induced by malignancy.

It has been suggested [18] that some tumours produce peptides, or other metabolitcs, which interact with host/turnout tissucs, inducing metabolic derangements and rclcasing peptides and/or amino acids that can be used by tumour tissue [19, 20]. Recent evidence, howevcr, suggests that metabolic changes are mediated largely by thc immune system [21]. Cachectin, a polypeptide hormone, is of particular interest, since it has been implicated in the causation of both shock [22] and the cachexia of chronic diseasc [23]. When administcrcd to animals, cachectin induces a state of anorexia and

Table 1. Pathogenesis of cancer cachexia

Possible contributory factors

Deficient food intake Anorexia Nausea and vomiting "l','tst c aberration Early satiety Mechanical obstruction

Excessive loss of body Vomiting protein Diarrhoea

Protein losing enteropathy Ulceration Haemorrhage

Malabsorption Radiation therapy Systemic drug thcrapy Surgery ? systemic cffccts of tumour

Metabolic disturbances Protein affecting: Carbohydrate

Fat Hormones Water Electrolytes

"t'umour metabolitcs 'Toxohormones', peptides, and other small molecules

'Nitrogen trapping' by thc tumour

weight loss, and an apathetic, unkempt appearance [21]. It secms, therefore, that the impact of cachectin induced catabolic effects may be sufficient to account for the wasting accompanying neoplastic disease [24, 25l. Cachectin may thus 'orchestrate' the complex metabolic derangements that result in cachexia [21].

In general cachexia appears to be of a multifactorial aetiology, with the factors acting synergistically to produce the clinical picture [26] (Table l). The relative importance of these factors is subject to considerable individual variation.

Inadequate food intake

This may be related to mechanical obstruction, anorexia and early satiety, taste aberration, food aversion, or methods of trcatment.

The anatomic location of the tumour may contribute to an inability to ingest, digest, or absorb nutrients via the gastrointestinal (GI) tract. In addition, it has been suggested that malignancy any- where in the body may be associatcd with secondary changes in the small intcstine, leading to hypoplasia or flattening of the mucosa and a sub- scquent malabsorption [27, 28]. A significant protein losing enteropathy follows secondary disorders of the GI lymphatic channcls or ulceration of a region of the mucosa [29, 30]. However, such changes may be the effect, rather than the cause, of cachexia [31]. Sincc the GI tract is one of thc most metabolically activc organs of the body it is not surprising to find marked intestinal changes accompanying malnutrition and, thcrefore, cachcxia. Certainly, in the malnourishcd individual, gastrointestinal efficiency is scverely reduced due to changes in the mucosal cells couplcd with a rcduc- tion in the brush border and a decline in intcstinal enzyme activity. GI motility also declines and an overgrowth of facultative and anaerobic bacteria occurs [32], resulting in greatly impaired absorption. It is not clear to what extent the intestinal changes are due to nutritional deficiency and to what extent they are due to the malignancy itself.

The aetiology of anorexia, like that of cachexia, has yet to be elucidated, although it too is believed

to be of multifactorial origin. Anorexia may vary from mild to severe and its severity may go un- noticed bv the patient 133]. The many factors that may cause anorexia are not mutually exclusive and mav act synergistically to exacerbate the problem. including: 1. Production of toxic factor(s) or hormone(s) that

interact in some way with one or more of the mechanisms involved in controlling feeding behaviour [34].

2. Abnormalities of hypothalamic control of feeding behaviour [e.g., 35].

3. Psychological and emotional responses to the disease and its treatment, including the depression, fear, and hopelessness felt by manv cancer patients [c.g., 36].

4. Metabolic abnormalities of uncertain origin, including increased tissue protein breakdown [37, 38].

5. Effects related to methods of treatment [c.g.,

391. It has been suggested that "toxohormones' produced bv tumours exert peripheral effects on both neuroreceptor or neuroendocrinc cells, or direct effects on the hypothalamus and other sensors within the central nervous system [34]. Although this hypothesis has received some support [40, 41]. and despite the isolation of cachectin [23], other workers [17] suggest that no such anorexigcnic peptides have bccn isolated to date. An alternative view states that tumour mctabolites are involved in the regulation of compounds (such as the catc- cholamines and serotonin) believed responsible for the regulation of nutritional homeostasis [18, 42]. It is clear that the mechanisms controlling food intake are complex and subject to a variety of internal and external influences. Despite this. body weight remains remarkably constant in the healthy individual, which suggests the presence of some form cff physiological control and raises the question of whether this physiological mcchanism fails in the presence of malignant disease.

One such mechanism has comc to be convention- ally regarded as the central site of the organisation and integration of feeding bchaviour. It has been suggested that the hypothalamus and related cen- tres play a major role in originating the sensations

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of both hunger and satiety, operating a reciprocal excitation/inhibition system [34]. The proposition [15, 44] that a tumour generates spurious signals that are interpreted centrally as indicators of satiety before true satiety signals have been generated has. therefore, received some support as the cause of the early satiety characteristic of malignant disease. However, neither damage to the ven- tromedial nuclei, which characteristically causes hyperphagia [44, 45] nor damage to the lateral nuclei, which causes anorexia [46], with subsequent recovery can block the development of anorexia or prevent cachexia. This suggests that depression of food intake is mediated extra-hy- pothalamically [16]. and is consistent with previous findings [47, 48] of decreased serotonin associated with increased food intake and a decrease in turnover, resulting in hyperphagia [49, 50].

Studies of plasma and brain amino acid patterns and central serotonin (5-HT) metabolism [51.52] have shown that, in the presence of malignancy, brain tryptophan levels decline as scrotonin rises, correlating closely with the onset of anorexia. It seems that tumour induced metabolic abnormalities result in a decrease in plasma albumin concentration in association with an elevation of plasma free fatty acids (FFA), with the rcsuh that, plasma free tryptophan rises, as tryptophan is the only amino acid binding to serum albumin and as plasma FFA compete for the same binding sites. This in turn leads to an increase in brain tryptophan conccntration, inducing an increascd synthesis and turnover of serotonin. When this is taken in con- junction with reports of serotonergic mechanisms of satiety [e.g., 47, 48] it becomes possible to suggest that anorexia is mediated by serotonin. How- ever, further studies [53] have shown that inhibition of serotonin synthesis can postpone but NOT eliminate the onset of anorexia, and others have failed to rcproduce previous findings [e.g., 54, 55]. It therefore becomes clear that although serotonergic mechanisms may play a contributory role in the anorexia of malignant disease, other mechanisms must also bc involved.

Anorexia is not exclusive to malignant disease, although its high incidence and prolonged deleteri- ous effects, together with its major role in the

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development of cachexia, make it a matter of considerable concern. Continued research into its pathogenesis is essential if effective methods of treatment are to be found.

Behaviourai and symptomatic contributors to anorexia

Although it appears that metabolic mechanisms play an important role in the genesis of anorexia, the important contribution of behavioural and symptomatic factors cannot be overlooked. There is little doubt that fear of cancer, and emotional responses to the diagnosis, can adversely affect appetite [36], although this does not cxplain the anorexia occurring in the undiagnosed paticnt.

There are periods during the course of the disease when the patient is particularly vulnerable to emotional distress [36], due to uncertainties associated with the disease, its diagnosis, and its treatment. Before the diagnosis is confirmed patients are subject to considerable stress; confirmation of the diagnosis promotes further emotional trauma. A weight loss of 5-10 lbs, related primarily to psychological/emotional factors rather than to the disease process itself [36], is not unusual during this period. Previous beliefs and attitudes towards cancer and its treatment [56], combincd with continued fear of recurrence, appearance of a new symptom (whether or not this is discasc related), and anxiety regarding methods of treatment are all important contributors to anorexia. Thus, as an emotional response, anorexia may be cxpcrienced throughout the course of the disease.

Continued progression of the disease can lcad to marked depression, which could be seen as a psychological basis for the anorexia/cachexia syndrome. In this case appropriate anti-dcpressivc therapy would be expected to reduce the incidence of weight loss/anorexia/cachexia. However, this has not responded to tricyclic drug therapy [33], and Plumb et al. [57], using the Beck Depression Inventory, have shown that affected patients ob- tain low scores on the non-physical symptoms of depression (such as worthlessness, loss of self esteem, pessimism, guilt, and suicidal tendencies).

High scores were demonstrated with regard to physical symptoms (such as anorexia, weight loss, insomn!a, fatigue, and loss of interest in usual activities), which appears to suggest that depression is not a significant factor in the pathogcnesis of anorexia. It is felt that the term 'depression' is often inappropriately applied to the cancer patient, in whom symptoms suggestive of deprcssion are often somatic in origin and reflect the physical rather than the psychological condition [36]. Depression, like anorexia, has been associated with serotonergic mechanisms, and it is possible that they are closely related; this area warrants further investigation.

Disruption of lifestyle resulting from the pre- scnce of malignant disease, combined with effects induced by treatment regimes, clearly highlight the close relationships between an individual's social, psychological, and cultural environment and his nutritional status. These, in turn, influence his quality of life.

Physical symptoms such as pain, nausea, and vomiting may also influence food intake; control of such symptoms is essential if nutritional status is to be maintained.

Taste aberration

Appetite changes and anorexia are often attribut- able to taste aberrations which, together with anosmia, may blunt the normal excitatory stimuli associated with food intake [58]. Such changes largely concern alterations in bitter and sweet thresholds [26, 59], although there is no consistent pattern. Limited evidence suggests such changes improve in patients showing an objective response to therapy [60]. The cause of taste changes is not yet clear, although evidence suggests a correlation with trace mineral deficiencies [61]; this has yet to be confirmed in cancer patients although it is suggested that such deficiencies are common.

Damage to the small intestine, such as that previously discussed, can result in significant losses of zinc that are reflected by low serum zinc levels [62]; rapid tissue breakdown, such as that induced by chemotherapy or radiotherapy, will increase excre-

tion. Zinc deficiency has, in turn, been associated with hypogucsia and dysguesia. This mechanism may, therefore, be responsible for the taste aberrations associated with cancer. The literature with regard to trace elements in malignant disease has been extensively reviewed [e.g., 63].

Learned food aversions may arise as a result of taste changes, as well as from an association between symptoms and the disease or its treatment [55, 64]. This has comc to be regarded as a variant of classical conditioning, in which a conditioned stimulus (taste) becomes associated with an uncon- ditioned response (e.g., discomfort) [65]. Animal studies [55, 66] have shown that just one pairing of a food with GI discomfort induced by radiotherapy is sufficient to promote continued avoidance of that food and repeated pairings of food with discomfort may cause aversion to even the most familiar foods [671: conditioned aversions such as these may persist long after symptoms have subsided [43, 64] and may be significant in the development of anorexia and the promotion of weight loss in patients ac- tively treated for cancer [64].

Metabolic abnormalities

Changes in energy expenditure

Many metabolic changes occur in the presence of malignant disease [68] and manifest themselves in alterations of energy expenditure.

Although there is considerable variation, man)' workers have demonstrated an increased energy expenditure in the tumour bearing host [e.g., 69]. Following tumour transplantation it has been shown that spontaneous motor activity declines [35], yet oxygen consumption is increased [70], suggesting the initiation of an unexplained process that increases energy requirements [71]. Two hy- potheses have been considered [72]: First, the metabolic activity of malignant tissue is continuous, in contrast to the diurnal periodicity of normal tissues, thus imposing a greater energy demand. However, the metabolic activity of tumour cells is low when compared to that of the host [73]. Sec- ond, alterations in pathways of intermediary' me-

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tabolism could result in a selective removal of nutrients by the turnout, forcing the host to use more energy-expensive pathways. For example, on the basis of animal studies [72] it was concluded that a tumour could act as a "nitrogen trap', sequestering host proteins in a competition for nutrients. How- ever, hyperalimentation does not decrease energy expenditure although both the nutrient supply and the metabolic pool are augmented.

The demonstrated increase in whole body glucose production [17. 20] could explain an increase in Cori cycle activity (Fig. 1), particularly in metastatic carcinoma [20]. This is an energy-wasting process that circumvents aerobic glycolysis, consuming energy and resulting in a net energy loss (8 molecules of ATP per mole of glucose). This glucose is lost to the host, who might have used it to generate ATP through the Tricarboxylic Acid Cy- cle [74, 75]. It has, however, been estimated that this increased activity is unlikely to have significant effects on daily energy expenditure [76].

Cancer patients commonly demonstrate disturbances of glucose metabolism. These have been reported variously as impaired glucose tolerance [77- 79], decreased insulin sensitMty [8, 80], decreased insulin release in response to a glucose load [77, 79], and decreased activity of energy producing enzymes in skeletal muscle [79]. Fasting plasma alanine levels are significantly decreased, while branched chain amino acids are unchanged. It has been suggested that an increased alanine flux for gluconeogenesis reflects a basic metabolic abnormality that could be explained on the basis of insulin resistance demonstrated in these patients [17].

Alternatively, the studies of Lundholm et al. [9] suggest differences in the intermediary metabolism of glucose in non-tumour involved host tissues, such as skeletal muscle. It is suggested that the increased glucose turnover primarily comprises increased Cori Cycle activity (80%), but also increased glucose oxidation (15%) [9], and has been

O f . O t calculated to explain 30/0-40 ,,, of the increased oxygen consumption in the eachcctic patient [81, 82].

Whatever the cause, these effects are associated with an inappropriately high oxygen consumption and lead to a negative energy balance. This may

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GLUCOSE

- 6 ATP

Tumour 1 ceil

GLUCOSE

+ 2 ATP

LACTATE

l LACTATE

HOST

Fig. 1. Glucose-lactate (Cori) cycle in the cancer patient

explain, at least in part, the progressive weight loss associated with some forms of malignant disease. However, the results of studies to date are equivocal, and not all tumours are associated with an elevated metabolic rate, It is clear, therefore, that this is not the only factor contributing to the observed nutritional depletion. However, when a patient has an elevated metabolic rate and is also anorectic he is at a considerable risk of malnutrition [83], although such individuals are not easily identified, and it will continue to prove difficult to promote anabolism in affected patients until the mechanism underlying thesc effects is elucidated.

Changes in protein metabolism

Tumour cells have been shown to have a high capacity for concentrating amino acids both in vivo and in vitro. The difficulties associated with the precise control of nutrient intake and the use of radioisotopes in patients with malignant discase have, however, meant that many aspccts of protein metabolism have been studied in animals, making direct extrapolation of data difficult.

Although thc studies of Feninger and Mider [72] were carried out in only a few neoplasms, this work led to the concept of 'nitrogen trapping' by the tumour, with subsequent evidence suggesting this may apply to some forms of cancer, particularly in experimental animals. It is questionable, however, whether the 'nitrogen trap' hypothesis applies in

human cancer when the ratio of tumour size to body size is much lower than in experimental animals [17]. It has been suggested [84] that progressive weight loss, abnormal gluconcogenesis, and the demonstrated lactate recycling may result from imbalance of the essential amino acids due to selective uptake of amino acids by tumour cells. The administration of radiolabellcd amino acids ini- tially results in marked labelling of normal tissues but, with time, tumour tissues display significantly higer specific activity as normal tissue protein turnover occurs. It has been demonstrated [85] that radiolabelled proteins are taken up by tumour tissues to a greater extent than non-neoplastic tissues, suggesting that tumours have a selective advantage in extracting whole proteins, such as albumin, from the circulation, particularly since hypoalbuminaemia is commonly associated with neoplastic disease. Such changes in amino acid metabolism may prevent the host from effectively de- creasing gluconeogenesis. It is also possible that the presence of malignancy may alter the regula- tory mechanisms of normal tissue. For example, it has been shown [86] that the livers of hepatoma bearing rats fail to respond to nutritional stressors, such as a protein free diet, in the same way as those of non-tumour bearing animals.

Although reports are equivocal it appears that the tumour bearing host responds to an increased tumour burden by increasing tissue protein breakdown, thus demonstrating a decreased ability to use those mechanisms designed to conserve lean body tissue and preserve total body protein. Mal- nourished cancer patients have been reported to differ from malnourished non-cancer bearing individuals by displaying both increased protein synthesis and protein turnover [87]. Thus, even in the presence of cachexia and the associated starvation there is a failure of adaptation, with the tumour failing to rccognise normal control mechanisms and maintaining its activity despite host starvation [88]. The reasons for this failure have not yet been elucidated.

Albumin metabolism

The metabolism of albumin is often regarded as an indicator of total protein metabolism, as it is the protein present in the plasma in the largest amounts. It is believed particularly relevant to the study of cachexia because it clearly demonstrates the differences between the hypoalbuminaemia associated with starvation and malnutrition and that associated with cachexia [89]. In simple starvation, once carbohydrate stores have been depleted as a source of energy, the body utilises fat; in cachexia, however, fat stores are not mobilised and, instead, muscle protein is broken down to provide energy through gluconeogenesis [88, 90].

Both albumin synthesis and catabolism are affected by many factors including nutritional status, physiological stress, osmotic pressure, hormones, and disease status [91]. The exogenous supply of amino acids is of particular importance, since even short-term protein deprivation will rcsult in a marked decrease in albumin synthesis.

As previously shown, hypoalbuminacmia is common in malignant disease. When this is associated with cachexia and PEM both synthesis and catabolism of albumin are reduced [92], although the causes of the hypoalbuminaemia of malignancy per se have not been established and the results of studies to date have been equivocal. It has been suggested that this results from a reduction in synthesis possibly associated with a low catabolic rate [93-961; others, [e.g., 971 have reported an increased catabolism. The albumin metabolism of patients with lesions of the GI tract, and an associated reduction in food intake, was compared with that of malnourished patients with anorexia secondary to widely disseminated malignant disease [89]. The former patients correlated closely with patients suffering PEM, displaying a low to normal fractional catabolic rate (FCR) and a normal to high fractional synthetic rate (FSR), while thc latter displayed a normal to high FSR and a markedly increased FCR. As a result it is suggestcd that an elevated FCR may correlate with a poor prognosis unless the tumour is responsive to anti-neoplastic therapy. However, it is to be expected that the response to such therapy will be reduced in the

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presence of hypoalbuminaemia, since albumin functions in the binding of many substances within the circulation, including many of the cancer chemotherapeutic agents. The future of successful treatment depends on an understanding of both the changes in whole body protein metabolism and the causes of hypoalbuminaemia. Without this, drug therapy may be of limited value, and the efficiency of nutritional support may also be limited [98]. Clearly, the apparent inevitability of hypoalbuminaemia means that this cannot be used as an index of nutritional status in these patients [99].

Changes in fat metabolism

Most workers agree that a loss of fat accounts for the majority of the weight loss observed in cancer patients [69, 100, 10]]. Studies have shown that. during the course of tumour growth, carcass fat (exclusive of that present in the tumour) declines to less than 10% of its normal value in a number of tumour systems [102-104]. Despite the presence of anorexia this fat loss cannot be exclusively attributed to an inadequate food intake, since pair- fed controls carry considerably more fat than turnout bearing animals and force feeding does not prevent the loss [105, 106].

Marked hyperlipidaemia, which is not accompanied by ketosis or kctonuria, has been noted in turnout bearing animals [107], suggesting that fat lost to the body during turnout growth is com- pletely oxidised. As energy expenditure is greater in tumour bearing animals and as this could be quantitatively accounted for in some studies by the energy value of the 'lost' lipid, it seems possible that fat is mobilised to meet the increased demand for energy [13, 14. 107]. Such animals also display a decreased ability to clear neutral fats from the serum [13, 14], although the rate of removal of infused lipids appears increased in the cancer patient [108]. It is worth noting that. although some tumours studied in vitro have demonstrated a pref- erence for fatty acids as an energy substrate [109], in vivo studies have demonstrated a slower tumour growth when the majority of calories in a total parenteral feeding regime are given as fat [110]. As

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cachexia seems to result from an almost obligatory 'parasitism' by the tumour [4] it would appear unlikely that a tumour would elaborate lipid mobilising substances [44], since this might restrict its growth. Yet fat mobilising peptides have been isolated from the urine of both fasted animals and humans [111, 112] and in those with widespread malignant disease even when food intake is 'normal'. Peptides with lipid mobilising activity have been isolated from both pituitary [113, 114] and hypothalamic [115] extracts and lipolytic activity has been reported in extracts from other parts of the brain. Such peptides could thus account for the hyperlipidaemia of malignant disease. However, studies suggesting a relationship bctwcen a rise in plasma FFA and clinical activity of the tumour [116] have not been confirmcd [20, 117]. Although FFA oxidation can be reduced by glucose administration in controls, it is less reduced in cancer patients [19], indicating a failure of normal homeostatic mechanisms that could be the result of insulin resistant

[81. These effects, whatever their cause, again con-

firm that the presence of malignancy results in alterations of the normal mcehanisms of control. Evidence for the role of lipid mobilising substances in the causation of hyperlipidaemia is equivocal, since this may restrict the growth of some tumours. The degree and extcnt of hyperlipidacmia may be dependent on the type of tumour. Nonetheless, the loss of body fat combined with inappropriate oxygen consumption and loss of lean body mass can only contribute to a state of negative energy balance and a continuing weight loss.

Micro (trace) nutrients and malignancy

Current knowledge regarding micronutrient requirements is inadequate and based only on the Recommended Daily Allowances (RDA) for the so-called 'normal' individual. The RDA itself rep- resents the minimum daily intake believcd necessary to prevent a recognisable deficiency disorder together with a 'safety margin' which varies with the nutrient. It does not represent an optimal intake. Since not all essential trace nutrients have yet

been identified, it is unlikely that a deficiency dis- ordcr would be recognised. Nonetheless, it is believed that deficiency is uncommon as long as a 'normal' food intake is maintained. This conclusion may well be invalid in the cancer patient. Indeed there are good grounds for considering that dietary requirements may be higher in cancer patients, for they may not be able to absorb nutrients efficiently via the GI tract. There are, in addition, many reasons to suppose that malignancy may alter micronutrient requirements, since uncontrolled tumour growth may result in varying degrccs of physiologic stress which, in turn, may alter both the acquisition and utilisation of micronutrients [118]. Thcre is, therefore, a great need for longitudinal mctabolic studies to indicate how micronutrients are handled by patients with cancer.

Vitamins

"Fable 2 shows that patients with malignant disease are likely to suffer some degree of vitamin deficiency; this may significantly affect their continuing resistance to the disease and determine their response to treatment. Undoubtedly, much of the depletion is sccondary to an inadequate intake, but this is exacerbated in some cases by abnormal losses through the alimentary and renal tracts [7]. Although the mechanisms through which these dc- ficiencics arise generally remain unrcsolved [2], they may result from the administration of anti- neoplastic drugs [1201.

Most of the available information about vitamins in the cancer patient concerns vitamins C, A, and

Table 2. Vitamin abnormalities in cancer patients:'

% Affected

Abnormal leucocyte Ascorbic Acid 71 Anaemia 49 Thiamine 37 Abnormal folio acid 23 Vitamin A 15 Carotenc 15 Abnormal vitamin B 0

,Based on Caiman (1975) [119].

B~ (riboflavin). Thiamine (B 0 deficiency is common and may be of clinical significance due to the close relationships between this vitamin and drug mctabolism [121]. Folic acid and vitamin E have also been studied.

Ascorbic acid (vitamin C)

It has been suggested that ascorbic acid has man)' roles in both the development and treatment of malignant discase [122, 123]. In addition, ascorbic acid plays a major role in drug detoxification through effects on hepatic microsomal enzymes and may, therefore, modify the activity of chemotherapeutic agents.

Both human and animal studies have shown that tumour tissues have a higher concentration of ascorbic acid than adjacent normal tissue [124]; at the same time plasma and leucocyte levels in patients with lung cancer, for instance, fall bclow the threshold levcls for incipient scurvy [125]. Simi- larly, in children, relapsed acute lymphoblastic leukacmia results in reduced plasma and leucocyte ascorbic concentrations that are unrelated to dietary intake, impaired absorption, or administration of chemotherapy [126].

Since ascorbic acid is closely involved in the modulation of the immunc system and in drug metabolism, and since increased utilisation has bcen demonstrated during tissue repair and following burns and surgery (i.e., following periods of physiological strcss), it seems possible to suggest that ascorbate utilisation may be increased in the cancer patient in whom many types of physiological stress are manifest. Evidence for such an increase in requirements has been obtained in breast cancer patients [127]. High dose ascorbic therapy, which has been used in the treatment of patients with advanced malignancy [121]. may therefore bc a useful adjunct to treatment. However, presently available evidence [128,129] docs not support this view. In studies of this kind greater attention should be given to tumour specificity; this is a criticism that can be made of many investigations into human cancer.

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Retinol (vitamin A)

Over 90% of human cancers are believed to be of epithelial origin [130]. As vitamin A is essential for maintaining the normal diffcrentiation of epithelial tissues [131]. and as cancer is regarded bv some as a disease of differentiation, it therefore seems possible that vitamin A (retinol), its prccursor [3 carotene, or its analogues, known collectively as retinoids [132], could be anti-carcinogenic by rein- forcing expression of the normal phenotype and preventing expression of the malignant phcnotype. If this is so then retinoids may function like steroid hormones to control phenotypic cxprcssions. It is therefore possible that adequate vitamin A or t3 carotene might prevent cancer, or that retinoids might be used to control the disease.

Considerable epidemiological evidencc suggests an association between reduced cancer risk and above average blood retinol levels [133] or above average intakes of carotene [134-137]. Peto et al. [137] proposcd a number of mechanisms that suggest that dietary 13 carotene, rather than retinol. may havc this effect. They suggcsted that carotcnoids may have a direct effect on cellular differentiation in target tissue, and may then be con- verted to retinoids in the target tissue and protect the tissue by either enhancing immunological function or quenching singlet oxygen.

However, thc case for a protective effect of [3 carotene dcpends entircly on epidemiological evidence, and interpretation of epidemiological dietary surveys is often uncertain. For instance, the protective effect observed may result not from the nutrient under study but from some other constituent of food; for example, it has been suggcsted that some othcr constituent of vegetables [138], such as ascorbic acid or phenolic compounds [139, 140], might have a protective effect.

Evidence appcars to support a relationship between low blood retinol Icvels and cancer. Thus, compared with non-cancer controls, low plasma retinol values have been found in patients with squamous and oat cell bronchial carcinoma [141], and low retinol values, associated with low retinol binding protein (RBP) concentrations, havc bccn reported in patients with lung canccr [142]. In a

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study of patients with cancer of the oropharynx and oral cavity, mean plasma retinol and 13 carotene levels fell with advancement of disease [143]. Fur- ther support for the view that retinol levels are related to the stage of the disease has been found in patients with bladder [144] and cervical [145] cancer; low plasma retinol concentrations associated with low RBP values were found only in patients with undifferentiated, extensive bladder cancer or with Stage III cervical cancer. It seems likely that the low retinol values in these patients were due to reduced synthesis of RBP, possibly due to malnutrition. This might account for the low retinol values observed in patients with lung cancer, which has been described as a 'starving disease'. If this is so, then the results of these studies lend little support to an anti-cancer role for retinol. However, this does not explain the results of prospective studies [133,146] in which lower retinol concentrations were found in subjects subsequently develop- ing lung cancer when compared with those who did not develop the disease (although it must be noted that measurements on subjects participating in the Basle Cardiovascular study during 1970-1973 failed to show such an association ]147]).

Evidence for the protective effect of vitamin A and its analogues against the actions of chemical carcinogens in experimental animals has been reviewed by Hicks [148]. The importance of animal studies lies in their use in elucidating the scientific basis of anti-tumour action, but care should be exercised in extrapolating the results to human cancer. For instance, the extrapolation of studies involving the importance of carotene to humans is complicated by the fact that rodents do not ac- cumulate carotenoids and are very efficient at con- verting carotene to retinol, while humans show a considerable accumulation of carotenoids and inef- ficient conversion of carotene [149].

Experimental evidence linking retinoids and cancer has led to studies of the value of retinoids in treating a variety of human pre-malignant and malignant conditions. These have included the treatment of cutaneous metastatic melanoma with all trans retinoic acid [150] and the use of "Ro 10-9359" in pre-malignant and malignant skin conditions [151] and in advanced ncoplasia [152].

Riboflavin (vitamin B2)

Rivlin [153] has reviewed the relationship between the induction of cancer, its subsequent growth, and the dietary intake of riboflavin. Dietary riboflavin deficiency has been shown to both reduce the incidence of tumours after the application of carcinogens and inhibit the growth of tumours.

Thiamine (Vitamin Bl)

Thiamine deficiency is common in both early malignancy and advanced disease [154], particularly when treatmcnt with 5-fluorouracil (5-FU) is in- stigated either alone or in combination with other drugs [155]; this deficiency can be corrected by giving large doses of the vitamin. Although 5-FU is a cocarboxylase antagonist affecting the conversion of thiamine to thiamine pyrophosphate [2, 154], it is by no means certain that giving thiamine will not stimulate tumour growth or decrease the anti-neoplastic effect of the drug [98]. Further work is clearly necessary before patients being treated with 5-FU can bc given large doses of vitamin B r

Folic acid (folate)

Folate is essential for cell division; as a result folate status is of considerable importance in malignant disease. Folate deficiency has been associated with malignancy [156,157], and abnormalities in its metabolism have been linked to acute and chronic leukaemias, disseminated lymphomas [158], and various metastatic carcinomas [159]. Catabolism of folate is reduced in the presence of malignancy [160], at least in the rat, which suggests that the low folate levels are the result of sequestration by tumour tissues [160[, reflecting an increased require- ment for folatc in malignant disease due to the presence of additional cell mass. Thus, the specific interaction between the drug methotrexate (a folate antagonist) and folate can be used to inhibit tumour growth, although a folate 'rescue' is essential following a period of drug action. However, administration of flflate, except under carefully

controlled conditions, may increase or stimulate turnout growth, so caution should be applied when considering folate as a supplemental therapy.

Tocopherol (vitamin E)

It is assumed that vitamin E acts as a "scavenger' of free radicals through its actions as an electron do- nor, and in this way plays a role in the prevention of carcinogenesis. Its role in malignant disease is un- clear, although it has been shown that tocopherol utilisation differs between normal and malignant cells [118].

Studies of tocopherol accumulation by tumour tissues have produced equivocal results, with some suggesting this is decreased [161, 162] and others that it is increased [163]. This situation remains unresolved, so it is not possible to postulate what, if any, changes occur in vitamin E status within the cancer bearing host. As a result it is not possible to assess the rolc of supplemental vitamin E in the treatment of malignant disease, although it is commonly recommended by many of the "alternative' approaches to cancer treatment because of its antioxidant activity [164]. This approach may, in fact, be detrimental to the host.

Trace elements

The growing awareness of the importance of trace elements in health has led to an increased interest in the trace element status of the cancer patient. It is now clear that trace metals are fundamental to many biological processes that may be disrupted by an impaired intake, increased utilisation, and/or increased excretion. The cancer patient may suffer any or all of these effects, and trace element deft- ciencv may contribute to many of the metabolic alterations manifested in the presence of malignancy: this area may bc worthy of investigation. In general the role of trace metals in carcinogenesis has received more attention than their metabolism in the cancer bearing host. Data currently available rclatcs principally to surveys of the serum, urine, and tissue concentrations of various elements. Fcw

367

replacement studies have been reported, an excep- tion bcing zinc replacement therapy [165], which has been shown to improve oral ulceration following chemotherapy and, at the same time, to stimulate appetite and improve taste sensation. It is, however, possible that the latter effects result sim- ply from an improved oral status rather than from a systemic effect of zinc. However. some changes have been observed in the metabolism of certain trace elements, notably iron, selenium, copper, and zinc.

Iron

The role of iron in the initiation of carcinogenesis warrants further study, since the incidence of neo- plasia appears to incrcase in conditions of iron excess. For example, primary hepatic carcinoma develops in African populations in whom siderosis is common. It has been suggested that iron functions as a cocarcinogen through its activation of free radical mcchanisms [166], since iron has been shown to be a potent initiator of lipid peroxidation.

In the presence of malignancy, radio-labelled iron is cleared from the plasma at an accelerated rate that increases in parallel with the rate of tumour dissemination [118]: these effects are similar to those seen during the inflammatory response. A direct correlation has been shown between the extent of disease and decreases in the saturation of transferrin in patients with Hodgkin's disease [167]. Although the uptake of nutrients may vary between normal and malignant cells an increased storage of iron has not generally been demonstrated: in fact, the iron content of certain tumours (e.g. kidney, lung, and stomach) has been shown to be lower than that of adjacent normal tissues [118]. However, mammary tumours and the Reed- Stcrnberg cells of Hodgkin's disease contain a significantly increased iron concentration, suggesting that significant variations exist between tumours of different types.

The role of iron, and/or changes in its mctabolism or utilisation, in the presence of malignancy remain to be resolved; this may bc of significance when planning appropriate nutritional support regimes.

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Copper, zinc and selenium

Copper, zinc, and selenium are all essential nutrients; selenium is essential for normal growth (at least in some species) and copper and zinc are co-factors in a number of important enzyme systems [168, 169].

Many forms of malignancy (e.g., acute/chronic leukacmia, Hodgkin's and non-Hodgkin's lymphoma, gastric and lung cancers) are associated with abnormalitics of copper status, and hyper- cupremia is common. Serum copper levels can, thcrefore, be used to indicate tumour activity 12] and to evaluate subsequent response to treatment

11181. Zinc is cssential to malignant growth [170 I. It is

possible that uptake of zinc by tumour cells results in deficiency in the host and, as zinc deficiency is known to inhibit protein synthesis, it has bcen suggested that zinc deficiency may reduce the availability of those micronutrients reliant upon serum transport proteins [171]. When combined with anorexia and other disturbances to food (nutrient) intake this could, in itself, explain many of thc micronutricnt abnormalities associated with neoplastic disease and could, in addition, form the basis of the mechanism underlying the commonly reported taste changcs, since both hypoguesia and dysguesia arc frequently associated with zinc deficiency.

It has been suggested that selenium dcficiency is a predisposing factor for malignant and cardiac disease, both of which have been associated with oxidative damage. Since selenium is known to function as an antioxidant [172}, being an important constituent of the enzyme glutathione perox- idase, this hypothesis appears to have some merit. In addition, selenium is believed to play a role in immunostimulation, enhancing the ability of the immune system to prevent neoplastic growth [173 ]. It is therefore possible that an adequate selenium intake could help to prevent the occurrence of malignant disease, although it must be noted that selenium is associated with a marked toxicity, so supplementation is not generally recommended. Despite this, selenium is now recommended by some of the 'alternative' approaches to treatment

[e.g., 164], although its effects on established tumours are not yet known. However, it has bcen suggcsted [174] that selcnium has an inhibitory effect on the growth of malignant cells through selectivc effects on c-AMP metabolism. Further study is urgently needed in this area.

Fluid and electrolyte disturbances

Patients with cancer often present with systemic symptoms of their underlying disease, the severity of which may bear no relationship to the site or extent of the tumour. Fluid and electrolyte disturbances are common and, in patients with advanced malignancy, both intra- and extra-cellular water is incrcased [175]. Such fluid retention can mask a loss of body tissue, so as disease progresses the measurement of body weight declines in value as a means of assessing nutritional status.

Hyponatracmia is the most frequent electrolyte abnormality and is usually of a multifactorial actiology. However, fluid retention and increased urinary sodium Iosscs have been attributed to an inappropriatc secretion of antidiuretic hormone (ADH), usually, but not exclusively, in conjunc- tion with bronchogenic or oat cell carcinomas [176].

Ilypercalcaemia, associated with fatigue and anorexia and accompanied by both weight loss and constipation, is also common. In fact, malignant disease is thc most common cause of hyper- calcacmia in hospitaliscd patients [177]. The cause is uncertain. It has been suggested that, in patients with bone metastases, hypercalcaemia is due to the release of calcium following bone destruction [177]. It is clear, however, that hypcrcalcaemia can arise even when there is no direct bonc involvement when removal of the tumour may result in the return of serum calcium to within the normal rangc. Such effects are most common in squamous cell carcinomas of the bronchus or head and ncck, or in renal cancers [1781. This suggests a role for a circulating mediator such as parathyroid hormone (PTH), although intestinal absorption of calcium is not, in general, increased, and circulating PTH levels are elevated only in about 10% of hypcr- calcaemic cancer patients [177].

Certain tumours (such as medullary tumours of the thyroid) secrete excessive amounts of cap citonin [179]. prostaglandins [180], and histamine [181], which may serve to explain hypercalcaemia in the absence of bone disease. Calcitonin induces secretion of water and electrolytes by the jejunal mucosa [182] and could, therefore, be a factor contributing to both diarrhoea and electrolyte disturbances in patients with extra-intestinal malignancy. Malabsorption and diarrhoea have also been associated with an increased secretion of histamine [1831.

Prostaglandins are known to cause bone destruction, and prostaglandin production has been shown to occur in invaded bone [185]: this could account for both the pain and the destruction associated with bone metastases, although it seems unlikely that it could contribute to the hypercalcaemia occurring in the absence of bone disease.

It is clear that hypercalcaemia is a common cause of morbidity in cancer patients and one that is exacerbated by immobilisation and dehydration. Although successful methods of treatment are available (e.g., Mithramycin, steroid therapyl, attention should be directed towards its prevention; continued research into its causes is thus essential.

Other electrolyte abnormalities, together with disturbances of acid-base balance, may result from complications of the disease itself or from its treatment [185,186]. Weight loss and accelerated catabolism can result in urinary losses of both sodium and potassium, although serum levels remain within the normal range. Hypocalcaemia may arise in the presence of hypoalbuminaemia.

The preceding discussion has shown that almost all tumours result in significant nutritional and metabolic alterations in the host. These may appear early in the disease, or later as the cancer progresses and metastasises. These alterations result in changes that act synergistically to create 'chaos" in host metabolism [187]. Although the mechanisms by which many of these effects arise are not yet understood, it is clear that cancer cachexia has marked effects on the patient's ability to withstand the impact of both the disease and its treatment. causing a decline in nutritional status and quality of life. Due to this incomplete understanding it is not

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possible, at present, to take effective measures to prevent its development except through control of the primary disease by effective anti-neoplastic therapy. There are, however, secondary factors that may contribute to a further decline in the nutritional condition; these include side effects and complications of treatment.

Nutrition and cancer therapy

The treatment of neoplastic disease can impose many significant nutritional disabilities on the patient as a result of factors that either limit food intake or cause malabsorption of nutrients. Such effects may be transient or severe and permanent; they assume particular importance when viewed in the context of the many other factors that may interact to put the patient at nutritional risk.

Surgery

The many biochcmical and physiological disturbances following surgcry are well-documented [e.g., 188]; in general these are short-lived and do not result in long-term nutritional disability, unless surgery is extensive, complicated, or superimposed upon the nutritional consequences of cancer per se.

However, as surgery is the treatmcnt of choice for most tumours within the gastrointestinal (GI) tract, it is to be expected that such tumours, and their treatment, may have a major impact on nutritional status. The extent of the rcsultant nutritional disability depends upon many factors, including the site of the tumour and the extent of resection (Table 3).

Mastication and deglutition may be severely disrupted by resection of tumours of the oropharnyx, mandible, or tongue, and difficulties such as xerostomia and fibrosis add to the difficulties in swap lowing. Many of tile problems can be alleviated by tube feeding although this may be required for prolonged periods: for example, Pittam et al. [189] found 45°/,, of patients required enteral feeding for more than 15 days post-operatively. For the patient at serious risk of aspiration, permanent tube feeding may be necessary.

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Oesophagectomy may induce gastric stasis, hypochlorhydria, diarrhoea, and significant malabsorption of fat leading to steatorrhoea [190]. Simi- lar effects are noted following truncal vagotomy; it has been suggested that such symptoms are related to the bilateral vagotomy that is inherent in the procedure, rather than to the oesophagectomy per se. However, the precise mechanisms are unknown [190, 191]. Physiological and nutritional consequences of partial and total gastrectomy have been extensively reviewed [191]. These effects increase proportionately with the extent of resection. Mal- absorption of both protein and fat are common [192], although this does not always correlate with the observed degree of weight loss. Nonetheless, malnutrition, defined by a weight below 85% of ideal body weight, has been found in 30% of patients [193]. A major contributor to weight loss appears to be self-imposed dietary restriction that may arise for several reasons including oesophagitis, loss of the food 'reservoir', and dumping syndrome. Myriad GI symptoms may follow gastric surgery; these include nausea, vomit-

Table 3. Possible nutritional effects of gastrointcstinal surgery

Resection of the oropharyngeal region

Ocsophagcctomy Oesophageal reconstruction

Duodenum Jejunum Ileum

Gastric resection (Partial/total)

Small intestine

Colon

Pancreatectomy

Massive resection

ing, abdominal cramps, and diarrhoea, as well as an increase in sympathetic autonomic discharge; these symptoms can be so unpleasant that an aversion to eating develops. Dumping syndrome occurs in between 10%-25% of all patients undergoing subtotal gastrectomy; in total gastrectomy the percentage is still higher [191]. The incidence can be reduced, and nutritional deficits corrected, by well- planned dietary measures involving frequent small meals with high protein and fat and low carbohydrate content. Persistent anorexia may have to be treated by slow drip, tube feeding. Functional pancreatic insufficiency may arise due to rapid entry of food/fluid into the small intestine, which results in dilution of the digestive enzymes; in such cases the use of pancreatic enzymes may be helpful [83].

Resection of the small intestine can result in significant nutritional or metabolic disturbances, the extent of which is dependent on the area re- sected. Although the absorptive area may be reduced following resection, malabsorption does not usually reach significant proportions until at least 75% of the bowel is removed since the remaining

Chewing/swallowing difficulties Prolonged dependence on tube feeding

Gastric stasis Hypochlorhydria } Fat malabsorption - steatorrhoea Diarrhoea

Dumping syndrome Malabsorption Achlorhydria - Pernicious anaemia

(lack of intrisic factor) tlypoglycaemia

Pancreatobiliary deficiency Decreased efficiency of absorption Bile salt malabsorption Pernicious anaemia (B~2 malabsorption) Hyperoxaluria Severe malab~rption Malnutrition Metabolic acidosis

Fluid and electrolyte imbalance

Pancreatic exocrinc insufficiency Diabetes mellitus

Secondary to vagotomy

bowel has been shown to increase its absorptive capacity [194-196]; subsequent radiation therapy may exacerbate malabsorption in affected patients.

Ileal resection is associated with poor absorption of vitamins of the B group and conjugated bile salts, so that administration of the B vitamins is necessary to prevent deficiency. Inhibited reabsorption of bile salts results in prolonged and distressing diarrhoea; cholestyramine can be used to bind bile salts and minimise symptoms [197]. These are excreted when bile salt reabsorption ccascs and the limited ability of the liver to replace them re- suits in a decreased luminal concentration of bile salts so that fat absorption is impaired and steatorrhea results [197]. This leads to calcium ion deficiency due to the formation of insoluble calcium soaps that are subsequently excreted. Such deficiency, in turn, increases the likelihood of hyperoxaluria with the associated risk of renal calculi, as urinary oxalatc is increased due to a failure to precipitate oxalate as calcium oxalate in the intestine [198].

Dieta~ measures can be taken to overcome these problcms. ]'he diet should include an increased intake of medium chain triglycerides (MCT), since they do not require emulsification prior to absorption, together with a reduction in long chain fats and oxalate containing foods and an increased intake of calcium salts. Hypomag- nesaemia may also occur, so a magnesium-rich diet may also bc important.

The effects of large bowel resection on nutritional status are limited. Total resection or ileoanal anastamosis mav cause profuse diarrhoea leading to significant losses of both fluid and electrolytes. Such losses diminish as the remaining bowel adapts.

Pancreas

Although only about 10% of patients are suitable for resection, it has been suggested that total pancreatectomy is the only treatment for tumours of the pancreas [199,200]. Resection has a significant effect on nutritional status, leading to a loss of digestive enzymes as well as to diabetes mellitus.

371

All patients will develop diabetes which, in 20% of the patients, will be partcularly labile [201]; pancreatic exocrinc insufficiency leads to malabsorption of fat and fat soluble vitamins as wcll as of amino acids and some minerals, notably calcium and magnesium [202]. Similar effects are sccn in 22%-28% of all patients undergoing pancreatic duodencctomy for disease of the head of pancreas or periampulary regions [203-205]. Administration of pancreatic enzyme preparations can significantly ameliorate these symptoms, and the use of MCT and oligosaccharides may be beneficial sincc pancreatic enzymes seem less necessary for their absorption [83]. The management of diabetes is less straightforward, since the "traditional" diabetic diet with its increased percentage of fat and protein may exacerbate preexisting steatorrhea [202].

Cancer chemotherapy

Most of the drugs used to treat malignant disease exert profound cytotoxic effects and, since they are unable to discriminate between normal and cancer cells, may have marked effects on healthy "normal' tissues. This lack of selectivity is the cause of many of the toxicities observed with this form of treatment. However, the continued development of new drugs, together with variations in their dos- ages, have resulted in marked changes in the treatment of malignant disease. Nonetheless, cancer chemotherapeutic agents continue to contribute to host malnutrition through a variety of direct and indirect mechanisms that cause many symptoms such as nausea and vomiting, mucositis/stomatitis, organ injury, and learned food aversions. Many drugs adversely affect intestinal function to a degree dependent on the dose and duration of treatment, the rate of drug metabolism, and individual susceptibility. The current tendency to administer cyclic chemotherapy in multiple combinations can increase both the range and severity of side effects. Because most chemotherapeutic agents adversely affect dietary intake [206] (Table 4), there may be prolonged periods of impaired food intake leading to weight loss and a progressive debility.

Virtually all drugs will cause nausea and vomit-

372

ing, although certain agents, notably chloroethyl- nitrosurca, streptozotocin, cis-platin, and im- idazole carboxamide (DITC) [207], arc most commonly involved. These effects, normally mediated by the arca postrema (a chcmorcceptor zonc of the fourth ventricle) [208], can have a significant nutritional impact on the host, causing anorexia and a decline in voluntary oral intake as well as fluid and electrolyte imbalance, general weakness, fatigue, and weight loss.

General mucosal toxicity may result in diarrhoca accompanied by severe abdominal pain and, in severe cases, proctitis, mucosal ulceration, haemorrhage, and/or intestinal perforation. How- ever, since the renewal rate of the GI mucosa is rapid, such effects are usually short-lived. If prolonged, the result may be dehydration, electrolyte imbalance, inanition, and accelerated malnutrition. Alternatively, constipation may occur, particularly when vinca alkaloids arc empioycd, causing pain and adynamic ileus through effects on the autonomic nervous systm [209-211]. Diarrhoea can contribute to the malabsorption of nutrients that is a common effect of antineoplastic therapy. This results from toxic effects on the intestinal mucosa and/or the major organ systems.

Patients undergoing chemotherapy are 'at risk' of nutritional difficulties; active and aggressive nutritional support should be considered as a means of helping the patient to cope with the problems associated with this type of treatment and enhancing both response to treatment and quality of life.

However, the indirect effects of chemotherapy may also play an important role in the decline of nutritional status. For example, moniliasis or can- didiasis are common, particularly in paticnts with leukaemia and lymphoma affecting the oral cavity, pharynx, or oesophagus and causing a sore, painful mouth, odynophagia, dysphagia, and a dramatic decline in oral intake.

Learned food aversions may also arise as the result of an apparent association between specific foods and GI discomfort. In fact, it has been estimated that some 43% of patients receiving GI toxic chemotherapy develop such aversions [64], usually to novel foods [212], although repeated associ- ations between GI discomfort and specific foods can cause aversion to even familiar foods. Such effects may persist well after symptoms have subsided and may have significant implications for the nutritional support of such patients, indicating the

Table 4. Effects of some cancer chemotherapeutic agcnts on the gastrointestinal tract

Drug Anorexia Mucositis Nausea and oral ulceration

Vomiting Diarrhoea Intestinal ulceration

Other

Adriamycin "

Bleomycin * Cytarabinc

Cis-platin * Dactinomycin 5-Fluorouracil " Melphalan 6-Mercaptopurine "

Methotrexatc * Procarbazinc * Vinblastine * Vineristine

Hepatic dysfunction

Altered taste Abdominal pain

Hepatic dysfunction Abdominal pain

Abdominal pain Constipation Jaw pain

need for flexible feeding regimens and the availability of a variety of flavours and textures.

Radiation therapy (Table 5)

Since the intestinal mucosa is second only to the bone marrow in its sensitivity to radiation, curative doses of irradiation, particularly when directed at any portion of the GI tract, can result in severe nutritional deficiencies in a small, but significant. number of patients receiving either internal or external radiation and in whom intestinal toxicity may prove a limiting factor to intensive treatment. "l-his arises from effects of treatment on normal tissues and appears dependcnt on the dose. time. and fractionation of the administered dose as well as the arca of the treatment field. Acute or chronic effects may arise during, immediately following, or many years after radiotherapy; these include changes in the vasculoconncctive tissue and result in changes in the small blood vessels, destruction of the endothelium, and degeneration of the muscle. Because affected tissues are fibrotic and poorly vascularised, they are less resistant to mechanical injury and infection; after irradiation minor trauma, or infection, may induce serious complications in an already compromised tissue. As a result, flattening and/or ulceration of the mucosa epithe-

Table 5. Sequelae of radiation therapy: nutritional implications

373

lium, telangiectasis, arteritis, fibrosis, stenosis, or fistula formation may occur, and patients undergoing abdo-pelvic irradiation may experience nausea, vomiting, severe diarrhoea, and abdominal cramps [213] or. alternatively, may present with complete or partial intestinal obstruction which, on occa- sions, fail to respond to conventional treatment (although they may clear spontaneously after 4-5 days) [214]. Such symptoms are disabling and de- bilitating and can result in malnutrition and malabsorption, since the patient ingests less food and is less able to digest and absorb those nutrients available. Yet they must be accepted to some extent if an adequate dose of radiation is to be administered to a tumour lying in or near the GI tract. This makes aggressive nutritional support an obligatory adjunct to radiation therapy, both to prevent dete- rioration of nutritional status and to allow compen- satory hyperplasia of the undamaged bowel, for which an adcquate nutrient intake is essential [84].

It is clear that as malignancy progresses an affected individual is subject to many anatomic, physiologic, biochemical, and pharmacological effects that may result from one or more of the following: the systemic effects of malignancy, the local effects of the tumour, or one of man}' effects induced by treatment.

Treatmerll area During treatment Post lrcatnlCnl

Oropharyngeal region l.oss of taste Altered taste Xerostomia Xerostomia Odynophagia Damage to teeth Poor dentition Stomatitis.,'mucositis Mandibular nccrosi.,,

Lower ncck.'mediastinum Oesophagitis Ulceration Dysphagia Fibrosis Stcnosis.'stricturc Oesophageal stricture

Abdomcn.'pclvis Acute bowel damage Chronic bowel damage (enteritis) Diarrhoea Diarrhoca Malabsorptlon Malabsorption Obstruction Fistulae lormation

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Nutritional support in the cancer patient

The preceding discussion clearly demonstratcs the close relationship betwccn nutritional status and malignant disease, in which the altcrcd metabolism and the side effects of treatment frequently com- bine leading to protein energy malnutrition. Such malnutrition, in turn, interferes with the response to treatment and enhances morbidity, so that weight loss must be regarded as an important prog- nostic factor [6] and regular nutritional asscssment is mandatory, while nutritional support forms an important part of care and treatment. The objec- tives of nutritional support have been defined as a) supportive - to maintain nutritional status or to rehabilitate an already debilitated individual, b) part of a therapeutic regime (adjunctivc), and c) a means of maintaining life [7].

Although its aetiology is not understood, the long-term goals of nutritional support should be to prevent (or reverse) development of the cachcctic syndrome and, at the same time, to enhance the response to treatment. But, as cancer is only rarelv an acutely fatal disease [7], the short-tcrm benefits of nutritional care must also bc considered when support may result in a marked improvement in well-being and quality of life. It is now clear that malnutrition is NOT an obligatory accompaniment of cancer [7], and institution of nutritional support early in the course of the disease will help to prevent its occurrence; it is considerably morc difficult to rehabilitate an already malnourished individual. Each patient should be individually assessed so that factors inducing depletion can be identified.

The anorectic patient perhaps poses the greatest challenge, since such a patient is unlikely to meet his requirements through the oral route alone. Pro- vided GI function is reasonably normal, tube feeding, using a flexible, fine bore, non-irritating tube is the preferred means of supplementation through which complete feeds can be introduced into thc stomach or uppcr small intestinc. Enteral feeding has many metabolic advantages, particularly when compared to parenteral feeding, and is associated with fewer complications. 'Ready made' commer- cial formulae or locally produced fceding solutions can be used to feed the patient by this method. For

the patient with moderate malabsorption, slow, continuous gravity drip feeding is indicated [84]. However, nasogastric feeding may be associated with both emotional and physiological strcssors [215] including nasal soreness, oesophagitis, and deprivation of the pleasures gained from tasting, drinking, and chewing food [216], so that active steps should be taken to overcome such difficulties. The nasoenteral route may also increase upper airway resistance and interfere with respiratory ex- change [216], so an alternative solution should bc sought in thc patient with respiratory disease; feeding can bc carried out through an oesophagostomy, gastrostomy, or jejunostomy. These techniques are not restricted to use in the hospital setting, and patients and their relatives can be successfully taught to carry them out at home [202]. Thus, for the patient at continual risk of aspiration, cntcral feeding techniques can be used to avoid the need for continued hospitalisation.

However, enteral feeding is not always possible, particularly for the patient with severe malabsorption, persistent nausea and vomiting, or functional/ mechanical intestinal obstruction. As a result, considerable attention has bccn focussed on the use of total parenteral nutrition (TPN) and many workers have shown this to be beneficial in preparing patients for specific anti-tumour therapy and enabling its completion [c.g., 217 l. TPN has also been shown to improve wound healing and recovery [218] and the healing of post-operative fistulae, as well as improving general condition and mood. In some cases, for example in the patient with severe radiation enteritis, long-term survival may be dependent on TPN and home TPN is indicated; training of the patient, and/or a family member, can make this a feasible proposition [219, 220].

The increasing availability of many different methods of nutritional support means that it is rare to find a patient who cannot be supported in this way. Nutritional support is always indicated in the malnourished individual for whom aggressive anti- neoplastic therapy is planned and in the individual who may be expected to become malnourished as a result of such therapy. Although there is little doubt that nutritional status, turnout growth, and anti-tumour therapy are intimately related, it must

bc recognised that nutritional support per sc will not cure cancer unless the anti-neoplastic therapy is inherently effective [221]. It does, nonetheless, prevent malnutrition inevitably presages a poor outcome and, at the same time, enhances the patient's quality of life [222].

However, in the patient who fails to respond to anti-neoplastic therapy and for whom only pallia- tive care is possible the value of nutritional support may be questioned. It can be distressing for all those involved to watch the patient 'wasting away' as the disease, and the associated malnutrition, progress, and it can be very disturbing if nutritional suport is withdrawn. Good nutritional care can help to maintain the patient's morale, which is of particular importance when this is restricted by advancing disease; thus, if the patient wishes, support should continue using oral supplements or even tube feeding. However, there comes a point at which it is no longer appropriate to prolong life by forcing the patient to cat unwanted food, and aggressive nutritional support should not be continued. At this stage the patient should be given whatever food is desired in whatever form is re- quested. Nutrition no longer matters: what matters is to maintain the patient's morale and cncourage whatever enjoyment remains in the sight, smell, and taste of food.

C o n c l u s i o n s

- Continued research into both the pathogenesis and treatment of anorexia is essential before effective treatment can be identified.

- Anorexia is a significant factor in the decline of food intake. Whatever its cause, it is clear that the effects of malignancy result in a negative encrgy balance and contribute to the observed weight loss. The mechanisms must be elucidated before catabolism can be promoted in patients with cancer.

- Control of pain/discomfort/other symptoms is essential if food intake is to be maintained.

- Hypoalbuminaemia may disrupt drug therapy, reducing its effectivencss.

- Hypoalbuminacmia is common, and therefore

375

cannot be used as an effective indicator of nutri-

tional status. - The future of successful treatment depends on

an improved understanding of the changes in both protein metabolism per se and albumin metabolism, without which drug thcrapy may be of limited value and/or the efficiency and effectiveness of nutritional support may be lim- itcd.

- The role, function, and existence of lipid mobilising substances is cquivocal.

K e y u n a n s w e r e d q u e s t i o n s

- Do changes in energy metabolism apply equally

to all tumours? - To what degree are the reported intestinal

changes dependent on nutritional deficiency and to what extent do they depend on malignancy itself?

- Is anorexia, like depression, associated with serotonergic mechanisms - are they inter- related? ls another neurotransmitter involved?

- Do tumours elaborate lipid mobilising substances, or cause these to be produced else- where? l fso, is this significant in the weight loss observcd?

- Do lipid mobilising peptides account for hyperlipidaemia?

- ls the degree/extent of hyperlipidaemia dependent on the type of tumour?

- What, is the role of vitamins and trace el- ements2

- Are there any tumour specific (or site specific) metabolic changes?

- What will further longitudinal studies show?

R e f e r e n c e s

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3. Brennan MF: Total parenteral nutrition m the cancer patient. New Engl J Med 305: 375-382, 1981

4. I.andel AM, Hammond WG, Mcguid MM: Aspects of

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9. Lundholm K, Edstrom S, Karlberg I, Ekman L, Schcrsten T: Glucose turnover, gluconeogencsis from glycerol, and estimation of net glucose cycling in cancer patients. Can- ccr 50: 1142-1150, 1982

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11. Norton JA, Shamberger R, Stein TP, Milne GWA, Bren- nan MF: The influence of tumour bearing on protein metabolism in the rat. J Surg Res 30: 456-462, 1981

12. Midcr GB: Some aspects of nitrogen and cnergy metal'x)- lism in cancerous subjects: a review. Cancer Res 11: 821- 829, 1951

13. Begg RW, Lotz F: Clearing factor and hyperlipidacmia in tumour bearing rats. Proc Amcr Ass Cancer Res 2: 93--97, 1956

14. Begg RW, Lotz F: Further studies on clearing activity in tumour bearing rats. Proc Amcr Ass Cancer Rcs 2: 187- 195, 1957

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A ddre~s .[or of Iprints: Department of Biochemistry University of Storey, Guildlord. Surrcy GU2 5XH. United Kingdom

malignant disease: nutritional implications of disease and treatment

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