Int. J. Cancer: Supplement 11, 73–75 (1998) r 1998 Wiley-Liss, Inc. Publication of the International Union Against Cancer Publication de l’Union Internationale Contre le Cancer AGGRESSIVE ORAL, ENTERAL OR PARENTERAL NUTRITION: PRESCRIPTIVE DECISIONS IN CHILDREN WITH CANCER Paul B. PENCHARZ* Division of Gastroenterology and Nutrition, Research Institute, Hospital for Sick Children, Departments of Paediatrics and Nutritional Sciences, University of Toronto, Toronto, Canada Over the past 18 years, our laboratory has been interested in the pathogenesis of energy imbalance caused by a variety of diseases. Our view is that a clear understanding of the various factors causing negative energy balance, which in turn results in malnutrition, is the most effective way of designing preventive and therapeutic nutritional strategies. Thus, in cancer, one of the common factors is anorexia, due either to the primary tumor or to the effects of cancer therapy. Currently there is little evidence of increased resting energy expenditure in children with cancer, except in cases with very high tumor burden. Conversely, there are suggestions of a failure to down-regulate resting energy expenditure in the presence of reduced food intake in patients with cancer. Damage to the gastrointestinal tract, due to the effects either of the tumor or of tumor therapy, may result in maldigestion and/or malabsorption. Thus, as a result of a combination of reduced intake, reduced absorption and increased needs, the child with cancer may become malnourished. Prevention and treatment are dependent on the type of cancer and the pathogenesis of the negative energy balance. In broad terms, we try as far as possible to use external routes. With the advent of percutaneously placed gastrostomies and gastrojejunal tubes, we use these methods increasingly to provide nutritional support. Only in patients whose gastrointestinal tract cannot be used do we turn to i.v. feeding. In these patients, the placement of a central venous line is required, but great care must be taken to avoid infection. Whatever form of nutritional support is used, whether enteral or parenteral, we measure the body composition and energy expenditure in the patient, so that the nutritional therapy can be tailored to the child’s specific needs. Using these approaches, we are having significant success in preventing and reversing malnutrition in children with cancer and those undergoing bone-marrow transplantation. Int. J. Cancer Supplement 11:73–75, 1998. r 1998 Wiley-Liss, Inc. mediated through cytokines, including tumor necrosis factor (TNF). Some interesting insights have been obtained in animal studies, when infusion of TNF resulted in both anorexia and weight loss. There was no down-regulation of energy expenditure associated with this anorexia and weight loss, hence energy expenditure, the unit of lean mass, was not decreased (Hoshino et al., 1991). Other studies have shown that fat metabolism tends to be suppressed in favor of glucose metabolism (Sakurai et al., 1993; Beisel, 1995). This is in fact a futile cycle and does waste energy. Lean mass appears to be affected differentially, with more wasting of skeletal mass than of visceral protein mass (Cohn et al., 1981; Emery et al., 1984). Children with cancer are at a risk of suffering from undernutrition (Kien and Camitta, 1981), which, if severe, affects tolerance of therapy and may influence the overall survival of the patient. An important difference between nutritional support in children and in adults is that children, particularly those who are younger and smaller in size, have fewer reserves and therefore are at higher risk of developing malnutrition (Zlotkin et al., 1985; Pencharz, 1988; Wilson and Pencharz, 1997). Chronic diseases in childhood and/or their treatment can also have an adverse effect on growth (Zlotkin et al., 1985). All these considerations need to be kept in mind when managing the nutritional care of an infant or child with cancer. ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) AS A MODEL FOR METABOLIC DISTURBANCES PATHOGENESIS OF NUTRIENT IMBALANCE Cancer, like other chronic diseases, can affect nutrient balance adversely by a combination of factors. Cancer or cancer therapy can result in anorexia, vomiting or mal-digestion/mal-absorption, the net result being the reduction of absorbed nutrient intake. Metabolic disturbances can affect nutrient metabolism and result in inefficient use of nutrients. In some instances, energy expenditure is increased (Dempsey et al., 1984), but the available data for childhood cancer suggest that this occurs only when there is a high tumor burden (Stallings et al., 1989). In adults there are some tumors that appear to have more widespread metabolic effects, which are not fully understood. However, they are thought to be MALNUTRITION IN CANCER PATIENTS Malnutrition in pediatric cancer patients is not very common, at least in industrialized societies. Kien and Camitta (1981) reported on a prospective study of out-patients and in-patients. The prevalence of malnutrition in the out-patients was quite low, and consisted mostly of the wasting of fat mass. Conversely, in the in-patient population, the prevalence of wasting was higher and could be as high as 20% of their population. In this group there was wasting of muscle mass and of fat mass. More detailed body composition studies conducted in adults permitted measurements of total body potassium, nitrogen, water spaces and fat mass (Cohn et al., 1981). Interestingly, these authors showed that, in most cancer patients, weight loss is associated with loss of water and potassium, with some fat-mass loss and relative preservation of total body nitrogen. This implies that the lean mass lost is primarily skeletal muscle. There are few studies of the effects of cancer or cancer therapy on the protein and energy metabolism of children. Work by Kien and Camitta (1987) showed an increase in protein turnover in children presenting with acute lymphoblastic leukemia, also a highly significant correlation between resting energy expenditure and whole-body protein synthesis. Our group has also studied effects of ALL on protein energy metabolism and the changes seen with treatment (Stallings et al., 1989; Vaisman et al., 1993). The majority of the children, who were studied at diagnosis, had no changes in resting energy expenditure. However, a small group with hepatosplenomegaly and high tumor burden had an increase in resting metabolic rate (Stallings et al., 1989). Over the first 2 weeks of treatment, this hypermetabolism disappeared as the total tumor volume reduced. Protein synthesis and turnover were increased at presentation, and changed little in response to the first 2 weeks of therapy. Urinary urea excretion doubled in response to therapy over the first week, and remained high to the end of 2 weeks of treatment. *Correspondence to: Division of Gastroenterology and Nutrition, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada. Fax: (416) 813-4972. E-mail: firstname.lastname@example.org PENCHARZ 74 Subsequently, we studied children with ALL who were in remission on maintenance therapy consisting of oral 6-mercaptopurine (6 MP) and methotrexate given intravenously (Vaisman et al., 1993). 6-mercaptopurine increased protein synthesis by approximately 50%. However, 6 MP had no affect on fasting use of carbohydrate or fat. Conversely, the addition of methotrexate resulted in inhibition of carbohydrate utilization and promotion of fat utilization. This was also evident in the fed state. NUTRITIONAL SUPPORT Nutrient deficiency develops over a period of time, depending on the degree of negative balance and the amount of nutrient-energy reserve available. Therefore, with infants, it is important to be vigilant and to intervene early, whereas with adolescents, who have much larger reserves, there is more time to wait (Zlotkin et al., 1985; Pencharz, 1988; Wilson and Pencharz, 1997). We regard nutritional assessment as an important process in making a diagnosis with a view to intervention and treatment, and in monitoring that treatment. Nutritional anthropometry is used principally: careful measurements of weight and height are important, since from these parameters it is possible to calculate weight as a percent of ideal weight for height (Moore et al., 1985). We have also found mid-arm parameters to be very helpful, since the combination of mid-arm circumference and triceps skin fold allows the calculation of fat reserves from the triceps skin fold, and of muscle-protein reserves from the arm-muscle circumference or area (Pencharz, 1988). Per unit of body weight, requirements for protein (amino acids) and energy are higher in infants than they are in older children, and children have higher requirements than adolescents, ranging from 2.5 grams of protein/kg/day in infants down to 1 to 1.5 in adolescents. Similarly, energy requirements range from a high of 90 to 100 kilocalories/kg in infants to a low level of 40 kilocalories/kg in adolescents. FEEDING ROUTES Whenever possible, dietary therapy is to be preferred. However, mucositis (including esophagitis and gastritis), as well as disturbances of intestinal motility, may make oral feeding difficult if not impossible. In another chronic disease, cystic fibrosis (CF), we found that a general clinic policy towards improving dietary intake (high calorie and high fat; 30–40%) helped a great deal in avoiding the need for gastrostomy or i.v. feeding. Oral supplements are used widely, yet data regarding their effectiveness are largely absent. We conducted a study in children and adults with CF to determine whether ingestion of liquid supplements (such as Ensure, Pediasure or Boost), in addition to improving dietary intake, increases their energy intake (Kalnins et al., 1996), and found that it did not, in fact, it simply displaced food. Conversely, supplemental tube feeding by gastrostomy administered overnight, in similar patients with CF, in addition to oral intake during the day, was able to increase the total 24-hr intake and restore normal nutritional status. The advent of incisionless gastrostomy in the early 1980s has transformed the ability to provide enteral nutritional support. First was percutaneous endoscopic gastrostomy. One of the disadvantages of this technique, at least in cancer patients, is that the tube has to be pulled through the esophagus. If there is disease of the esophagus (such as mucositis), this might result in procedural difficulties and potential complications. In our own center we prefer to use radiologically placed gastrostomy tubes, and we now have experience with over 800 such tubes being placed in children with a wide variety of different conditions (Grunow et al., 1994). We use total parenteral nutrition (TPN) in a small proportion of patients with cancer, particularly those undergoing bone-marrow transplantation. We found that the use of central lines and concentrated solutions to minimize the amount of fluid administered has been a highly successful way of providing nutritional support. While we have been able to minimize the loss of lean tissue and fat reserves, there remain many unanswered questions on how to optimize such therapy. Due to the gastrointestinal disturbances in most of the children undergoing bone-marrow transplantation, fairly extensive periods of TPN are required. Having come through the bone-marrow transplant successfully, some of these patients in fact have feeding aversion and prove to be quite a challenge in the restoration of oral feeding. We now use cyclical TPN routinely and it has been helpful, in our experience, in getting the majority of these patients back on to oral feeds. In a small minority, we have had to turn to the placement of a percutaneous gastrostomy tube as a means of providing supplemental feeding at night. This allows the child’s feeding aversion to disappear gradually over a period of months at home. EFFECT OF DRUGS ON METABOLISM We have alluded already to the effects of chemotherapy on protein and energy metabolism. In relation particularly to energy balance, there have been suggestions that steroids might affect energy expenditure. However, carefully conducted studies showed that steroids have no effect on energy expenditure (Zeitlin et al., 1992). Conversely, ␤-adrenergic drugs, such as salbutamol, increase resting energy expenditure by 10 to 15%, and do so over a period of some hours (Vaisman et al., 1987). EFFECTS OF REFEEDING In our experience, nutritional rehabilitation is successful only when the patient is metabolically stable. Infection, for example, interferes with nutrient utilization. Similarly, some cancers, presumably those that secrete a lot of humoral factors including cytokines, disturb metabolism and thereby make nutritional rehabilitation difficult. Taking Crohn’s disease as another situation in which cytokines are secreted, we showed that, with effective therapy of the disease, it was possible to rehabilitate the patient nutritionally, restoring body composition to normal (Azcue et al., 1997). Nevertheless, the resting metabolic rate was still moderately increased per unit of lean mass. Care needs to be taken during refeeding not to cause fluid overload and the development of edema. In studies carried out in patients with anorexia nervosa, as a model of otherwise uncomplicated malnutrition, we showed that, during the early phases of refeeding, there was expansion in extra-cellular fluid volume even without the appearance of clinical edema (Vaisman et al., 1988). When refeeding a patient, with any condition, we do so slowly, at least during the first week. After that the level of energy and nutrients is moved up. SUMMARY AND CONCLUSION 1. Both the tumor and the therapy can have adverse effects on the nutritional status of children. 2. Generally, anorexia and other gastrointestinal side effects are manageable. 3. With some tumors, the metabolic effects of cytokine overproduction remain a problem and, for adults with cancer, thought is being given to using anti-cytokine therapy. Presently, there are no relevant data for children. 4. Graft vs. host disease in the bowel is an occasional but significant problem in some children after bone-marrow transplants. 5. Feeding aversion may be a long-term problem in the cancer patient who requires prolonged therapy, e.g., after bonemarrow transplantation. This may necessitate the placement of a gastrostomy tube for longer-term feeding. 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