Supportive Nutritional Intervention in Pediatrie Cancer1 · [CANCER RESEARCH (SUPPL.) 42, 766s-773s, February 1982] 0008-5472/82/0042-OOOOS02.00 Supportive Nutritional Intervention

[CANCER RESEARCH (SUPPL.) 42, 766s-773s, February 1982]0008-5472/82/0042-OOOOS02.00

Supportive Nutritional Intervention in Pediatrie Cancer1

Karyl A. Rickard, ' Robert L. Baehner, Thomas D. Coates, Robert M. Weetman, Arthur J. Provisor,

and Jay L. Grosfeld

Departments of Pediatrie Nutrition and Dietetics [K. A. R.¡, Pediatrie Hematology/Oncology [R. L. B., T. D. C., Ft. M. W., A. J. P.], and PediatrieSurgery [J. L. G.], James Whitcomb Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, Indiana 46223

Abstract

Nutritional support of the child with cancer now is recognizedas an important adjunct to cancer treatment. Protein-energymalnutrition frequently accompanies the diagnosis and treatment of children with neoplastic diseases. Common risk factorsfor the development of protein-energy malnutrition include ad

vanced stages of disease, lack of tumor responses, intensetreatment with curative intent (including chemotherapy cyclesat <3-week intervals, abdominal operative procedures, or ab

dominal and pelvic irradiation), and the absence of a supportivehealth care team which implements effective nutritional support. The impact of malnutrition may be reflected in toleranceof treatment, tumor response, and survival as well as in theincidence of complications. The risks and benefits associatedwith enterai and parenteral nutritional support are reviewed.Preliminary data from our institution document the severity ofalterations in nutritional status and the ¡mmunological competence associated with multimodal treatment of children withadvanced cancer. The effectiveness of enterai and parenteralnutrition in supporting a satisfactory nutritional status and/orreversing protein-energy malnutrition was evaluated in 28 chil

dren, ages 1 to 19 years, with a variety of neoplasms (21 solidtumors, 7 leukemia-lymphoma). A comprehensive enterai nu

trition program which included intense nutrition counseling andoral supplements was found to be ineffective in preventingnutritional depletion during initial intense treatment of mostchildren. Sixteen of 21 patients who received a comprehensiveenterai nutrition program had a decreased kilocalorie intake[48 ± 24% (S.D.) of the Recommended Dietary Allowance]and significant weight loss (16 ±6%). On the other hand, totalparenteral nutrition provided at a kilocalorie intake of 100% ofthe Recommended Dietary Allowance and 2.5 to 3 g aminoacids per kg for 28 or more days effectively restored muscleand fat reserves, increased serum albumin and transferrin tonormal concentrations, and, in most patients, reversed anergyto recall skin test antigens. A shorter period of total parenteralnutrition (9 to 14 days) did not restore appropriate weight forheight, fat reserves, and albumin concentration, although transferrin concentration was normalized and quality of life wasimproved. Of the group of 28 patients, 9 children (ages 1 to 7years) with Wilms' tumors had the most severe and predictable

malnutrition. A dramatic loss of weight (22 ±7% by 26 ±17days from the beginning of treatment) was associated withinitial intense treatment in children who received enterai nutrition. Every patient who received parenteral nutrition gainedweight despite continuing treatment. These data suggest that

most children with advanced Wilms' tumors will benefit from

early and continued provision of adequate nutrition, such asthat provided by total parenteral nutrition. Once patients completed the initial phase of treatment, however, enterai nutritionwas effective in restoring or maintaining muscle and fat reserves in patients who had no evidence of tumor. Furtherresearch is needed to determine the roles of enterai andparenteral nutritional support in children with specific tumortypes, when and how to implement effective enterai nutritionprograms, and the value of parenteral nutrition in the supportof the nourished child.

Nutritional support of the patient with cancer is attractingconsiderable attention as an important adjunct to cancer treatment. Effective nutritional support has been one of the mostimportant and potentially beneficial advancements in patientcare in the last 10 years. This report identifies children at highrisk for nutritional depletion, discusses the significance ofnutritional support, reviews the risks and benefits of enteraiand parenteral nutritional support, provides data regarding theeffectiveness of these modes of nutritional support in selectedpopulations of children with neoplasms, and summarizes conclusions regarding the use of enterai and parenteral nutrition inthe clinical management of children with cancer.

Childhood Neoplasms with High Risk for PEM

PEM2 is frequently observed at the time of diagnosis and

during treatment of childhood cancer (54, 59, 70). The incidence of PEM at diagnosis of childhood neoplasms varies from6% to as high as 50% (Table 1), depending upon tumor type,stage of disease, and criteria for PEM. Although data regardingthe incidence of malnutrition associated with specific tumortypes of childhood neoplasms and their treatment are sparse,some generalizations can be made which are consistent withclinical observations previously noted at this institution. Atinitial diagnosis or at the time of relapse, children with advancedstages of solid tumors have a higher incidence of PEM than dochildren with localized disease or children with leukemias.Although PEM may not be present at diagnosis, it may occurfrequently during treatment. A number of factors may significantly increase the risk of development of PEM in children withneoplasms (Table 2). The extent of disease at diagnosis or theintensity and mode of treatment designed to eradicate theneoplasm and tumor response are determinants for the development of PEM. In addition, the absence of a supportive healthcare team and lack of attention to enterai nutrition increase the

1 Presented at the Pediatrie Cancer and Nutrition Workshop, December 11

and 12, 1980, Bethesda, Md. Supported in part by Grants RO1 CA28005 andRO1 CA28531 from the National Cancer Institute, NIH, Bethesda, Md. 20205.

2 The abbreviations used are: PEM, protein-energy malnutrition; TPN, total

parenteral nutrition; RDA, recommended dietary allowance.

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Table 1

Frequency of various types of childhood neoplasms and associated risk of PEMat diagnosis

% of totalchildhood neo

Type of neoplasm plasms(63)Acute

leukemiasLymphocyticNonlymphocyticLymphomasHodgkin'sNonHodgkin'sCentral

nervous systemtumorsNeuroblastomaRetinoblastomaSoft-tissue

sarcomaWilms'tumorBone

sarcomasOsteosarcomaEwing'sLiver

tumorAllothers30.225.74.513.64.39.318.67.72.66.56.14.62.32.31.28.9Incidence

of PEM atdiagnosis2/34?;

6%"(54)10-1

5%°(17)79/19?75/161/8;4/6;??;

47%c;3\%d12.5%"

(70)67%"(70)

" Based on weight:height ratio of 80% <50th percentile for age or serum

albumin <3.0 g/dl.Adults; based on >10% weight loss.

0 Children with metastatic neuroblastoma at diagnosis; based on weight-for-

height <fifth percentile, >5% weight loss, or serum albumin <3.2 g/dl.Based on weight-for-height <fifth percentile, >5% weight loss, or serum

albumin <3.2 g/dl.

risk of PEM. The effects of therapy on nutritional status arediscussed in detail elsewhere in this workshop (22).

Significance of Supportive Nutritional Intervention

The impact of malnutrition in children with cancer may bereflected in their tolerance of treatment (28, 71), response tochemotherapy (10, 43), and duration of survival (17). In aprospective study of more than 3000 adults with cancer,DeWys ef al. (17) demonstrated a statistically significant effectof weight loss on median survival of patients with solid tumorswhen performance status and metastatic anatomic sites werecategorized. The effect of weight loss on survival, however,was not significant in patients with acute nonlymphocytic leukemia, possibly because of their poor survival rate. Preliminarydata from children with neuroblastoma at this institution supportthis observation (9). Nourished children with metastatic neuroblastoma at diagnosis appear to have a longer remissionperiod and survive longer than do malnourished patients.Whether the malnutrition present at the beginning of treatmentis simply a predictor rather than an influence on tumor responseto treatment is yet to be determined. Suffice it to say, however,that nutritional support will not cure cancer; rather, it canfunction only as adjuvant supportive therapy which allowssuccessful provision of oncological treatment.

Supportive nutritional intervention in children with cancer isbased upon the idea that vital organ system function is bettermaintained when the nutritional status of the patient is preserved. The functions of the pulmonary, cardiac, gastrointestinal, hepatic, lymphoreticular, and hematopoietic organ systems have been studied in animals as well as in humans invarious states of PEM. During PEM, alterations have beendocumented in each of these systems (Table 3). An adaptativephenomenon may preserve life of noncancer patients in statesof mild and moderately severe malnutrition. However, patientswith cancer may be stressed beyond adaptation because organsystems may be affected not only by malnutrition but also by

the cancer therapy (5, 44). The ability of the liver to metabolizechemotherapeutic agents and of the gastrointestinal tract toabsorb drugs and nutrients may be compromised in the malnourished state. In addition, malnourished children regularlyhave an impaired ¡mmunocompetence as evidenced by a frequent lack of response to skin test antigens (8, 25, 49). In thecancer patient, the immune status may be further compromisedby chemotherapy (41 ) or by radiotherapy to large segments ofthe bone marrow resulting in granulocytopenia due to bonemarrow suppression. Intercurrent infection and bleeding arefrequent complications and common causes of death in thesepatients (38). The effects of PEM on organ function are furtherdiscussed elsewhere in this workshop (30).

Risks and Benefits of Enterai and Parenteral Nutrition

Successful nutritional support of the child with cancer isdependent ultimately upon the provision of adequate nutrients,regardless of the route of administration. Enterai nutrient requirements, however, may differ from parenteral nutrient requirements because of selective absorption of some nutrientsby the gastrointestinal tract. Furthermore, nutrient requirements of cancer patients may differ from noncancer patients.Lawson (45) reported metabolic balance data which compared9 patients hyperalimented centrally with 6 cancer patientshyperalimented enterally and with similarly treated malnourished controls. Cancer patients who received hyperalimenta-

Table 2

Common risk factors for development of PEM in childhood neoplasms

Advanced disease at diagnosis or during treatment

Lack of tumor response

Abdominal and pelvic irradiation

Intense frequent courses at s3-wk intervals of cytotoxic chemotherapywhich cause nausea and vomiting, gastrointestinal toxicity, or hepatictoxicity in the absence of corticosteroids or appetite stimulants

Operative procedures of the abdomen or other abdominal complicationssuch as adynamic ileus, etc.

Psychological depression, absence of supportive health care team, andlack of attention to enterai nutrition

Table 3Organ system alterations associated with PEM in humans and animals

Pulmonary Lung vital capacity decreased by 30%; respiration duringexercise reduced (42)

Cardiac Decreased cardiac output; atrophie heart muscle (42)Gastrointestinal Morphological and cellular kinetic changes, resulting in

short, flat villi with decreased absorptive area (61); decreased production of pancreatic enzymes, especiallylaclase (67); altered bile acid synthesis (62); decreasedgastric motility and gastric emptying time (42); increased incidence of peptic ulcers (42)

Liver Atrophy and fatty degeneration (42)Spleen Atrophy of lymphoid tissue and Malpighian bodies; reduc

tion in splenic sinuses (42)Renal Relatively resistant (42)Hematopoietic Degeneration of fatty bone marrows; hyperplasia of red

marrow (42); normocytic, normochromic anemia (42)Lymphoreticular Thymus, T-lymphocytes, and cell-mediated responses im

paired (8, 27. 49); immunoglobulins usually normal orincreased (8)

Neurological Relatively resistant: peripheral neuropathies (?B vitamindeficiencies) (42)

Muscle Atrophy

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tion centrally retained significantly less phosphorus and magnesium than did noncancer controls, and cancer patients whowere given hyperalimentation enterally retained significantlyless phosphorus, potassium, nitrogen, chloride, and magnesium than did controls. We are at the beginning of an era whichhopefully will provide a better understanding of the nutrientrequirements of children with cancer and increased effectiveness in nutritional intervention. Data regarding the roles ofenterai and parenteral nutrition in support of children withspecific tumor types, when and how to implement effectiveenterai nutrition support programs, and the value of parenteralnutrition in the support of the nourished child are sparse.Known risks and benefits of enterai and parenteral nutrition willbe reviewed in the following sections.

Enterai Nutrition. Provision of nutrition via the enterai routeis the preferred method of feeding because it is more physiological, has a lower risk of infection and other catheter-relatedcomplications, is less expensive, and encourages more normalplay activities and life style. Often the disease or its treatmentinterferes with eating, taste sensations, or function of thegastrointestinal tract (13-15, 18, 20, 21, 23, 51). Alterations

in taste sensations noted in some adults are of particularinterest. Changes in taste sensation have been correlated withsymptoms of the patients, i.e., a general decrease in tastepleasurability with elevated sucrose thresholds (7, 73), meataversion with low bitter thresholds (14), and preference for tartjuices with increased sour acuity (73). In addition, elevated saltthresholds have been observed (7, 14, 73). Furthermore, tasteabnormalities have been correlated with tumor extent (7, 14)and with reduced energy intake (7, 14, 32, 73). Conceivably,this information can be used to develop nutritional interventionstrategies which enhance acceptance of food (7, 14, 15, 18,73). For example, patients with an elevated sweet thresholdmay find that the addition of sugar enhances palatability, orpatients who have an aversion to meat because of tastechanges may enjoy alternate sources of protein such as eggs,peanut butter, and cheese.

A number of factors besides those directly due to the diseasemay contribute also to an inadequate food intake. For instance,misconceptions about food, fear of disease, unfamiliar foods,hospital routines which conflict with meals, lack of attention tothe needs of a patient, learned food aversions (1-3, 65),

trauma associated with medical procedures, and pain mayinterfere with eating. There are few data to evaluate the effectiveness of enterai nutrition when these factors are taken intoconsideration. An intense, individualized enterai feeding program that minimizes these obstacles still may provide an efficient method to support many children with cancer. Regardlessof the effectiveness of parenteral support, the limitations oftime and cost demand that enterai feeding be the primary modefor provision of nutrients during most of the treatment period.

Enterai nutritional supplementation (ad libitum) has beenreported to provide some benefit in delayed hypersensitivityskin test responses (24) and in preventing PEM (26) in someselected types of adult cancers. A patient's acceptance of

enterai supplements may be influenced by taste alterationsassociated with cancer. DeWys and Herbst (18) reported significant differences in supplement preference scores betweencancer patients and normal controls, and a correlation of bittertaste recognition threshold with overall preference scores.

Unfortunately, the patients with a low bitter taste thresholdwere more likely to give negative preference scores than werethose with a normal threshold. These findings are consistentwith our observations that the children who have a reducedintake and a particular need for supplements may be the leastlikely to accept them. In our experience with children who haveadvanced cancer, supplements have provided some benefit ina small subgroup of older infants and toddlers, especially thosewho were being bottle fed. The role of supplements in theprovision of enterai nutrition for children has not been extensively evaluated.

Donaldson et al. (23) suggested that the prophylactic use ofa special diet may prevent acute and chronic radiation enteritis.This diet was devoid of gluten, cow's milk protein, and lactose

and was low in fat and residue. Several other investigators (4,24) have reported the use of a defined formula for adult patientswho were receiving abdominal or pelvic irradiation. Perhapsthe most significant benefits observed in these patients werethe preservation of cellular immunity (24) and the minimizationof the decrease in total lymphocyte count following irradiation(4).

In children with neoplastic diseases, the currently availabledefined-formula diets with amino acids or hydrolysates substi

tuted for intact proteins have been almost universally rejectedby young children because of poor palatibility, nonacceptanceof a new and strange taste, or possibly aversive conditioning.Even more familiar foods may not be eaten during this time.Force feedings by nasogastric tube are not considered anacceptable option in very young children because of possibleemesis with resulting aspiration, the potentiation of nauseaduring abdominal irradiation and chemotherapy, and the youngpatients' resistance to insertion of a nasogastric tube. An older

child may cooperate and can be taught to pass his own nasogastric tube. Continuous-drip enterai tube feedings during the

night have been beneficial in a few patients with a functionalgastrointestinal tract. Every effort has been made to makeeating (and the hospitalizaron experience) a positive ratherthan an adverse experience. This is especially important because the duration of treatment may continue for several yearsand the child's cooperation with regard to eating programs is

essential over the long run. More acceptable options consist ofeither an enterai nutrition program which utilizes nutritiousfoods more familiar to children during treatment-free periods

or parenteral nutrition programs.Parenteral Nutrition. Parenteral nutrition bypasses the limi

tations of reduced caloric intake from nausea and vomiting aswell as from anorexia (15, 34, 47, 66) associated with tumorburden, cancer treatment, and/or PEM. Cost of parenteralnutrition is substantial, and a high quality of care is essential.Known risks or complications (e.g., infection, liver dysfunction,hepatomegaly, thrombus formation, and a multiplicity of metabolic complications) may be associated with TPN. Risks canbe minimized or safely controlled with careful patient management and strict adherence to a parenteral nutrition protocol. Ina multiinstitutional study of complications observed in adultpatients randomized to either TPN (125 patients) or control,non-TPN (126 patients) groups, Mullen (48) reported that theadministration of TPN adds little serious morbidity and mortality. An increased incidence of fever ( p < 0.003), anemia (p <0.09), and pulmonary dysfunction (p < 0.13) was observed in

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the TPN group; however, the frequencies of the latter 2 complications were not significantly different from those of thecontrol group. Although incidence of fever was higher in theTPN group, both groups had a similar incidence (25%) ofdocumented infections at distant sites. In the TPN group, 6%had catheter tip infections and 4% had infections at the catheter exit site. Thus, 30% in the TPN group and 11 % in the non-

TPN group had fevers of unexplained etiology. Van Eys et al.(71 ) reported a 3% incidence of catheter-related infections and

a 10% incidence of sepsis unrelated to the catheters in a seriesof 25 children who received TPN. Of interest was the fact thatthe infection rate was higher in malnourished children. Filler efal. (28) reported a sepsis rate of 8% associated with TPNadministered to a series of 65 children with cancer. The possibility that TPN stimulates tumor growth in excess of hostrepletion needs to be considered, although clinically this hasnot been observed when aggressive treatment is given simultaneously. In fact, it is conceivable that TPN may beneficiallystimulate cell replication and increase effectiveness of cellcycle-specific drugs, although this has not been apparent inseveral recent prospective controlled studies of adults withspecific types of tumors (50, 53).

The expense and risks associated with parenteral nutritionneed to be carefully considered in relation to potential benefits.Several controlled prospective studies of parenteral nutritiongiven by central vein to selected populations of malnourishedchildren with neoplastic disease have demonstrated the following benefits: effective reversal of PEM (59, 71); restoration ofimmunocompetence in some patients (57, 59); and fewer doseadjustments of chemotherapy (71). The benefits of parenteralnutrition for nourished children with cancer and for malnourished children with specific tumor types remain to be established.

Effectiveness of Enterai and Parenteral Nutrition: The RileyHospital Experience

Patients and Methods. In the absence of sufficient data inthe literature relating to the nutritional management of children,the effectiveness of enterai and parenteral nutrition regimenswas evaluated in children with advanced cancer (59) (Table 4).These children had the most aggressive treatment and, therefore, were expected to have the most significant nutritionalproblems. Similar treatment protocols were used for eachtumor type. Children with Stage III and IV solid tumors andsecond-relapse leukemia-lymphomas were assigned to 2

Table 4Types of neoplasms and frequency in the population of children studied at our

institution

The study comprised 14 females and 14 males; 1 to 19 years old (59).

No. ofaffected

childrenWilms'tumor

NeuroblastomaEwing's sarcoma

RhabdomyosarcomaNon-Hodgkin's lymphoma

Second relapse leukemia-lymphomaHodgkin's lymphoma

Embryonal cell carcinoma9

5333311

groups at diagnosis according to nutritional status (nourished,depleted).

Children received a comprehensive enterai nutrition programif they were considered nourished at diagnosis. This consistedof intense nutritional counseling and p.o. supplements. A concerted effort was made to encourage adequate p.o. intakethrough age-appropriate individual counseling, provision of

pediatrie menus, readily available snacks, an atmosphere conducive to eating in age-related-play dining rooms, child-ori

ented nutritional education experiences (19, 58), play activities, and parent care facilities. Continuity of nutritional carewas provided by the same pediatrie dietitian. Neither vitaminnor iron supplementation was used.

Children received TPN if they were considered nutritionallydepleted. Children were considered nutritionally depleted ifthey had a recent weight loss greater than 5%, were below thefifth percentile on weight-for-height grids, or had a serum

albumin concentration of less than 3.2 g/dl. Parenteral nutrition provided a synthetic nutrient mixture of amino acids (2.55g amino acids per dl; Free Amino II; McGaw Laboratories,Milledgeville, Ga.), glucose, minerals, and vitamins (1 ml Mul-

tivitamin Infusion; USV Pharmaceutical Corporation, Tuckahoe,N. Y.). Nutrients were administered through a central hyperal-

imentation catheter placed into the superior vena cava understerile conditions. The catheter was attached to on-line micro-

pore filters and pumps; catheter care techniques were described previously (59). Additionally, several nutrients weregiven weekly by i.m. injection including: 1 mg folie acid; 100mg hydroxycobalamin; and 1 mg vitamin K. Also, a fat emulsionwas administered (2 g fat per kg per day) via peripheral veins3 times per week. Concentrations of glucose (15 to 25 g/dl)and rate of administration were increased over a 5- to 7-day

period to provide an arbitrarily set goal of 100% of the RDA forkilocalories, since parenteral nutrient intake standards for children with cancer do not exist.

Children with Advanced Disease. At the beginning of therapy, 21 patients received an enterai nutrition program while 7received TPN. Sixteen of the 21 children who were considerednourished and received enterai nutrition at the beginning ofcancer treatment had a decreased nutrient intake [48 ±24%(S.D.) RDA] and significant weight loss (16 ±12%). Althoughenterai nutrition was generally ineffective, TPN provided for 28or more days was quite effective. A total of 18 children receivedTPN for an average of 24 days; kcal averaged 90 ±26% RDAduring weight gain. TPN effectively restored muscle and fatreserves, increased serum albumin from 3.06 ±0.38 to 3.48±0.53 g/dl, increased serum transferrin from 175 ±62 to236 ±40 mg/dl, and, in most patients, restored recall skintest reactivity to several antigens. At the beginning of TPN,only 1 of 18 patients was reactive to recall skin test antigens,whereas 7 of 11 children retested at the end of TPN werereactive. The total lymphocyte count, however, decreased from1102 ±966 to 737 ±677 despite nutritional repletion withTPN.

Since duration of TPN from the beginning to the end variedfrom 7 to 60 days, biochemical and anthropométrie measurements were further evaluated at short intervals (9 to 14 days)or long intervals (28 days) of TPN. TPN for 28 days significantlyimproved weight gain, subscapular skinfold measurements,serum albumin, and transferrin (Table 5). In contrast, TPN for

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Table 5

Effect of duration of TPN administration on repletion of anthropométrie and biochemical parameters of nutritionalstatus in children with advanced cancer (59)

Duration ofTPN (days)

Wt gainA subscapular skinfold

(mm) A albumin (g/dl)A transferrin (mg/

dl)

289-143.27 ±1.89a" (11)°1.33 ±0.95a (15)Ì6

±68 ±6+

0.98 ±0.58a (9)

+ 0.45 ±0.58 (6)+

0.62 ±0.43a (10)

-0.44 ±0.38 (9)+

62 ±42a (9)+ 45 ±46" (7)

Very significant difference; p < 0.01.0 Mean ±S.D.c Numbers in parentheses, number of determinants." Significant difference; p < 0.05.

9 to 14 days restored neither serum albumin concentrations,nor skinfold reserves, nor appropriate weight for heights (although weight increases were significant). These data documented nutritional and immunological benefits of a 28-day

course of TPN for malnourished children who were receivingintense treatment for advanced cancer. In addition, TPN allowed patients to continue vigorous treatment protocols whichotherwise may have been jeoparidized or impossible due tolack of tolerance. The small and heterogeneous group of patients from this early study did not allow conclusions regardingthe relationship of a satisfactory nutritional status throughouttreatment to tumor response or to length of survival.

Children with Wilms Tumors. Of the group of 28 patientsinitially studied, 9 children (ages 1 to 7 years, 8 female) withWilms' tumors had the most severe and predictable malnutrition

(60). These children received treatment outlined in the NationalWilms' Tumor Study II Protocol. Initial, intense treatment con

sisted of operative removal of primary tumor, 5 days of acti-

nomycin D, weekly vincristine, and abdominal irradiation to thetumor bed. Maintenance chemotherapy treatment included 5-

day courses of actinomycin D and vincristine at 3, 6, 9, 12,and 15 months from diagnosis. In addition, 4 patients receivedAdriamycin between the 3-month cycles. At diagnosis, 8 children received a comprehensive enterai nutrition program whileone received TPN. Four of those who initially received enterainutrition subsequently received TPN.

A dramatic loss of weight (22 ±7% by 26 ±17 days fromthe beginning of treatment) was associated with initial, intensetreatment in the children who received enterai nutrition. On theother hand, every patient gained when receiving parenteralnutrition. During the period of intense treatment and weightloss, intake of kilocalories averaged 64% RDA whereas TPNprovided 105 ± 9% RDA during weight gain. At the lowestweight (during enterai nutrition), 7 of the 8 patients were belowthe fifth percentile on weight-for-height grids (35) and belowthe tenth percentile on skinfold grids (40). Initial data indicatedthat 10 days of TPN was not sufficient for restoring an appropriate weight for height and, furthermore, that TPN was neededuntil the end of the intense treatment period (abdominal irradiation). Longer intervals (28 or more days of TPN) restored anappropriate weight for height, significantly increased serumtransferrin and albumin concentrations, and reversed anergyin 4 of 5 patients retested despite low lymphocyte counts.Once a patient completed the initial, intense phase of treatment, enterai nutrition was then effective in restoring or maintaining muscle and fat reserves in the children who had noevidence of tumor. Loss of weight and fat reserves precededthe clinical evidence of tumor relapse in 2 patients.

Conclusions and Implications for Clinical Management

A comprehensive enterai nutrition program was not effectivein preventing severe nutritional depletion during the initial andintense phases of cancer treatment for most of the childrenwith advanced disease, although some benefits from this program were observed. Emotional support and understandingwere provided for the child and his family during the treatmentof a disease which may otherwise engender an overpoweringsense of helplessness. A continuing relationship and soundnutrition philosophy were developed which facilitated the latersuccess of an enterai nutrition program, once the child waspast the most intense phase of his treatment. Nutritional depletion of children with Wilms' tumors was the most dramatic and

predictable. Once a patient became malnourished, anorexiaand other complications associated with PEM (6, 61, 62, 67)were compounded by the side effects and complications ofalmost continuous cancer treatment for 40 to 60 days (operative resection at diagnosis, chemotherapy, and abdominal irradiation of 1800 to 4000 rads). Preliminary data from thesepatients suggest that most children with advanced Wilms' tu

mors will benefit from early and continued provision of adequate nutrition, such as that provided by TPN, throughout theinitial and intense treatment periods. Adjunctive TPN (or othereffective nutritional support) seems imperative for patients withStage IV disease, patients with unfavorable histology whoreceive the most rigorous treatment, and those severely malnourished at the onset. In these patients, nutrient intake isunlikely to be adequate for maintenance of a satisfactorynutritional state or for repletion during the first 40 to 60 daysof treatment.

Based upon previous data, however, some nourished andmarginally nourished children can be adequately supportedwith enterai nutrition. Usually, these are older children who arein maintenance phases of treatment, who respond to treatment,or who have less advanced disease. While it is possible tomaintain nutrition enterally in some nourished children, it isvery difficult if not impossible to replenish patients enterally.Parenteral nutrition is delayed often in hopes that the malnourished child will start eating. It is our experience that the childwho is malnourished at diagnosis will remain so throughoutintense treatment with curative intent. Furthermore, the childoften becomes more severely malnourished and suffers numerous complications if not given adequate nutritional support.

TPN given for 28 or more days (at 90 to 100% RDA forkilocalories) was effective in nutritionally repleting patients.Administration of TPN for 9 to 14 days was not sufficient torestore an appropriate weight, fat reserves, and serum albumin

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concentrations, although serum transferrin concentration wasnormalized and quality of life was improved. These observations suggest that a 10-day interval of TPN provided at 100%PDA for kilocalories (in the absence of parenteral nutrientstandards for children with cancer) and 2.5 to 3 g amino acidsper kg is the minimum duration of treatment which providesbenefit for the malnourished child. Usually, 21 or more days ofTPN are necessary for restoration of an appropriate weight forheight and for normalization of serum proteins in the severelymalnourished child. Weight, skinfold measurements, and serumproteins provide only a gross estimate of renourishment. Therepletion of the cancer patient may not bezeuch a simpleprocess since body weight may increase with an unchangedcell mass and other minerals may remain depleted (45). Inadequate repletion noted in several recent TPN studies (50, 64)with adults who have cancer may be related to altered hostmetabolism (29, 36, 46, 72), to the composition of the nutrientmixture, to a nonoptimal route and schedule of delivery, and toinsufficient duration of therapy (16). The timing of parenteralnutritional support in relation to chemotherapy may be alsocritical in determining the myelotoxicity and cell cycle-specificdrug effectiveness (56). These are significant areas of concernwhich need further research.

References

1. Bernstein, I. L. Learned taste aversions in children receiving chemotherapy.Science (Wash.. D.C.). 200. 1302-1303, 1978.

2. Bernstein. I. L., and Bernstein, I. D. Learned food aversions and cancercachexia. Cancer Treat. Rep., in press. 1981.

3. Bernstein, I. L., and Sigmundi, R. A. Tumor anorexia: a learned aversion?Science (Wash., O.G.), 209. 416-418, 1980.

4. Bounous, G.. LeBel, E.. Shuster, J., Gold, P., Tahan, W. T., and Bastin, E.Dietary protection during radiation therapy. Strahlentherapie, 149: 476-483, 1975.

5. Brennan. M. F. Uncomplicated starvation versus cancer cachexia. CancerRes.. 37: 2359-2364. 1977.

6. Brunser. O , Castillo, C . and Araya, M. Fine structure of the small intestinalmucosa in infantile marasmic malnutrition. Gastroenterology, 70: 495-507,1976.

7. Carson, J. S., and Gormican, A. Taste acuity and food attitudes of selected .patients with cancer. J. Am. Diet. Assoc., 70. 361-365, 1977.

8. Chandra, R. K. Interactions of nutrition, infection and immune response.Acta Paediatr. Scand., 68. 137-144, 1979.

9. Coates. T. D., Detamore, C. M., Rickard. K. A., Grosfeld, J. L., Weetman, R.M., Provisor, A. J., and Baehner, R. L. Relation between nutritional Status atdiagnosis and outcome in Stage III and IV neuroblastoma. Proc. Am. Assoc.Cancer Res.. 22. 402. 1981.

10. Copeland, E. M.. Ill, Daly, J. M., and Dudrick, S. J. Nutrition as an adjunctto cancer treatment in the adult. Cancer Res.. 37: 2451-2456. 1977

11. Copeland. E. M., Ill, Daly, J. M., Ota, D. M., and Dudrick, S. J. Nutrition,cancer and intravenous hyperalimentation. Cancer (Phila.). 43: 2108-2116,1979.

12. Copeland, E. M., Ill, MacFadyen, B. V., and Dudrick, S. J. Effect of intravenous hyperalimentation on established delayed hypersensitivity in the cancerpatient. Ann. Surg., 184: 60-64, 1976.

13. Costa, G., and Donaldson, S. S. Effects of cancer and cancer treatment onthe nutrition of the host. N. Engl. J. Med., 300. 1471-1473, 1979.

14. DeWys. W. D. Changes in taste sensation and feeding behavior in cancerpatients: a review. J. Hum. Nutr., 32. 447-453, 1978.

15. DeWys, W. D. Anorexia as a general effect of cancer. Cancer (Phila.), 43.2013-2019. 1979.

16. DeWys, W. D. Nutritional support and cancer therapy. Cancer Treat. Rep.,in press, 1981.

17. DeWys, W. D.. Begg, C., Lavin. P., Band, P., Bennett, J., Berlino, J.. Cohen.M., Douglass, H., Engstrom, P., Ezdinli, E., Morton, J., Johnson, G., Moertel,C., Oken, M.. Perlia, C., Rosenbaum, C., Silverstein, M., Skeel, R., Sponzo.R., and Tormey, D. Prognostic effect of weight loss prior to chemotherapyin cancer patients. Am. J. Med., 69. 491-497, 1980.

18. DeWys, W. D., and Herbst, S. H. Oral feeding in the nutritional managementof the cancer patient. Cancer Res., 37. 2429-2431. 1977.

19. Dixon, G., and Richard, K. A. Nutrition education for young patients. Child.Today, 4: 7-11, 1975.

20. Donaldson, S. S. Nutritional consequences of radiotherapy. Cancer Res.,37:2407-2413. 1977.

21. Donaldson, S. S. Alterations of nutritional status: impact of chemotherapyand radiation therapy. Cancer (Phila.), 43: 2036-2052, 1979.

22. Donaldson. S. S. Effects of therapy on nutritional status of the pediatriecancer patient. Cancer Res. (Suppl.), 42: 729s-736s, 1982.

23. Donaldson, S. S., Jundt, S., Ricour, C., Sarrazin, D., Lemerle, J., andSchweisguth, D. Radiation enteritis in children: a retrospective review,clinicopathologic correlation and dietary management. Cancer (Phila.), 35.1167-1178, 1975.

24. Douglass. H., Milliron, S., Nova, H., Eriksson, B., Thomas, P.. Novick, A.,and Holyoke, E. Elemental diet as an adjuvant for patients with locallyadvanced gastrointestinal cancer receiving radiation therapy: a prospec-tively randomized study. J. Parenteral Enterai. Nutr. 2. 682-686, 1978.

25. Edelman, R. Cell-mediated immune response in protein calorie malnutrition—a review. In: R. M. Suskind (ed.). Malnutrition and the immune response, pp. 47-75. New York: Raven Press, 1977.

26. Elkort, R., Baker, F., Vitale, J., Varvousek-Jakuha, E., and Cordano, A.Optimal enterai nutritional support as an adjunct to breast cancer chemotherapy: Preliminary report. J. Parenteral Enterai Nutr. 2: 676-681, 1978.

27. Faulk, W. P., Mata, L. J., and Edsall, G. Effects of malnutrition on theimmune response in humans: a review. Trop. Dis. Bull., 50: 89-103, 1975.

28. Filler. R. M., Jaffe, N., Cassady, J. R., Traggis, R. G., and Das, J. B.Parenteral nutritional support in children with cancer. Cancer (Phila.), 43:2117-2120, 1979.

29. Gold, J. Hydrazine sulphate and cancer cachexia. Nutr. Cancer, 4: 4-9,1979.

30. Good. R. A.. West, A., Day. N. K., Dong, Z-W.. and Fernandes, G. Effects ofundernutrition on host cell and organ function. Cancer Res. (Suppl.), 42:737S-746S, 1982.

31. Gormican, A. Influencing food acceptance in anorexic cancer patients.Postgrad. Med., 68: 145-152, 1980.

32. Gorshein, D. Posthypophysectomy taste abnormalities: their relationship toremote effects of cancer. Cancer (Phila.), 39: 1700-1703, 1977.

33. Haffejee, A., and Angorn, I. Nutritional status and the nonspecific cellularand humoral immune response in esophageal carcinoma. Ann. Surg., Õ89:475-479, 1978.

34. Hall, J. C. The cachexia of cancer. Biomedicine (Paris), 30: 287-291, 1979.35. Hamill, P. V., Drizd, T. A., and Johnson, C. L. Vital and health statistics.

NCHS growth curves for children birth-18 years United States. Series II(165) Rockville, Md.: United States Department of Health. Education, andWelfare, Public Health Service. 1977.

36. Holroyde, C. P. Carbohydrate metabolism in the cancer patient. CancerTreat. Rep., in press, 1981.

37. Hugon, J. S., and Bounous, G. Elemental diet in the management of theintestinal lesions produced by radiation in the mouse. Can. J. Surg., 15:18-26,1972.

38. Inagaki, J., Rodriguez, V., and Bodey, G. P. Causes of death in cancerpatients. Cancer (Phila.), 33: 568-573, 1973.

39. Issell, B. F., Valdivieso, M., Zaren, H. A., Dudrick, S. J., Freireich, E. J.,Copeland, E. W., and Bodey, G. P. Protection against chemotherapy toxicityby i.V. hyperalimentation. Cancer Treat. Rep., 62: 1139-1143, 1978.

40. Karlberg. T., Taranger, J., Engstrom, E., Lichtenstein. H., and Svennbergre-degren, I. The somatic development of children in a Swedish urban community. Acta Pediatr. Scand. Suppl. 258, 1976.

41. Karnofsky, D. A. Late effects of immunosuppressive anticancer drugs. Fed.Proc., 26. 925-933, 1967.

42. Keys, A.. Brozek, J.. Henschel, A., Mickelsen. O., and Taylor, H. L. Thebiology of human starvation. Minneapolis: University of Minnesota Press,1950.

43. Lanzotti, V. J., Copeland, E. M. III. George, S. L., Dudrick, S. J., andSamuels, M. L. Cancer chemotherapeutic response and intravenous hyperalimentation. Cancer Chemother. Rep., 59: 437-439, 1975.

44. Lawrence, W. Effects of cancer on nutrition. Cancer (Phila.), 43: 2020-2029, 1979.

45. Lawson, D. H. Nutrition support of the cancer patient. Cancer Treat. Rep.,in press, 1981.

46. Lundholm, K. Metabolism in peripheral tissue in cancer patients. CancerTreat. Rep., in press, 1981.

47. Morrison, S. D. Origins of anorexia in neoplastic disease. Am. J. Clin. Nutr.,31: 1104-1107, 1978.

48. Mullen. J. L. Complications of total parenteral nutrition in the cancer patient.Cancer Treat. Rep., in press, 1981.

49. Neumann, C. G., Lawlor, G. J., Stiehm, E. R., Swendseid, M. E., Newton,C., Herbert, J., Ammann, A. J., and Jacob, M. Immunologie responses inmalnourished children. Am. J. Clin. Nutr., 28: 89-104, 1975.

50. Nixon, D. W., Moffitt, S., Lawson. D. H.. Ansley, J., Lynn, M. J., Kutner, M.H., Heymsfield, S. B.. Wesley, M., Chawla, R., and Rudman, D. Totalparenteral nutrition as an adjunct to chemotherapy of metastatic colorectalcancer. Cancer Treat. Rep., in press, 1981.

51. Ohnuma. T., and Holland, J. F. Nutritional consequences of cancer chemotherapy and immunotherapy. Cancer Res.. 37: 2395-2406, 1977.

FEBRUARY 1982 771S

on April 13, 2017. © 1982 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from

K. A. Rickard et al.

52. Paniagua. R., Santos, D.. Muñoz, R., Luengas, J., and Frenk. S. Renalfunction in protein-energy malnutrition. Pediatr. Res., 14: 1260-1262,1980.

53. Popp, M. B., Fisher, R. I., Simon, R. M., and Brennan, M. F. A prospectiverandomized study of adjuvant parenteral nutrition in the treatment of diffuselymphoma. I. Effect on drug tolerance. Cancer Treat. Rep., in press, 1981.

54. Ramirez, I., van Eys, J., Carr. D., Carter, P., Coody, D., Taylor, G. Malnutrition in children with malignancies. Proc. Am. Assoc. Cancer Res., 2). 378,1980.

55. Recommended Dietary Allowances, Ed. 8. Washington, D. C.: NationalAcademy of Sciences, 1974.

56. Reynolds. H. M., Daly, J. M.. Rowlands. B. J.. Dudrick, S. J., and Copeland,E. M. Effects of nutritional repletion on host and tumor response to chemotherapy. Cancer (Phila.), 45. 3069-3074, 1980.

57. Rickard, K. A., Baehner, R. L, Provisor, A. J., Weetman, R. M., and Grosfeld,J. L. The effects of hyperalimentation on immune function and tumor growth.In: Nutrition in the 1980s: Constraints on Our Knowledge, pp. 339-347,New York: Alan R. Liss, Inc., 1981.

58. Rickard, K. A., and Farnum, S. Food for fun and thought: nutrition educationin a children's hospital. J. Am. Diet. Assoc., 65. 294-297, 1974.

59. Rickard, K. A.. Grosfeld, J. L., Kirksey. A., Ballantine, T. V. N., and Baehner,R. L. Reversal of protein-energy malnutrition in children during treatment ofadvanced neoplastic disease. Ann. Surg., 790: 771-781, 1979.

60. Rickard. K. A., Kirksey, A., Baehner, R. L., Grosfeld, J. L., Provisor. A. J.,Weetman. R. M.. Boxer. L. A., and Ballantine, T. V. N. Effectiveness ofenterai and parenteral nutrition in the nutritional management of Wilms'

tumors. Am. J. Clin. Nutr., 33. 2622-2629, 1981.61. Schneider, R. E., and Viteri. F. E. Morphological aspects of the duodenoje-

junal mucosa in protein-calorie malnourished children and during recovery.Am. J. Clin. Nutr.. 25. 1092-1102. 1972.

62. Schneider, R. E., and Viteri, F. E. Luminal events of lipid absorption in

protein-calorie malnourished children; relationship with nutritional recoveryand diarrhea. II. Alterations in bile acid content of duodenal aspirates. Am.J. Clin. Nutr., 27. 788-796, 1974.

63. SEER Program. National Cancer Institute, 1973-1976 data. CA—Cancer J.Clin., 30. 38, 1980.

64. Serrou, B., Cupissol, D.. Plagne, R., Boutin, P., Carcassonne. Y.. and Michel,F. B. Parenteral intravenous nutrition (PIVN) as an adjunct to chemotherapyin small cell anaplastic lung carcinoma. Cancer Treat. Rep., in press, 1981.

65. Smith. J. C., and Blumsack, J. T. Learned taste aversion as a factor incancer therapy. Cancer Treat. Rep., in press, 1981.

66. Theologides, A. Cancer cachexia. Cancer (Phila.). 43: 2004-2012, 1979.67. Truswell. A. S. Carbohydrate and lipid metabolism in protein-calorie malnu

trition. In: R. E. Olson (ed.), Protein-Calorie Malnutrition, pp. 119-141. NewYork: Academic Press, Inc., 1975.

68. Valdivieso, M., Bodey. G. P.. Benjamin, R. S.. Barkley, H. T., Freeman, M.B., Ertel, M., Smith, T. L., and Mountain, C. F. Role of intravenous hyperalimentation as an adjunct to intensive chemotherapy for small cell broncho-genie carcinoma: preliminary observations. Cancer Treat. Rep., in press,1981.

69. Van Eys. J. Nutritional therapy in children with cancer. Cancer Res., 37;2457-2461, 1977.

70. Van Eys, J. Malnutrition in children with cancer: incidence and consequence.Cancer (Phila.), 43: 2030-2035, 1979.

71. Van Eys, J., Copeland, E. M., Cangir, A.. Taylor, G., Teitell-Cohen. B..Carter, P., and Ortiz, C. A clinical trial of hyperalimentation in children withmetastatic malignancies. Med. Pediatr. Oncol., 8: 63-73. 1980.

72. Waterhouse, C. Oxidation and metabolic interconversion in malignant cachexia. Cancer Treat. Rep, in press, 1981.

73. Williams. L. R., and Cohen, M. H. Altered taste thresholds in lung cancer.Am. J. Clin. Nutr.. 37: 122-125. 1978.

Discussion

Dr. Morrison: I'm confused. Are you equating what you call "comprehensive enterai nutrition program" with encouraged voluntary foodintake? I just feel that's a little misleading and not what I expect from

enterai nutrition, which I think of as being tube feeding.Dr. Jaffe: I think it would be important to indicate the extent of the

radiation treatment received by these patients with Wilms' tumor,

whether they received total abdominal irradiation or hemiabdominalirradiation. There are a number of patients with Wilms' tumor here, and

9 patients receiving abdominal irradiation. I would like to know exactlythe extent of the radiation they received.

Dr. Rickard: The radiation was 1800 to 4000 rads.Dr. Jaffe: And how many received hemiabdominal and how many

received total abdominal irradiation?Dr. Rickard: There were 4 that received total and the rest hemiab

dominal, and the radiation was 1800 to 4000 rads, age-adjusted to the

maximum ability to receive radiation.Dr. Jaffe: Was there any difference between the total abdominal

group versus the hemiabdominal group?Dr. Rickard: All of the 8 children who had Wilms' tumors lost weight.

I do not go further in noting the percentage of weight loss, because weinterrupted that weight loss with TPN.1 Usually, the ones who received

the full abdominal irradiation received TPN in order to continue theirradiation.

Dr. Jaffe: Let me emphasize that that question was asked becauseI think a lot of patients can get away with normal radiation without TPN,and it would be something of a disservice to the individual to indicatethat all patients receiving abdominal irradiation require TPN. I think theinformation regarding the extent of weight loss should be provided,whether it was hemiabdominal or total abdominal irradiation, and thelike.

Dr. Nixon: Both our results and your study showed that hyperalimentation puts fat on the cancer patient. The question is, is that a goodthing to do? Does fat weight help the cancer patient?

Dr. Rickard: Let me clarify. First of all, when we followed the children,we found that they actually improved their weightiheight ratios first and

' The abbreviation used is: TPN, total parenteral nutrition.

772s

then subsequently we began to see improvements in skinfolds, especially the subscapular skinfold. We didn't necessarily see the increasein fat at the onset. I'm saying that I'm not sure we necessarily saw

repletion of fat with short intervals of treatment.Dr. Nixon: Does your data indicate that the weight-for-height in

crease was something other than fat?Dr. Rickard: That's a sticky question. The one thing I can say is that

we did notice that, with 28 days of TPN, visceral proteins increased tonormal concentrations.

Dr. Nixon: The most important point of the data I presented was thatthe balance studies indicated that we were not repleting the lean bodymass with hyperalimentation. The argument has been presented, nothere but elsewhere, that we weren't hyperalimenting long enough, and

I fail to understand why 6 months, for example, of hyperalimentationwould make any difference when 1 month didn't replete lean body

mass. In a second group of patients with advanced colon cancer thatwas hyperalimented, their profiles of mood states increased; they toldus that they felt better, but their performance status in most casesactually decreased. We should be careful about interpreting the subjective good that hyperalimentation does.

Dr. Rickard: I appreciate that and I think that's a very difficult aspect

to measure. Let me say, though, that it might depend on the way youmanage the TPN patient, in terms of what sort of a flexibility they haverelative to normal activity. Certainly with children, we saw a dramaticimprovement in play activity.

Dr. van Eys: Dr. Rickard made an apology for what she said was avery trite statement, but I think it is not repeated often enough in thesediscussions, namely, that children are different, and what they do withcalories is very different from what adults do with calories. If you havea 3-year-old given inadequate calories, the child will not grow. If you

give the calories, growth rather than storage is the rule. So we have tobe very careful that we do not jump too quickly from a 60-year-oldcolon carcinoma patient to a 3-year-old child that has been deprived of

growing by inadequate calories. You will see differences.Dr. DeWys: I want to comment about the rate of weight loss in the

Wilms' patients. Because it was so rapid, one has to consider that

much of it is probably drawn from body muscle, with its high watercontent. You can lose weight more rapidly from muscle than you canfrom fat.

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1982;42:766s-772s. Cancer Res   Karyl A. Rickard, Robert L. Baehner, Thomas D. Coates, et al.   Supportive Nutritional Intervention in Pediatric Cancer

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