[CANCER RESEARCH 37, 2336-2347, July 1977]

Summary

As a basis for assessing energy metabolism and requirements in cancer patients, selected aspects of whole-bodyenergy metabolism are considered, with particular reference to basal energy metabolism and factors that affect it.The importance of protein metabolism in relation to wholebody energy metabolism is emphasized. The need to consider the intimate relationships between protein and energynutrition and metabolism in the comprehensive evaluationof the energy needs of cancer patients also is stressed.Published data on the basal metabolic rate of patients withmalignant disease are difficult to evaluate for their metabolic and nutritional significance. Quantitative estimates ofthe utilization of major fuel sources in cancer patients arestill quite limited, but the available data suggest that theremay be a change in the pattern of fuel utilization, with lipidsources predominating, an altered regulation of glucosemetabolism, and a reduced efficiency of energy utilizationin some, but not all, cancer patients. The best balance ofthe major exogenous energy sources and level of totalenergy intake sufficient to meet the energy demands oforgans and the whole body cannot be easily predicted and,therefore, only crude guidelines can be suggested.

Introduction

Investigations of the characteristics of energy metabolismand of the assessment of energy requirements in cancerpatients are limited. However, the maintenance of cell andorgan function involves decreased entropy, and this impliesan increased requirement for energy. Thus, an adequateunderstanding of the metabolism and utilization of fuelsources and of the regulation of whole-body energy expenditure is important in considerations of nutritional therapy for cancer patients.

An important question to explore is whether the presenceof cancer per se presents a unique set of problems inrelation to energy metabolism and requirements, orwhether the problems are similar to those of patients withnonmalignant disease. Because cachexia, accompanied byreduced food intake, is often a prominent feature of advanced cancer (17, 77, 80), it could be argued that there is afailure to maintain normal regulation and efficient patternsof fuel utilization and, therefore, body protein compositionand cell mass. Hence, some selected aspects of energymetabolism and factors that alter basal metabolism and the

I Based on a paper presented at the Conference on Nutrition and Cancer

Therapy, November 29 to December 1, 1976, Key Biscayne, Fla.

utilization and need for energy will be reviewed here as abasis for assessing the status of energy metabolism andrequirements in the cancer patient. It is hoped that this briefreview will help to identify those aspects of energy metabolism and nutrition that deserve more critical and extensiveinvestigation, in order to develop more effective and rational approaches to the nutritional support of patients withmalignant disease. Major emphasis will be given here todata from human studies.

Basal and Resting Metabolic Rate

Physical activity and basal metabolism are among themajor factors that determine total daily energy expenditure.The former will not receive detailed mention here; for thepresent, it will be assumed that, in energy expenditure dueto physical activity, differences between cancer patientsand those suffering from other disease states and normalsubjects are due to the intensity of physical exercise andtime devoted to such activities. The metabolic aspects ofenergy expenditure and utilization will receive the majorfocus in this paper.

For individuals who spend a large portion of the day ‘‘atrest,―the BMR,2 defined as the energy output of an individual under standard resting conditions (bodily and mentallyat rest, 12 to 18 hr after a meal, in a neutral, thermalenvironment), accounts for a significant proportion of totaldaily energy expenditure (16). It is appropriate, therefore, toconsider first the biochemical basis of the BMR and some ofthe factors that affect it.

At the outset, it must be noted that a precise determination of BMR is not easy to achieve in practice (20), and amore useful measure of metabolic rate may be obtained bymeasurement of the resting metabolic rate (14). This may bedetermined in a person at rest, 2 to 4 hr after a light breakfast. However, a distinction between basal and resting metabolism does not require particular emphasis in the discussion that follows and, forthe present purpose, these parameters of energy metabolism will be used synonymously.

Resting energy metabolism represents the combustion offuel sources needed to provide energy for metabolic processes involved in maintaining the function and integrity ofcells and body organs and for the mechanical processesinvolved in keeping the body alive. Synthetic processes,such as protein, nucleic acid and lipid synthesis and gluconeogenesis, transport processes, including the pumping ofions to maintain ion gradients within cells and organellesand, finally, mechanical processes involving muscular ac

2 The abbreviation used is: BMR, basal metabolic rate.

2336 CANCERRESEARCHVOL. 37

Energy Metabolism and Requirements in the Cancer Patient1

VernonR. YoungDepartment of Nutrition and Food Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

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Major source ofenergyTissueGlucoseEryth

rocytes, leukocytes, renal medulla, brain, skeletalmuscle (exercise), somemalignant tumors, fetal tissues, intestinalmucosaFree

fatty acids―Liver, kidney cortex, cardiacmuscle,skeletal muscle(except in severeexercise)Ketone

bodies―Cardiac muscle, renal cortex,skeletal muscle,brainOther

energysourcesAminoacids(minor)Lactate(derivedfromglucose)Ethanol,

glycerol, pentoses (minor)

Distribution of oxygen utilization among the major body organs inaresting,healthymanFor

a 65-kg man [from Passmore and Draper(65)].Oxygen

consumption (ml/ Resting metabo

Organ mm) lism (% oftotal)Liver(including 6727splanchnic

area)Brain4719Kidneys177Heart2610Skeletal

muscles 4518Remainder4819Total

280 100

Calculatedfrom data of Holrodye etal.(36).Status

ofbody wt

lossGlucose

turnover rate

(mg/kg/hr)Con

cycleactivity

(mg/kg/hr)%glucose

turnoverGlucose

oxidation(mg/kg/

hr)Progressive

None196±26@

110@26b90

±2119±243

±718±262

±448±6

Energy Requirements

tivity, require energy inputs. These are obtained from highenergy phosphate compounds, usually ATP, generated during the oxidation of the major energy-yielding substrates.Hence, these various processes and their associated energyneeds constitute a biochemical basis of the basal rate ofenergy expenditure. Various factors alter the activities ofthese processes and the types of substrate used for supplying energy.

The contribution made by the various body organs toBMR in the healthy adult is summarized in Table 1. It hasbeen estimated that the liver accounts for approximately27% of resting metabolism, with the brain, skeletal muscle,and remainder also being important sites of total bodyenergy expenditure (65). Thus, the proportion ofthese bodyorgans in relation to total body weight will affect values forBMR when expressed per unit body weight or surface area.Because the relative contributions of the body organs tototal body weight change with growth and development(53), aging (72), malnutrition (21), and pathological states,interpretation of the metabolic significance of differences inBMR among differing groups of patients must be cautious.It is possible that alterations in the body organ compartments would bring about differences in BMR without anyreal change in the status of energy metabolism within theorgans themselves.

Fuel Sources in Relation to Resting Metabolism

The major substances used as sources of energy in mammalian tissues are glucose, fatty acids, ketone bodies,amino acids, and lactate (9, 45). Although these are interchangeable sources of energy in the whole organism, mdividual organs show some specificity with respect to theiruse of fuel sources (Table 2).

For a well-nourished adult subject in the basal state,glucose is utilized at a rate of 140 g/day, equivalent to 560kcal. The oxidation of amino acids, liberated during thecourse of tissue protein breakdown, can be estimated toamount to 75 g/day, or 375 kcal. The rest of the daily energyflux is accounted for largely by the oxidation of 130 gtriglyceride, equivalent to 1170 kcal.

In the resting human adult, about 20 g lactate are formeddaily, mainly by blood cells, and, in the fasting organism,

Table 1

this lactate is more or less quantitatively resynthesized toglucose (45). This cyclic metabolic pathway, involving conversion of glucose to lactate and the return of lactate toglucose, is termed the Con cycle. Utilization of lactate forglucose synthesis is an energy-requiring process, and anincreased rate of conversion of lactate to glucose has beenproposed as a mechanism for the increased energy expenditure of the tumor-bearing patient (17, 25). It is well knownthat tumors show high rates of anaerobic glycolysis withproduction of lactic acid (24, 79), and studies in cancerpatients show increased lactate production.

Holroyde et al. (36) recently reported a series of studieson Con cycle activity in a heterogeneous group of patientswith metastatic carcinoma (Table 3). Patients without progressive weight loss appeared to have normal glucose metabolism, but Con cycle activity was increased in patientswith progressive weight loss, showing that lactate production rates were higher in these patients.

Gold (25) proposed that the increased rate of resynthesisof glucose in the liver from the lactate produced by thetumor acts as a significant energy drain on host tissues.However, from the data shown in Table 3 and from additional estimates of the rate of lactate production and recycling in cancer patients (68, 81), increased Con cycle activity does not appear to account for a significant fraction ofdaily energy expenditure. Thus, if 6 moles of high-energy

Table 2Fuelsof individual tissues

[Modified from Krebs (45).]

a These sources can be used in quantitatively significant

amounts by tissues shown.

Table 3

Glucose turnover and Con cycle activity in patients with metastaticcarcinoma

a Mean ± S.D. for 8 patients.

S Mean ± S.D. for 6 patients.

JULY 1977 2337

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V. R. Young

phosphate are consumed for each mole of glucose produced from lactate (51), this would involve a substrate energy requirement of about 110 kcal. From the data providedby Holroyde et al. (36), it can be estimated that less than10% of daily energy expenditure can be accounted for bythe conventional cost of lactate recycling. Analyzing thisproblem from a somewhat different perspective, it can beestimated that, if 15% of total lactate production is oxidizedto CO2and H2O,and 85% of lactate is converted to glucose,there will be a maintenance of high-energy phosphate balance. This assumes, of course, that lactate is the onlymetabolite being utilized (51). It is difficult to accept, therefore, that changes in Con cycle activity are a significantcause of the marked body wasting in patients with progressive neoplasia. Nevertheless, it is of interest that Holroyd etal. (36) observed highest Con cycle activity in patients withgreatest total energy expenditure.

The pattern of fuel sources changes markedly if fastingcontinues significantly beyond the usual overnight period.For a fast lasting 3 days or longer, glucose oxidation isdecreased, in parallel with reduced rates of gluconeogenesis (9, 64) and the oxidation of fatty acids and ketone bodiesis increased, with the brain making major use of the latter asits principal fuel source (63). A picture of fuel utilizationduring short and long-term fasts is shown in Chart 1. Thischange in the pattern of fuel sources and utilization isaccomplished by alterations in substrate availability, in hormonal balance, and by the regulatory effects of ketonebodies on amino acid oxidation in peripheral tissues (71).

In terms of energy requirements, glucose and lipidsources are utilized with about the same efficiency, at leastwhen assessed in terms of the potential yield of ATP (44)from isocaloric intakes of glucose and fat. Protein is some

what less efficient as a source of energy, depending uponthe amino acid composition of the protein and becauseenergy is used for the elimination of nitrogen via urea synthesis (44).

It should be recognized, however, that an estimation ofthe availability.of utilizable energy from carbohydrate (glucose) and lipid fuel sources, based on calculation of maximum ATP yield, may have limited significance in relation toan assessment of the status of energy metabolism andsubstrate utilization in the whole organism. Various factorsserve to modify the yield of utilizable energy which may bederived from the combustion of these fuel sources. Theimportance of these factors may vary among individuals andwithin subjects due to changes in physiological and pathological states (34).

The efficiency of generation of ATP might vary due tochanges in the coupling of oxidative phosphorylation, andthe efficiency of utilization of ATP does not necessarilyremain constant, due to factors such as tissue phosphataseactivity and ion concentration. Furthermore, a variable activity of “futile―cycles would result in changes in theamount of energy available for use in energy-requiringprocesses. These cycles occur when there are 2 opposingmetabolic pathways in the cell in which the reactions in theforward and reverse directions are catalyzed by separateenzymes (40, 60). For example, 3 futile cycles in carbohydrate metaboli@mare shown in Chart 2. In one direction, the

GLUCOKINASE

AlP ADP

GLUCOSE GLUCOSE 6P

POSTABSORPTIVE BRIEF FAST (2-3 DAYS)

PROLONGED FAST

(_v %t-_..-JGLUCOSE ,“

‘•@),‘KETONE BODIES •q

‘ DECREASED

AMINOACIDS

Chart 1. Major patterns of fuel utilization in the postabsorptive state(overnight fast) and after short- and long-term fasts. Glucose utilization ishigh in the postabsorptive state with depletion of glycogen reserves andgluconeogenesis increasing during the short-term fast. Subsequently gluconeogenosis and flow of amino acids from muscle are reduced with a risein blood ketone bodies and increased utilization by the brain. Thus, thequantitative contribution of the fuel sources to overall body energy metaboiism depends upon the nutritional state. This picture is based principallyon work reviewed in Refs. 9, 63, 64, and 71. FFA, free fatty acids.

GLUCOSECYCLE

GLUCOSE 6P PHOSPIIATASE

PHOSPHOFRUCTOKINASEFRUCTOSE 6P@

FRUCTOSE 6P FRUCTOSE diP

FRUCTOSE diP PHOSPHATASE

PEP

CYCLE

ADP APPEP PYRUVATE

GOP ATP

PEP @“-GTP ADP.*―j PYRUVATECARBOXYKINASE OAA OAA CARBOXYLASE

(CYJ@)(,Mit)

Chart 2. Three futile cycles in carbohydrate metabolism: the glucose 6-phosphate (glucose 6F), fructose 6-phosphate (fructose 6P), and phosphoenolpyruvate (PEP) cycles. The variable activity of these cycles, which donot involve a net change in the levels of reactants (e.g. , glucose, fructose 6-phosphate or phosphoenolpyruvate), will result in changes in rates of ATPgeneration, relative to rates of ATP hydrolysis. Taken from Katz and Rognstad (40). OAA, oxaloacotic acid; CYTO, cytoplasmic; MIT, mitochondrial.

CANCERRESEARCHVOL. 372338

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Energy Requirements

to, the sodium pump is relatively small.Cell protein synthesis appears to be of quantitative sign if

icance in relation to the utilization of energy substratesunder basal conditions, and various observations may beused to support this concept. Thus, the relationship between the intensity of whole-body protein metabolism inmammalian species and adult body size is described by thesame power of body weight as is basal energy metabolismamong these species. Brody (7) showed that the variation inobligatory nitrogen losses, assumed to be an index of thedynamic state of body protein metabolism, among 9 mammalian species, ranging in size from the mouse to the cow,correlated with the 0.72 power of body weight, expressed inkg (Chart 3). This is essentially the same function of bodyweight that best correlates basal energy metabolism amongthese various species (43). More recently, Munro (58) reviewed this aspect of body protein metabolism and cornputed the power function of body weight that best correlated various parameters of tissue and whole-body proteinmetabolism, including albumin and ceruloplasm turnoverand liver RNA content, among mammals of different bodysize. The estimates of Munro (58), together with those ofBrody (7), demonstrate a close relationship between theintensity of body protein ‘r*ietabolismand rate of energyexpenditure in mammals, including man.

Estimates of the rate of whole-body protein synthesis inadult human subjects provide additional support for theview that protein turnover (synthesis and breakdown) accounts for a significant proportion of basal energy expenditure. Table 4 summarizes some published estimates of ratesof whole-body protein synthesis in well-nourished adultsubjects. Although the estimates vary, depending upon themethod used forthe determination (86), whole-body proteinsynthesis approximates 3 to 4 g per kg body per day or 200to 300 g for a 70-kg subject. Assuming each mole of peptidebond requires the equivalent of about 5 moles of ATP andthat ATP is formed from glucose at a cost of 18 kcal/mole(44), it can be calculated that about 180 kcal of substratewould be required to support this amount of peptide bondsynthesis. This would be equivalent to about 10% of basal

reaction requires the participation of a high-energy cornpound, such as ATP, while the reaction in the oppositedirection is energetically spontaneous. Although there is nonet flux of reactants in these cycles, the cycling causes ATPhydrolysis, and thus an energy ‘‘wastage.―However, therecycling may not be as wasteful as it appears, as pointedout by Katz and Rognstad (40), if these cycles serve a role inmetabolic regulation.

Although there are no adequate experimental data toestimate the fraction of total ATP formed and used in recycling, a variation in the activity of futile cycles has beenproposed as a basis for adaptation to high-energy intakes(74) and for differences in the propensity of individuals withgenerous energy intakes to become obese (39). Similarly,it can be speculated that the changes in the availability ofATP and in the efficiency of energy utilization might arise asa consequence of changes in recycling in disease statesand under the varying conditions of therapy. This problemdeserves investigation.

Another factor that must be mentioned is that, if glucoseor other carbohydrate sources are converted first to fat forthe temporary storage of energy, before being used to meetenergy requirements, there is a reduction in the amount ofutilizable energy obtained from the intake of a given amountof carbohydrate. Krebs (45) estimated that this loss of utilizable energy is equivalent to 2 molecules of ATP per C2segment of long-chain fatty acid or about 7% of the utilizable energy to be stored. Flatt (18) estimates the loss ofutilizable energy to be equivalent to about 20% of the caloric value of the glucose channeled into lipogenic pathways, and this appears to be a significant energy cost.Whatever the precise value, there is an energy cost associated with storage and the later utilization of fuels. Hencethe efficiency of substrate utilization for meeting the basalenergy requirement will be determined, in part, by the metabolic pathways followed before the fuel sources reach theterminal stage of oxidation.

Significance of Ion Pumping and Protein Turnover in EnergyExpenditure

Two processes thought to account for a significant fraction of the basal energy expenditure are ion pumping andprotein turnover (synthesis and breakdown). The maintenance of electrochemical gradients through the activetransport of ions requires energy; it has been suggestedthat 40 and 52% of the in vitro aerobic energy expenditure ofkidney cortex and brain slices, respectively, is linked tosodium-potassium pumping (91). Similarly, the transport ofsodium and potassium in liver (15) and tumor cells (48) hasbeen estimated to account for 35 and 85% of energy metabolism in these tissues, respectively. Support for the conceptthat ion pumping is an important component of basal energy metabolism is suggested from the increased metabolicrate in response to thyroid hormone and catecholamineswhich appears to be due to increased ATP utilization as aconsequence of altered activity of sodiurn-potassium-ATPase (35). However, Himms-Hagen (35) has concluded that,for most normal tissues, the proportion of total cell andorgan energy metabolism controlled by, or directly related

zzw0

2>---

—

:@—

U)

0zw00zw

I0,0005,000

I ,000500

I 00

50Ql .0 10 00 500kg

BODY WEIGHT (N)

Chart 3. Schematic relationship between the obligatory urinary nitrogenloss (urine nitrogen output after initial adaptation to a very low or protein-freeintake) and adult body size in mammalian species. As shown, the output ofnitrogen is related to the 0.72 power of body weight (expressed in kg)suggesting, as discussed in the text, that nitrogen output or metabolism isclosely correlated to energy metabolism. Drawn from the data of Brody (7).

JULY 1977 2339

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Total daily protein synthesis in relation to energy metabolisminprematurebabies, infants, young male adults, and elderlywomenSummarized

from Young et al. (94). Studies with infantsfromPicouand Taylor-Roberts (67).Total

body proteinsynthesisg/kg/Group

Age dayg/kcalNewborn

1-46 days 18 0.15 ±0.09Infant10-20 mos.7Young

adult 20-23 yr 3 0.1 1 ±0.01Elderly69-91 yr 2 0.11 ±0.03

Some estimates of the mean rate of whole-body protein synthesis in adult subjects,determined by constant infusion of labeled aminoacidWhole-body

Subjects protein synthesis (g/kg/

No. and sex Age (yr) Label day)Author(s)3

M 19-50 L-[U-'4CjLysine 2.6 Waterlow(85)3 M, 1 F― 52-75 L-[1-14C]Leucine 4.1 O'Keefe et al. (62)6 M 31-64 L-[U-14C]Tyrosine 4.6 James et al. (38)5 M 31-46 L-[a-15N]Lysine 3.5 Halliday and Mc

Keran(33)4 M, 2 F 20-25 [15N]Glycine 3.0 Steffeeet a!. (75)

V. R. Young

energy expenditure. This estimate does not account for theenergy costs of amino acid transport, RNA synthesis, turnover of the —CCAterminus of tRNA, synthesis of nonessential amino acids, and energy cost of protein breakdown.Furthermore, it is assumed that the oxidation of glucoseresults in the generation and availability of 36 moles ATPper mole glucose oxidized, but as discussed earlier, thismaximum yield of ATP is subject to variation and in alllikelihood it will be less. Millward et al. (54) have estimatedthe energy cost of protein synthesis to be about 1.4 kcal/gprotein. On this basis, protein turnover in the adult subjectwould account for about 25% of the basal metabolic rate.These figures underestimate the quantitative contributionof protein synthesis and breakdown to basal energy metabolism. Thus, it is reasonable to assume that about one-halfof resting energy metabolism may be associated with protein turnover. For this reason, it would be anticipated thatthe replenishment of tissue and organ protein content in theinitially depleted patient would require an increased energyintake above that required for normal maintenance. Furthermore, evidence indicating a high energy cost of growthin infants and children (47, 66) supports this view.

Finally, resting energy metabolism per unit of bodyweight declines with progressive growth and developmentwithin a mammalian species (43). This fall parallels thereduced intensity of whole-body protein synthesis duringthis period (e.g., Ref. 88). We (95) have explored the relationship between whole-body protein synthesis rates andenergy metabolism in human subjects at various ages, andthe results of these studies are shown in Table 5. It can beseen that there are marked differences in the intensity ofwhole-body protein synthesis, expressed per unit of bodyweight, among the various age groups. However, thesedifferences are not as evident for whole-body protein synthesis expressed per unit of resting energy metabolism.These observations emphasize further the close and, presumably, causal relationship between whole-body proteinturnover and resting energy metabolism.

Changes in host tissue and total-body protein metabolismdue to the presence of a growing tumor (26), physicaltrauma (19), and surgery (62) and alterationsthat may occuras a result of chemotherapy and radiation treatment wouldinfluence also the utilization and requirements for energy.Thus, a critical assessment of energy utilization and requirements in the cancer patient should take into account

these intimate interrelationships among body protein andenergy metabolism.

Factors Affecting BMR

Age, nutritional status, temperature, hormones, andpathologicalstates,includingtrauma and infection,affectthe resting metabolic rate. The effects of age have beendiscussed by others (43, 66, 72). Also, changes in deep bodytemperature are well established (20). If body temperature israised by 1°,either by fever or by warming the body, themetabolic rate increases by about 12%.

The effect of nutritional state is important in the contextof energy metabolism, particularly because body nutrientdepletion is common in cancer patients. The effects ofstarvation and undernutrition on basal metabolism havereceived considerable investigation, and this has been thetopic of several reviews (20, 30, 42, 87). Brief fasting doesnot change total-body oxygen consumption and, thus, heatproduction, but a longer period of restricted food intakedoes influence whole-body energy expenditure (31).

Chart 4 summarizes results, discussed previously by Oarrow (20), of a study by Benedict et al. (2). The major findingsof this study are shown here to emphasize a number ofpoints that should be considered in evaluating results ofstudies of energy metabolism in cancer patients. First, itcan be seen that undernutrition reduces BMR to a greaterextent than the effect on body weight. Thus, the fall in BMR,under these conditions is due to changes in the metabolicactivity of tissue as well as a loss of active tissue mass. Onthe basis of studies during acute starvation, Grande et a!.

Table 5

Table 4

a Preoperative patients. Other studies involved healthy subjects.

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0

0U

z0I-U

S

a.I-4UiI

-i4U)4

Changesin rates of whole-bodyprotein synthesisandbreakdownin5 moderatelyobese womenafter a 1-weektotalfastFromunpublishedresultsofJ. C. Winterer, B. R. Bistrian, andV.R.

Young.Estimatesof proteinsynthesisand breakdownmadewiththeuseof the [15N]glycinemodel of Picou and Taylor-Roberts(67).Protein

synthesis (g/ Protein breakDiet period kg/day) down(g/kg/day)Control

1.91.8Fast1.4―1.8%

change —26 0

I7OO@

I600@

I500 P

I40O@

I300[

Effect of extent of thermal injury on whole-body proteinsynthesisandbreakdown rates inchildrenUnpublished

results of C. L. Kien, J. F. Burke, and V. R.Young.Burnpatients ranged in age from 5 to 12years; unburnedcontrolswereages4 to 18 years.Whole-body

protein (g/kg/day)Burn size (% No. of obsersurface area) vations SynthesisBreakdown0

11 3.53.10.5-254 4.03.325-60

10 5.23.96010 7.1 6.3

Energy Requirements

refeeding than during initial adaptation to a fast in a healthysubject.

In addition to undernutrition, the effects of excessiveenergy intakes on energy expenditure and BMR have beenreviewed recently by others (20, 52, 74). Overfeeding ofnormal subjects does not always result in the expectedweight gain despite unaltered physical activity. Variousstudies indicate that, over a period of excess energy intake,there is an increase in oxygen consumption in the restingstate and that this thermogenic effect of high energy intakesis greater during exercise (52, 74).

From these various observations it is difficult to generalize about the effect of nutritional state on basal metabolism.It will depend upon when it is measured, how it is calculated, and current as well as previous nutritional history.These points should be kept in mind in the critical evaluation of energy metabolism in cancer patients.

Physical trauma, e.g., due to burns or leg fracture, altersthe basal metabolic rate, the degree of change dependingupon the severity of trauma (92). The hypermetabolism maycause a marked weight loss if it is not met by substantialincreases in energy intake, and Wilmore et al. (93) haveproposed that the calorigenic action of catecholamines isthe cause of the increased metabolic rate. However, themechanism of increased heat production in burned patientsrequires further exploration, and accelerated rates of gluconeogenesis and ureagenesis would account, in part, for thisincrease in metabolic rate (92). Furthermore, it seems likelythat an increased rate of whole-body protein turnover is animportant factor. Recent studies (C. L. Kien, J. F. Burke, andV. R. Young, unpublished results) summarized in Table 7, onthe effects of thermal injury, have shown that the rates ofwhole-body protein synthesis and breakdown are higher inchildren with larger burns. This higher rate correlates with

SEPT OCT NOV DEC JAN FEB27 27 26 26 25 24

Chart 4. Changes in basal heat production and body weight in 7 healthysubjects studied for the effects of a restricted energy intake. Taken fromBenedict et al. (2). The dietary restriction began on October 4, 1917, andfinished on February, 3, 1918, but it was interrupted with a free-choice dietbetween November 29 to December 2, inclusive, and December 20 to January6, inclusive.

Table6

a Different from control (p < 0.05).

Table7

JULY 1977 2341

CHRISTMAS

THANKSGIVING

@i@ :

(31) suggested that the loss of tissue accounts for about30% of the decrease in metabolism. On the other hand, inlong-term undernutrition, the loss of tissue is a major factordetermining the reduction in energy expenditure (20).

The results shown in Chart 4 also indicate that basalmetabolism is rapidly restored to normal levels upon refeeding. In this case, BMR, expressed per unit of body weight,increases to greater than normal during early refeeding. Anincreased rate of energy expenditure also occurs aftermeals in children during early recovery from severe proteincalorie malnutrition (1, 8, 46). Brooke and Ashworth (8)propose that this increased energy expenditure with refeeding is due to the increased rate of protein synthesis whichwould involve an increased rate of ATP generation andutilization. Of additional interest is that the fall in BMR withcontinued fasting in obese subjects (5) also appears to be

‘. related to a fall in whole-body protein synthesis. Using a

constant [‘5N]glycine infusion model, we (J. C. Winterer,

B. R. Bistrian and V. R. Young, unpublished results) haveobserved that there is a significant decrease in the overallbody protein synthesis rate during a week-long fast in obesewomen (Table 6).

Finally, the results of Benedict et al. (2) suggest that BMRfalls more rapidly with fasting after a period of temporary

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A listing of some published results on thebasal metabolic rate of cancerpatientsDescription

of populationBMRCommentAuthor(s)Leukemia,

16 casesUsually >120%normalFew

detailsBoothby and Sandiford(3)Chronic

myelocyticLow, normal,Watkin(89)leukemia,4casesincreasedMalignant

disease,—10% aboveWaterhouse(82)5casesnormalMultiple

myeloma—14-60% abovenormalFew

detailsSilver et a!.(73)Carcinoma,

local —6-57%aboveFew detailsSilver et al.(73)izednormalLeukemia,

myeloid—12-91% aboveFew detailsSilver et al.(73)andlymphaticnormalMalignant

neo 0-30% aboveWaterhouse et al.(84)plasms,4casesnormalLeukemiaIncreasedFew

detailsMinot and Means(55)Neoplasticdisease,Low and aboveWatkin andSteinfield4

casesnormal(90)Variouscancers, 9Usually aboveTerpeka and Water

casesnormalhouse (76)

RAPID SLOW

@ —@

+6

- +6

V. R. Young

the increased basal metabolic rate and energy expenditurefree fatty acid oxidation, as well as carbon dioxide producwhich occur in extensive body burns (92).tion, in 5 patients with metastatic malignant disease; stud

It must be concluded, therefore, that the basal metabolicies were conducted in patients under basal conditionsandratechanges in response to various physiological and path during glucose loading. The results of their studiesareological

conditions. This makes it difficult to evaluate fullyshown in Charts 5 and 6. Under basal conditions, ratesofthelimited published data obtained in studies of energyglucose and free fatty acid ([1-'4Cjpalmitate) oxidation,andmetabolism

in patients with malignant disease, and to de total CO2 production did not differ substantiallybetweenterminewhether cancer has a direct influence on energycancer patients and controls. However, when aglucosemetabolism

and, particularly, on energy requirements.load was given, these investigators observed that the oxidation of free fatty acid was suppressed less in cancerpatientsResting

Metabolism in Cancer Patientsand that there was a lower rate of ‘‘slow―oxidation ofglucose, compared with controls (Chart5).In

Table 8, a summary is made of some results of studieson the basal metabolic rate in patients with cancer. In viewof the various factors that affect metabolic rate, and , in part,because of the limited information supplied in many of thepapers, it cannot be concluded that resting metabolism isconsistently increased in the cancer patient, compared withhealthy controls. Resting energy metabolism appears to beCalculation

of the contribution to CO2 production bynonprotein sources, unlabeled by the administered[14C]glucose and [14C)palmitate, indicated that glucoseloading reduced their oxidation in normal subjects but notin cancer patients (Chart 6). Waterhouse and Kemperman(83) interpret this finding to mean that continued intracellular oxidation of free fatty acids occurs with glucoseloading.increased

in many patients with Hodgkin's disease or leukemia. There is considerable variation in reportedBMR'samong

and within the various studies. Thispresumably@NCERreflectsdifferences in methodological and biological varia

Response of Energy Metabolism to Dietary Intake In the

bles, as well as possible effects of different cancers andseverity and stage of disease. In a study of the partition ofenergy expenditure between host and tumor in tumor-bearing rats, Morrison (56) did not find evidence of a consistentchange in resting metabolism.

bility that the response of the cancer patient to semistarva

Cancer Patient

Potentially of greater nutritional significance is the possi

tion or nutritional rehabilitation may differ from that of.4

- +6

0.5 -@@@@

06

+6

I@

II02healthysubjects or from patients suffering from nonmalig

nant diseases. Waterhouse and Kemperman (83) have examined this possibility by determining rates of glucose andChart

5. Estimates of glucose pool and rates of glucose (“rapid―and“slow―pools) and free fatty acid (FFA) oxidation in normal and cancerpatients studied under basal conditions and during a glucose load (+G).Drawn from tabular data of Waterhouse and Kemperman (83).

GLUCOSEPOOL(“aol,/kglNORMALGLUCOSE OXIDATION FFA OXIDATIONIaaol,/Rg/h,I

NORMAL CANCER

fiTable 8

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-2

-4

-6

Energy Requirements

This suggests that there is a disturbance in normal homeostatic mechanisms involving the utilization of glucose andother important fuel sources in patients with malignantdisease. In this context, changes in hormonal balance maybe of significance, and Goodlad et a!. (28) found reducedinsulin production in tumor-bearing male rats. Thus, analteration in insulin function might account for the abnormal glucose regulation.

The nutritional implications of these findings are moredifficult to assess. If glucose is not oxidized directly but isfirst converted to fat before supplying utilizable energy, thiswould involve an energy cost and, thus, a relatively higherenergy intake to meet the needs of body tissues.

Whether gluconeogenesis is inhibited by exogenous glucose as effectively in the cancerous as in the normal patientdoes not appear to have received critical investigation.However, sepsis increases gluconeogenesis, and this path

way is not responsive to the administration of glucose during the stress of infection (32). Thus, of possible interest inrelation to metabolic regulation by exogenous substrate isthe observation that treatment of rats with hepatocarcinogens results in a loss of dietary feedback control of cholesterol biosynthesis (70). Additional studies would be desirable to explore the regulation of carbohydrate and lipid metabolism and the dynamic interrelationships between glucose, lipid, and amino acid metabolism in cancer patients.

Several investigators (12, 84, 89, 90) have stated that thelevel of energy intakes needed to maintain body energybalance are higher for cancer patients than for other subjects. Thus Waterhouse et a!. (84) determined energy balance, using the indirect method of Newburgh etal. (59) in agroup of 4 patients with leukemia, Hodgkin's disease, andcarcinoma of the pancreas. The results obtained with 2 ofthese patients are summarized in Chart 7, and it may beseen for 1 patient that, even at a liberal energy intake, bodyenergy balance was markedly negative throughout. Thisimplies that, in some but not all cancer patients, dietaryenergy sources are utilized with relatively low efficiency.However, it must be recognized that the precision of theestimates of energy balance made by Waterhouse et al. (84)is not known and that accurate determinations of energybalance are difficult to undertake. The magnitude of theerror in energy balance which could lead to marked bodyweight loss is quite small compared with the range of energy intakes and requirements within a group of subjects(20). Furthermore, Garrow (20) concluded from his reviewof the literature that rarely is energy balance establishedover a period of a week or even longer periods in normalsubjects, and that an energy imbalance of up to 60,000 kcalis tolerated by the control system in many people. It is notsurprising that little is known about the quantitative effectsof cancer on energy utilization and body energy balance inhuman subjects.

As reviewed above, continued weight loss and clinicaldeterioration have been observed in some patients, evenwhen given generous energy and protein intakes. However,the effects of the cancer or treatment conditions may not be

, GLUCOSE —UNLABE LENON - PROTEIN

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‘:___Chart 6. Total carbon dioxide production and the contributions from oxi

dation of labeled glucose and fatty acids and from unlabeled nonproteinsources in normal subjects and in cancer patients studied under basalconditions and during a glucose load (+G). Drawn from tabular data ofWaterhouse and Kemperman (83).

J. F(ACUTE LEUKEMIA)

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JULY 1977 2343

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V. R. Young

exerted directly on the yield or availability of utilizable energy from energy sources. Changes in energy balance or inthe capacity to achieve body energy equilibrium may besecondary to alterations in the status of protein metabolisminbody tissues.

Goodlad et a!. (27-29) and Clark and Goodlad (11) haveshown that myofibrillar protein synthesis in skeletal muscleof tumor-bearing rats is reduced and they (11) have concluded that this impairment is due to a defect in the capacityof the 40 S ribosome subunit to promote a postinitiationstep in polypeptide synthesis. Lundholm et a!. (50) haveexamined in vitro protein synthesis in muscle biopsies obtamed from a heterogeneous group of cancer patients, andthe results of these studies are shown in Chart 8. Proteinsynthetic activity was impaired and the rate of proteinbreakdown was increased in muscle samples from cancerpatients, compared with metabolically healthy controls.However, Lundholm et al. (50) also observed that proteinsynthesis in muscle from cancer patients, as well as normalsubjects, could be stimulated by the addition of high levelsof amino acids to the incubation medium (Chart 8). Thissuggests that in the cancer patient there is a reduced efficiency of amino acid utilization for muscle protein synthesisat normal levels of amino acid supply, but that this may beovercome by raising the supply of amino acids to muscle.The favorable gains in body weight and nitrogen retention,as well as reduced morbidity and mortality, achieved by i.v.feeding of cancer patients ( e.g., Ref. 13), support thisconclusion.

Energy Requirements of the Cancer Patient

Partly because the effects of cancer on host tissue andwhole-body energy metabolism are only partially understood, it is not possible to be precise about the minimumintake of energy which would be sufficient to meet energyneeds and maintain body energy balance in cancer patients.Furthermore, the balance between major exogenous energy

-

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Chart 9. Schematic depiction of results of Rutten et al. (69) showingrelationship between energy intake (expressed as a fraction of calculatedbasal energy expenditure) and changes in body nitrogen balance in 13postoperative patients, including a total of 4 patients with cancer of the lung.bladder, esophagus, and uterus.

sources, glucose or other carbohydrates, and lipid, whichwould promote maximum efficiency of energy utilization,cannot be stated yet. There are no more than a few studiesthat help to provide only crude guidelines for this purpose.

Rutten @ta!. (69) have shown in a group of postsurgicalpatients, including some with cancer, that hyperalimentation with a fluid providing 160 kcal/g nitrogen could supportbody nitrogen balance when total energy intake approximated 1.7 to 2.0 times the calculated basal metabolic rate(Chart 9). Similarly, at nitrogen intakes of 240 mg nitrogenper kg per day, or more than twice the nitrogen allowancefor healthy adults (16), Long et al. (49) concluded thatenergy balance was achieved in a group of septic patients,including 2 with cancer of the bladder, with energy intakebeing about 1.5 times basal energy expenditure.

The studies of Rutten et a!. (69) and Long et al. (49)provide only a partial basis for assessing the adequacy oflevels of energy intake, and studies of this kind should beextended , particularly in view of the close interrelationshipsbetween energy and protein in nutrition and metabolism.We (22, 23) and others (10, 37) have explored the sensitivityof body nitrogen balance to changes in energy intake inhealthy subjects. In these studies it was shown that generous intakes of energy result in a sustained increase innitrogen retention and dietary nitrogen utilization. However, the effects of changes in the level of energy intake onprotein and energy utilization may be modified by the levelof protein intake (57). Hence, the definition of an adequateenergy intake for the nutritional therapy of the cancer patient is dependent upon a variety of dietary and host factors.These factors, together, will determine the appropriate energy intake for the individual patient. Finally, the attendingphysician and hospital dietitian have little useful information to follow in deciding on the level and sources of energyto provide a particular patient and they must rely upon theclinical progress of the patient, supplemented with someobjective biochemical and physiological assessment of thepatient's nutritional state.

Better knowledge of the interrelationships among energy

20

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fibers from cancer patients, in relation to normal subjects. The relativeresponse of protein synthesis in vitro to high levels of amino acid supplementation (10 times normal plasma levels) obtained with muscle samples fromcancer patients and control subjects is also shown. Drawn from results ofLundholm et al. (50).

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PLASMA GLUCOSEPLASMA FREE FATTY ACIDSPLASMA GLYCEROLPLASMA AMINO ACIDSPERIPHERAL METABOLIC STATE

FEEDBACK ELEMENTS

Chart 10. Simplified elements of the system responsible for regulation of body energy stores in human subjects, as proposed by Bray and Campfieid (6).The model consists of a controller, acting upon the controlled system, with effectors including plasma glucose, amino acids, fatty acids, and status ofmetabolism in peripheral tissues.

Energy Requirements

and protein metabolism clearly would help to develop betterdiagnostic aids for the evaluation of nutritional status andlead to the design of improved nutritional therapies fortreatment of cancer patients. In addition, this information isnecessary for an understanding of the anorexia that is regarded as a major contributory factor to body energy lossand the eventual cachexia in cancer patients (77). Obviously, energy balance will not be achieved if intake andabsorption fail to meet the energy demands of the body.Alterations in intestinal function due to alimentary tractneoplasms or the effects of surgery, chemotherapeuticagents, and radiation may affect energy metabolism bychanging the digestive-absorptive phase of nutrient utilization. This topic is discussed elsewhere in this symposium.

The regulation of energy intake in normal and cancerpatients is beyond the scope of this paper, and the reader isreferred to reviews which have discussed this aspect ofenergy metabolism in normal subjects (e.g., Ref. 61) and inrelation to cancer (78). Of particular interest, however, is areview by Bray and Campfield (6) which considers the various metabolic factorsinvolvedin the regulationof foodintake. These investigators proposed that body energystores are the regulated variable and that energy intake orexpenditure is altered to maintain a particular level of totalcaloric storage. The major features of the control systemdiscussed by Bray and Campfield are given in Chart 10. Asseen from this chart, the plasma concentrations of aminoacids, glucose, glycerol, and free fatty acids, as well as thestate of peripheral metabolism, including the quantity ofadipose tissue, glycogen, and protein, serve as feedbacksignals on the ventromedial nucleus, which is assumed tobe the long-term monitor of energy balance in the body.This model was proposed to provide a possible frameworkwhich might help identify possible changes of system errorin relation to obesity, or body energy excess. Similarly, it

CONTROLLER

might offer an approach to testing hypotheses proposed toexplain the actual or relative reduction in food intake anddevelopment of negative energy balance which occurs during the onset and development of neoplasia. Of significancein the present context is that the model involves considerations of important energy-yielding substrates, glucose, andfatty acids, and of the amino acid levels in blood plasma.Changes in glucose, fatty acid metabolism, and in aminoacid and protein metabolism in cancer patients have beendiscussed above. Furthermore, differences in blood aminoacid levels of cancer patients, compared with controls, havebeen described (e.g., Refs. 4, 41).

An adequate exploration of energy metabolism and nutrition should, for these reasons alone, include as many observations as possible within a single patient, on the utilization and metabolism of the principal fuel sources (carbohydrate, lipids, and protein). There is also a great need to applyand improve upon modern methods for measurement ofwhole-body energy expenditure in human subjects in general and in patients with malignant disease in particular.

Conclusion

Based on the above, it is clear that various factors affectbasal and total daily energy expenditure. This makes itdifficult to assess the significance of published data onbasal metabolism in cancer patients. Also, there are significant quantitative relationships between whole-body energyand protein metabolism, and these must be considered inassessing energy status and requirements in cancer patients who may often be depleted of body protein and require vigorous nutritional support to reverse this state andto maintain adequate nutritional status. Although the limited data available suggest that the pattern of fuel utilization

I. NEURAL

COR T E X

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INTESTINAL MUCOSA

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P I T U I TA R YADRENAL

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CONTROLLER SYSTEM

@IEDISTRIBUTION

CALORIE STORAGE

CALORIE DISPOSAL

STORED

CALORIES

JULY 1977 2345

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20. Garrow, J. S. Energy Balance and Obesity in Man. Amsterdam, TheNetherlands: North-Holland Publishing Co., 1974.

21. Garrow, J. S., Smith, R., and Ward, E. E. Electrolyte Metabolism InSevere Malnutrition, p. 168. New York: Pergamon Press, 1968.

22. Garza, C., Scrimshaw, N. S., and Young, V. R. Human Protein Requirements: The Effect of Variations in Energy Intake within the MaintenanceRange. Am. J. Clin. Nutr., 29: 280-287, 1976.

23. Garza, C., Scrimshaw, N. 5., and Young, V. R. Human Protein Requirements. Evaluation of the 1973 FAO/WHO Safe Level of Protein Intake forYoung Men at High Energy Intakes. Brit. J. Nutr. , In press.Gold, J. Metabolic Profiles in Human Solid Tumors. I. A New Techniquefor the Utilization of Human Solid Tumors in Cancer Research and ItsApplication to the Anaerobic Glycolysis of Isologous Benign and Malignant Colon Tissues. Cancer Res., 26: 695-705, 1966.

25. Gold, J. Cancer Cachexia and Gluconeogenesis. Ann. N. Y. Acad. Sci.,230: 103-110,1974.

26. Goodlad, G. A. J. Protein Metabolism and Tumor Growth. In: H. N.Munro (ed), Mammalian Protein Metabolism, Vol. 3, Chap. 20, pp. 415-444. New York: Academic Press, Inc., 1969.

27. Goodlad, G. A. J., and Clark, C. M. Activity of Gastrocnemius and SoleusPolyribosomes in Rats Bearing the Walker 256 Carcinoma. European J.Cancer, 8: 647-651 , 1972.

28. Goodlad, G. A. J., Mitchell, A. J. H., McPhail, L., and Clark, C. M. SerumInsulin and Somatomedin Levels in the Tumor-bearing Rat. European J.Cancer, 11: 733-737, 1975.

29. Goodlad, G. A. J. . and Raymond, M. J. The Action of the Walker 256Carcinoma and Toxohormone Incorporation into Diaphragm Protein.European J. Cancer, 9: 139-145, 1973.

30. Grande, F. Man under Caloric Deficiency. In: Handbook of Physiology:Adaptation to the Environment. Sect. 4, Vol. 1, Chap. 59, pp. 911-937.Washington, D. C.: American Physiological Society, 1964.

31. Grande, F., Anderson, J. T. , and Keys, A. Changes of Basal MetabolicRate in Semistarvation and Refeeding. J. Appi. Physiol., 12: 230-238,1958.

32. Gump, F. E., Long, C. L.. Geiger, J. W., and Kinney, J. M. The Significance of Altered Gluconeogenesis in Surgical Catabolism. J. Trauma,15:704-710,1975.

33. Halliday, D., and McKeran, A. 0. Measurement of Muscle Protein Synthetic Role from Serial Muscle Biopsies and Total Body Protein Turnoverin Man by Continuous Intravenous Infusion of L-[a-'NjLysine. Clin. Sd.,49: 581-590,1975.

34. Hegsted, D. M. Energy Needs and Energy Utilization. Nutr. Reviews, 32:33-38, 1974.

35. Himms-Hagen, J. Cellular Thermogenesis. Ann. Rev. Physiol., 38: 315-351, 1976.

36. Holroyde, C. P., Gabuzda, T. 6., Putnam, R. C., Paul, P., and Reichard,G. A. AlteredGlucoseMetabolismin MetastaticCarcinoma.cancerRes., 35: 3710-3714, 1975.

37. lnoue, G., Fujita, Y. , and Niiyama, V. Studies on Protein Requirements ofYoung Men Fed Egg Protein and Rice Protein with Excess and Maintenance Energy Intakes. J. Nutr. , 103: 1673—1687,1973.

38. James, W. P. T., Garlick, P. J., Sender, P. M., and Waterlow, J. C.Studies of Amino Acid and Protein Metabolism in Normal Man withL(U―C)TyrOsifle.Clin. Sci., 50: 525-532, 1976.

39. James, W. P. T., and Trayhern, P. An Integrated View of the Metabolicand Genetic Basis for Obesity. Lancet, 2: 770-773, 1976.

40. Katz, J., and Rognstad, R. Futile Cycles in the Metabolism of Glucose.Current Topics Cellular Regulation, 10: 237-289, 1976.41.Kelley,J.J.,andWaisman,H.A.QuantitativePlasmaAminoAcidValuesin Leukemic Blood. Blood, 12: 635—643,1957.

42. Keys, A., Brozek, J,, Henschel, A., Mickelsen, 0., and Taylor, H. L. BasalMetabolism. In: The Biology of Human Starvation. Vol. 1, Chap. 17, pp.303-339. Minneapolis: University of Minnesota Press, 1950.

43, Kleiber, M. The Fire of Life. New York: John Wiley & Sons, 1961.44. Krebs, H. A. The Metabolic Fate of Amino Acids. In: H. N. Munro and J.

B. Allison (eds.), Mammalian Protein Metabolism, Vol. 1, Chap. 5, pp.125-176. New York: Academic Press, Inc., 1964.

45. Krebs, H. A. Some Aspects of the Regulation of Fuel Supply in Omnivorous Animals. Advan. Enzyme Regulation, 10: 397-420, 1972.

46. Kreiger, I. The Energy Metabolism in Infants with Growth Failure Due toMaternal Deprivation, Undernutrition and Causes Unknown. MetabolicRate Calculated from Insensible Loss of Weight. Pediatrics, 38: 63-76,1966.

47. Krieger, I., and Chen, Y. C. Calorie Requirements for Weight Gain inInfants with Growth Failure due to Maternal Deprivation, Under-nutrition, and Congenital Heart Disease—ACorrelation Analysis. Pediatrics,44: 647-654, 1969.

48. Levinson, C., and Hempling, H. G. The Role of Ion Transport in theRegulation of Respiration in the Ehrlich Mouse Ascites-Tumor Cell.Biochim. Biophys. Acta, 135: 306—318,1967.

49. Long, C. L. , Crosby, F., Geiger, J. W., and Kinney, J. M. ParenteralNutrition in the Septic Patient; Nitrogen Balance, Limiting Plasma Amino

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V. R. Young

in neoplastic disease states may differ from that of healthysubjects, with lipid sources predominating, an altered regulation of glucose metabolism, and less efficient utilization of

food energy, further studies are needed to verify and establish the nutritional and metabolic significance of this observation. Whether particular cancers, other than those di

rectly involving the neuroendocrine system, affect energymetabolism and requirements in different ways cannot be 24.determined from the available literature, nor is the role ofseverity of the disease state, in this regard, adequatelyunderstood . Only crude guidelines can be suggested for thelevels of energy intake and optimum relationship betweenprotein and energy requirements for the feeding of cancerpatients. A better understanding of the characteristics ofthe utilization and metabolism of the major fuel sources incancer patients should lead to improved diagnostic tests forassessing body energy balance and needs during the various phases of the disease and under the differing conditions of therapy. In part, this will require much better information on the regulation of energy metabolism and utilization of energy sources at the whole-body level in healthysubjects.

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79. Warburg, 0. Metabolism of Tumors. London: Constable and Co. , 1930.80. Warren, S. The Immediate Causes of Death in Cancer. Am. J. Med . Sci.,

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Energy Requirements

JULY 1977

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