[CANCER RESEARCH 37, 3109-3114. September 1977]

Metabolic Response to Total Parenteral Nutrition in CancerPatients1

Christopher P. Holroyde,2 Richard N. Myers, Robert D. Smink, Richard C. Putnam, Pavle Paul, and George

A. Reichard

Clinical Oncology Program and Division of Research, Lankenau Hospital, Philadelphia, Pennsylvania 19151

SUMMARY

In order to evaluate the metabolic response of nutritionally deprived cancer patients to parenteral nutrition, metabolic parameters including glucose turnover, oxidation,and Cori cycle activity were measured in eight patientsbefore and during short-term (5 to 10 days) i.v. nutrition,with solutions containing amino acids and hypertonic glucose. Before parenteral nutrition, five patients had essentially normal glucose turnover, oxidation, and Cori cycleactivity, whereas three patients had moderately increasedglucose turnover and markedly increased Cori cycle activity. In response to parenteral nutrition, plasma glucose,insulin, and venous láclate concentration increased andfree fatty acid decreased. The percentage of respiratory CO,from glucose oxidation and the rate of oxidation increased.CO2 production increased, whereas O-, consumption wasessentially unchanged. Respiratory quotient rose to >1.0.Endogenous glucose production and high basal Cori cycleactivity were decreased. Total parenteral nutrition wasjudged clinically beneficial in five patients, whereas onepatient was unchanged. Deleterious responses, includingmoderate lactic acidemia, occurred in two of three patientswith elevated basal Cori cycle activity.

INTRODUCTION

It is generally believed that poor nutritional status contributes to the debility and morbidity of patients with malignantdiseases. Because earlier attempts at forced oral feeding ofnutritionally deprived cancer patients resulted in variableclinical responses (32), this approach has not been activelypursued until recently, largely due to the acceptance ofTPN3 as an important therapeutic modality (6-8,11, 25, 29).

TPN is known to alter the metabolic and biochemicalprofile of normal subjects. Because abnormalities of glucose and lactate metabolism can occur in some cancerpatients (18, 34, 35), we have studied 8 nutritionally deprived patients before and during short-term TPN by isotopetracer techniques, in order to evaluate resulting host metabolic responses.

1 Supported in part by NIH Research Grants AM-13527 and GM-21549.2 To whom requests for reprints should be addressed.3 The abbreviation used is: TPN, total parenteral nutrition.

Received September 3, 1976; accepted June 6, 1977.

MATERIALS AND METHODS

Patients. Eight hospitalized patients with metastatic solidtumors were selected for study. In all cases life expectancywas estimated to be >60 days, and no patient was totallyconfined to bed. Relevant details pertaining to clinical status are shown in Table 1. At the time of study all patientsexcept C. W. had lost >10% of body weight as a direct resultof their disease. No patient was acutely ill, and none wasfebrile. No patient received chemotherapy or glucocorti-coids during the preceding 3 weeks. The purpose and potential risks of hyperalimentation and the isotope tracerprocedures were discussed with each patient, and informedconsent was obtained.

Metabolic Studies and Methods. Metabolic studies wereperformed on each patient after an overnight fast of 12 to 14hr and again after 5 to 10 days of parenteral nutrition.Patients had been maintained on the same quantity of nutrient solution for at least 2 days before the 2nd study. Plasmaglucose turnover and Cori cycle activity were measured bypreviously described methods (18, 27). Fifty to 100 /j.C\ (3 to6 mg) of [1-14C]glucose were rapidly administered at zero

time, and beginning 1 hr later, blood samples were collected at 30-min intervals for 4 hr. Plasma samples weredeproteinized, and the protein-free filtrate was passedthrough a column of Amberlite MB-3 resin (HCO:r form).One aliquot of the column eluate was used to determineradioactivity in carbon 6 of glucose by periodate oxidationand formaldimedone precipitation as previously described(27). Radioactivity in all glucose carbons was determined ina 2nd column aliquot by oxidizing glucose to gluconic acidwith glucose oxidase, followed by absorption of gluconateto and elution from a column of Amberlite CG-400 resin,with 0.5 M NaCI (14).

Respiratory gas samples were obtained simultaneouslywith each blood sample and analyzed for O-,,CO,, and 14CO2

content by standard methods (19). Immunoreactive insulinwas determined by the method of Hales and Rändle(17),free fatty acids were determined by the method of Dole andMeinertz (10), lactate was determined by the modificationby Strom (31) of the method of Barker and Summerson (2),and glucose in plasma and parenteral nutrition solutionwere determined by using Glucostat reagent (WorthingtonBiochemical Corp., Freehold, N. J.). Total energy balancewas estimated in each patient before parenteral nutrition byconventional indirect calorimetry.

The parenteral nutrition solution utilized in these studiescontained approximately 218 g glucose and 4.5 g nitrogen

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C. P. Holroyde et al.

Table 1Clinical data

Patient Age Sex Diagnosis Wt«(kg)

R. S. 44 M Cancer of bronchus; retro- 62.9, 60.5peritoneal métastases

M.B. 46 M Cancer of colon; liver metas- 73.2,76.4tases

S. M. 60 M Cancer of bronchus; bone 61.8,62.7and liver métastases

C.W. 79 M Cancer of colon; lung me- 61.4,65.9tastases

F. R. 67 M Cancer of stomach 52.3, 58.6L. R. 79 F Cancer of stomach; liver me- 44.3,45.3

tastasesR. E. 53 F Cancer of breast; liver, 31.8,32.8

bone, and s.c. métastasesC. Y. 52 F Cancer of breast; cuta- 40.9, 44.4

neous, mesenterio andliver métastases

" Denotes weight before and at the completion of TPN.

(Amigen, protein hydrolysate) per liter. The techniques usedfor parenteral nutrition at this institution have been reportedpreviously (26).

The patient voided before each turnover study, and urinewas collected throughout and at the close of the experimental period. A sample of the parenteral nutrition solutionwhich each patient was receiving at the time of the studywas also obtained. Nitrogen in urine and parenteral nutrition solution were determined by the method of Ferrari (13).

Calculations. The rate of glucose turnover and Cori cycleactivity were calculated by using assumptions and equations described previously (27). In all studies, a linear decline in the specific activity of plasma glucose and reasonably constant plasma glucose concentrations indicated thatsteady-state conditions were present. The glucose turnover

rate was obtained as the product of the glucose pool andthe fractional replacement rate, corrected for radioactivityrecycled into glucose carbons 1 to 5. The glucose pool wascalculated by extrapolating the specific activity of plasmaglucose to zero time, a procedure which assumes a singlehomogenous glucose pool of constant size.

Cori cycle activity, determined from radioactivity recycledinto glucose carbon 6, was calculated as a fraction of thefractional replacement rate. The rate of plasma glucoseoxidation was obtained from the known rate of CO, outputand the percentage of the exhaled CO-, derived from oxidation of plasma glucose. This latter value was calculated asthe ratio of the maximum CCX specific activity achieved tothat of the plasma glucose specific activity at the same time,i.e., at fmaxof the respiratory CO, specific activity curve (1).Values for the percentage of CO, derived from plasma glucose oxidation and the rate of glucose oxidation obtained inour patients before parenteral nutrition are in good agreement with those reported by others who used this method ofcalculation (1, 24).

RESULTS

Rates of glucose turnover, oxidation, Cori cycle activity,and other metabolic parameters obtained before TPN in 5 of

the 8 patients in this study have been reported previously(18). Patients L. R., R. E., and C. Y. were subsequentlyadded forthis investigation. In the present study the volumeof parenteral nutrition solution administered to each patientranged from about 1.5 to 2.5 liters/day. Thus, patients R. S.,M. B., and C. W. received glucose at a rate that providedcarbohydrate calories 10 to 15% in excess; Patients S. M.,L. R., R. E., and C. Y. received it at a rate 22 to 26% inexcess; and Patient F. R. received it at a rate 45% in excessof measured basal energy expenditure. Patients L. R., R. E.,and C. Y. received 8.1 to 9.4 g nitrogen per 24 hr, whereasthe remaining patients received 10.3 to 13.1 g nitrogen per24 hr. On the basis of urinary nitrogen excretion during the4-hr glucose turnover study period, positive nitrogen bal

ance (0.3 to 2.9 g nitrogen per 24 hr) was achieved in all but2 patients. Negative nitrogen balance was observed in M. B.and R. E. with values of -5.6 and -1.7 g nitrogen per 24 hr,

respectively.In response to TPN, plasma glucose, insulin, and venous

lactate concentrations increased, and free fatty acid decreased (Chart 1). No patient developed significant hyper-glycemia, glycosuria was absent, and no patient requiredexogenous insulin supplementation. Mean venous lactateconcentration before TPN was 1.34 mM and rose to 2.05 mMduring TPN. Two patients (M. B. and S. M.) with the highestinitial lactate concentrations developed moderate lacticaci-demia of 2.7 and 3.5 mM, respectively. Mean O, consumption rose slightly but not significantly in response to TPN,whereas mean CO-, production increased markedly (p <0.01 ) (Chart 2). Respiratory quotient rose to >1.0 except in 1patient, S. M.

Time-course changes in the specific activity of plasma

glucose carbons 1 to 5, carbon 6, and respiratory CO2 inPatient R. S. before and during parenteral nutrition areshown in Chart 3. During each glucose turnover study period the plasma glucose concentration was reasonably constant, averaging 86 mg/100 ml before and 114 mg/100 mlduring parenteral nutrition. There was a linear decline in thespecific activity of glucose carbons 1 to 5 in each studyperiod, but during TPN the decline was much steeper, indicating a more rapid turnover rate. Before TPN, the specificactivity of glucose carbon 6 rose gradually, reached a peakat 2 hr, and then declined. During TPN in this patient, thesame general pattern was noted except that the peak occurred at an earlier time, and the entire curve was shifteddownward relative to the carbon 1 to 5 specific activitycurve. The change in respiratory CO2 specific activity withtime in the study before TPN is similar to that previouslyreported by us and others, by the single injection techniquefor [14C]glucose administration (1, 24, 28). During TPN, the

CO-, specific activity curve reached a peak at an earlier time,and the ratio of CO, specific activity to that of the carbon 1to 5 specific activity at each sampling period was somewhatgreater than was observed before TPN.

Rates of glucose turnover, oxidation, and Cori cycle activity observed in the 8 patients before and during TPN areshown in Table 2. Before nutritional therapy, 3 patients (R.S., M. B., and S. M.) had moderately increased glucoseturnover rates and markedly elevated Cori cycle activity,whereas 5 patients (Table 2, C. W. to C. Y.) had essentiallynormal glucose turnover and Cori cycle activity. In the latter

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200

150

Chart 1. Plasma glucose, immunore-active insulin i/fl/i. free fatty acids(FFA), and venous láclate levels before and during parenteral nutrition.nil, microunits; /, liters.

100

50

60

40

20

PLASMA GLUCOSE

mg/WOml

Response to Parenteral Nutrition in Cancer

1 5i- 35,—

1.0

0 5

25

1.5

0 5

PLASMA IRI

fjU/ml

PLASMA FFA

mEq/l

VENOUS LACTATE

m M

450

350

250

02

CONSUMPTION

mmolel J m/hr

1 2

1 .0

BEFOREHYPERALIMENTATION

DURINGHYPERALIMENTATION

C02

PRODUCTIONR Q

mmote/ m/hr

Chart 2. Oxygen consumption, carbon dioxide production, and respiratory quotient (RQ) before and during parenteral nutrition.

patients, Cori cycle activity was about 22% of the totalglucose turnover, a value which is close to that obtained innormal humans by isotope tracer techniques (22, 27). It isalso similar to the fraction of hepatic glucose output attributable to lactate uptake determined by direct catheteriza-tion of the splanchnic bed in normal humans (22). The rateof plasma glucose oxidation averaged 59 mg/kg/hr (range,36 to 82) and accounted for 22% (range, 15 to 32) of the totalCO-,output.

In response to TPN, plasma glucose turnover and oxidation increased. The total glucose turnover rates shown inTable 2 include Cori cycle activity. The difference betweentotal glucose turnover and Cori cycle activity should represent endogenous glucose production from all other sourcesand, during TPN, should be equal to the known rate ofglucose administration if endogenous production was completely suppressed. In our studies during TPN, calculatedrates of endogenous production averaged 90% of theknown rates of glucose administration. There are severalpossible reasons for this discrepancy. First, in patients re-

CO¿

§2_j >• 0 100

S«

r'20°~°--0"-°L n o S

HOURS

Chart 3. Time-course changes in plasma glucose concentration and specific activity and respiratory CO specific activity before and during parenteral nutrition (hyperalimentation). Values of specific activity have beenmultiplied by 10" for purposes of graphical display.

ceiving TPN, the fractional replacement rate of plasma glucose was increased because of exogenous glucose administration. Although radioactivity was present in glucose carbon 6, the small quantities found preclude accurate assessment of the calculated fractional rate of recycling. Thisuncertainty, coupled with even small experimental errorsinvolved in estimating the rate of glucose administrationand turnover, may account for the differences observed. A2nd reason is that the small but persistent recycling ofradioactivity may be due to processes not reflecting netglucose synthesis from lactate, i.e., isotopie exchange of

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C. P. Holroyde et al.

Table 2Glucose metabolism before and during parenteral nutrition

PatientR.

S.M.B.S.

M.C.

W.F.

R.L.

R.R.

E.C.

Y.Glucose

infusion rate

(mg/kg/hr)03310324039902400441032503990335TGT"(mg/kg/hr)221340283312209409108234105470148395177399111339Cori

cycleactivitymg/kg/hr12418193621017626192762413229311927%

ofTGT°565681948192482613258168178%

of CCXfrom Glucose oxi-plasma glu- dation rate

cose(mg/kg/hr)255327492253185215553262183719417020276161601703612040203822035615053147Glucose

oxidizedGlucose infused

x 1006150435046633844

" TGT, total glucose turnover rate.

labeled glucose carbon (21). Supporting this possibility arereports that lactate extraction by the splanchnic bed of thehuman was virtually abolished during suppression of endogenous glucose production by p.o. or i.v. glucose administration (12, 33).

During TPN, Cori cycle activity, expressed as mg per kgper hr, apparently decreased or remained essentially unchanged , whereas, when expressed as a fraction of the totalglucose turnover, a uniform decrease was noted in all patients. Because of the previously mentioned uncertaintiesconcerning the calculations and significance of Cori cycleactivity during TPN, firm conclusions regarding the physiological significance of these changes cannot be stated atthis time.

The rates of plasma glucose oxidation were increased 2-to 5-fold during TPN and, although the data are limited,were apparently proportional to the rates of glucose administration. The percentage of C02 derived from the immediate oxidation of plasma glucose ranged from 37 to 62%,indicating that glucose provided a major share of the totalenergy expenditure of the patient. Oxidation accounted for38 to 61% of the glucose administered in the parenteralnutrition solution.

Parenteral nutrition was judged clinically beneficial in 5patients; 1 patient (R. S.) was unchanged, whereas 2 patients (M. B. and S. M.) deteriorated clinically. The latter 2patients both had initially high Cori cycle activity and developed the described moderate lacticacidemia in response toTPN. Clinical response was judged solely on the basis ofsubjective changes, and no attempt was made to evaluateobjective changes in measurable lesions during the short-term study. Thus, beneficial responses occurred in patientsclaiming an improved sense of well-being, whereas.deleterious responses occurred in patients who described a significant worsening of all symptoms before TPN.

It should be noted that weight changes during TPN areincluded for the purposes of calculation and, with the exception of R. S., are likely to reflect short-term fluid accumulation. Two patients (R. E. and M. B.) developed modestascites during nutritional therapy, but this factor alone did

not affect the final subjective evaluation of response.Although M. B. and S. M., with adverse responses to TPN,

had liver dysfunction secondary to métastases,similar degrees of liver dysfunction were noted in C. R., R. E., and C.Y., in whom beneficial responses were reported.

DISCUSSION

It is recognized that the patients selected for this initialstudy are both clinically and metabolically heterogeneous,reflecting the diverse nature of the hospitalized cancer patient population. Because TPN alters the metabolic andbiochemical profile of even normal subjects (9) and becauseabnormalities of glucose and lactate metabolism maypreexist in some cancer patients in the basal state (18, 34,35), TPN was delivered as a strictly short-term adjunct before specific anticancer therapy in this group of patients.

In response to TPN, plasma glucose and insulin concentrations increased, and free fatty acids decreased as wouldbe anticipated after an infused glucose load. Impaired glucose tolerance has been described in nutritionally deprivedcancer patients (5) and in some trauma patients receivingTPN (16). The absence of significant induced hyperglycemiaduring TPN, however, excludes the possibility of major disturbances of carbohydrate tolerance in the patients studied.

The administration of exogenous glucose to normal humans results in a decrease in its endogenous production(12, 23, 33). At least qualitatively, the suppression of endogenous glucose production observed in our patients duringTPN is in agreement with those observations.

Major increases in OL>consumption and basal metabolismrate were not observed in our patients, contrasting withprevious reports by Terepka and Waterhouse (32) on themetabolic response to forced feeding in some cancer patients. The percentage of CO.,derived from immediate oxidation of plasma glucose during TPN averaged 50% (range,37 to 62), indicating that glucose provided a major share ofthe total energy expenditure of the patient. The wide rangeof values is probably related to the nutritional status of the

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Response to Parenteral Nutrition in Cancer

patients and to the rate of exogenous glucose administration.

That glucose was apparently not a more important energy-yielding fuel during TPN is somewhat surpnsing. Thepercentage of CO2 derived from glucose oxidation and therate of glucose oxidation may have been underestimatedbecause of isotopie exchange of the labeled glucose carbonwith and into other compounds (21). However, amino acidand fatty acid oxidation probably also contributed to thecaloric requirement of patients during TPN. The urinarynitrogen excretion in our patients, calculated from a 4-hrurine collection during each metabolic study period, averaged 10.7 g/24 hr (range, 5.9 to 18.7). Since the caloricequivalent of urinary nitrogen is 26.4 kcal/g, this rate ofurinary nitrogen excretion is equal to about 280 kcal/24 hror 20% of the estimated total energy expenditure of thesepatients (18). Rates of plasma free fatty acid oxidation havenot been measured in the human during periods of sustained glucose administration. However, a short-term glucose administration to the human (36) or animals (15) hasbeen shown to decrease but not abolish fatty acid oxidation. By using an average plasma free fatty acid concentration of about 0.2 /^.Eq/rnl, which was observed in our patients during TPN, and on the basis of data extrapolatedfrom normal humans studied over a wide range of plasmaconcentrations (19), it is possible to calculate that about15% of their total caloric expenditure was probably derivedfrom oxidation of plasma free fatty acids. Thus, during TPN,about 85% of the total caloric expenditure of our patientscould be accounted for by oxidation of glucose, aminoacids, and plasma free fatty acids. The remainder of thetotal caloric expenditure may have been satisfied by glucose oxidation which was underestimated because of methodological and experimental errors involved in estimatingthis process.

With the exception of 1 patient, respiratory quotient values exceeded 1.0 during TPN, implying the synthesis of fatfrom carbohydrate. Diets rich in carbohydrate have beenshown to increase triglyceride-fatty acid synthesis in thehuman (3). It is therefore possible that some glucose administered during TPN was converted to triglycérides in liverand subsequently oxidized in peripheral tissues. Dilution ofthe administered [14C]glucose carbon and delayed appearance of 14CO2resulting from this process could result in an

underestimation of the extent to which glucose contributedto total energy expenditure during TPN.

The elevation of venous lactate concentration after TPNrequires special comment. Blood lactate concentration isknown to rise after glucose administration (12) and duringTPN (20), but the mechanism has not been clearly determined. Felig ef al. (12) have suggested that the hyperlacta-temia after p.o glucose administration may be due, at leastin part, to a decreased splanchnic uptake. During TPN, 2patients in our study (M. B. and S. M.) developed moderatelacticacidemia of 2.7 and 3.5 mM, respectively, after apparent suppression of high Cori cycle activity. Although thismay represent decreased clearance of lactate by means ofglucose resynthesis, increased lactate production may alsobe involved. The possibility exists that increased lactateproduction may reflect enhanced tumor growth rates, sincethis phenomenon has been observed during animal studies

involving forced feeding (4, 30).Although it is recognized that patient numbers are small,

the clinical response to parenteral nutrition during thisstudy is worthy of comment. Five patients were subjectivelyimproved, and 1 patient was unchanged, whereas 2 patientsfelt significantly worse and appeared to observers to deteriorate at an accelerated rate. We have not attempted todistinguish between the possibly deleterious effects of glucose versus infused amino acids in this initial study. Thegreatest benefit occurred in 2 patients with intestinal obstruction who subsequently responded to additional chemotherapy. The deleterious responses occurred in 2 of 3patients with initially high Cori cycle activity and moderatelyincreased glucose turnover rates, O2consumption, and total caloric expenditure. Neither of these latter patients responded to treatment. It seems evident that parenteral nutrition can play a valuable adjunctive role in the management of patients with malignant disease. Our general observations, however, are in accord with those of Terepka andWaterhouse who commented on the sometimes adverseclinical response of cancer patients to forced p.o. feeding(32). Clearly, further studies are required in a more homogeneous population of patients before general acceptance ofparenteral nutrition as an adjunct to cancer therapy can beestablished.

ACKNOWLEDGMENTS

We are indebted to Maureen Donohue. Joseph Ottaviano, and PatriciaNojunas, R.N. for excellent technical assistance.

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