effects of total parenteral nutrition and chemotherapy on the … · effects of total parenteral...

[CANCER RESEARCH 44,1706-1711, April 1984]

Effects of Total Parenteral Nutrition and Chemotherapy on the MetabolicDerangements in Small Cell Lung Cancer1

David McR. Russell, Moshe Shike,2 Errol B. Marliss, Allan S. Detsky, Frances A. Shepherd, Ronald Feld,William K. Evans, and Khursheed N. Jeejeebhoy3

Departments of Medicine and Health Administration, Faculty of Medicine, University of Toronto [A. S. D.]; Toronto General Hospital [D. M. R., M. S., E. B. M., F. A. S.,W. K. E., K. N. J.Â¡;and Princess Margaret Hospital [FI. F.], Toronto, Ontario, Canada

ABSTRACT

Changes in energy metabolism, substrate use, and hormoneprofiles were prospectively studied in 31 patients with small celllung cancer receiving chemotherapy. Patients were randomizedto receive either 4 weeks of total parenteral nutrition (n = 15) orto continue self-regulated p.o. diet (control group; n = 16). The

initial actual resting energy expenditure measured by indirectcalorimetry was 31% higher than the predicted resting energyexpenditure determined by the Harris-Benedict formula. The p.o.

calorie intake was inappropriately low for these hypermetabolicpatients. Total parenteral nutrition resulted in a significant positive net energy balance, but in follow-up was associated with

prolonged anorexia and a negative energy balance. Completeresponse to therapy reduced resting energy expenditure andincreased calorie intake, whereas the contrary was true in non-responders. Elevated plasma-free fatty acids (800 Â±62 ^M; S.E.)

and a low respiratory quotient (0.74 Â±0.02) indicate that thedominant energy source in patients with small cell lung cancer isfat, and that increased fat oxidation continues despite tumorresponse. Elevated fasting plasma catecholamines and insulinresistance may contribute to continued fat mobilization. Initially,there was a significant increase in blood lactate (1118 Â±95 MM)suggesting either increased tumor or tumor-mediated glycolytic

activity. Response to therapy was associated with a fall in bloodlactate levels. The most effective way of improving the metabolicderangements in patients with small cell lung cancer was toachieve tumor response to therapy.

INTRODUCTION

Significant weight loss is often the first manifestation of amalignant neoplasm. In SCLC,4 an apparently small tumor burden

may be associated with significant weight loss (18) and a poorprognosis (13). In general terms, weight loss may result from anegative energy balance due to: (a) increased energy requirements; (b) reduced calorie intake; or (c) metabolic derangementsthat impair nutrient use. Isolated reports of metabolic abnormalities have been noted in a variety of cancers (2, 3, 5, 8, 11, 12,14, 15, 20, 23). These may also result in a negative energybalance, and include: (a) increased resting energy expenditure

' Supported by an NIH Contract with the University of Toronto (Contract NOI-CM-97267), the Ontario Ministry of Health (Grant PR 228), and various sponsors.

2 Present address: Memorial Stoan-Kettering Cancer Center, New York, NY

10021.sTo whom requests for reprints should be addressed, at No. 6352, Medical

Sciences Building, University of Toronto, Toronto, Ontario, Canada M5S 1A8.' The abbreviations used are: SCLC, small cell lung carcinoma; REE, resting

energy expenditure; RQ, respiratory quotient; TPN, total parenteral nutrition; CAV,induction chemotherapy; FFA, free fatty acids.

Received February 22, 1983; accepted December 20, 1983.

(2, 19, 26); (b) reduced calorie intake due to anorexia (4), tasteabnormalities (6); or abnormalities of central hypothalamic control(13); and (c) impaired substrate use due to preferential mobilization of fat (10) and insulin resistance (16).

Despite such sporadic data, resting energy expenditure,calorie intake, substrate oxidation, and hormonal milieu have notbeen systematically examined in SCLC under controlled conditions of nutrient administration. This study was a randomized,controlled trial in which patients receiving total parenteral nutrition were compared with those eating a normal diet. Furthermore, we were able to study both the acute effects of chemotherapy and the effects of a complete response to therapy onthese metabolic parameters.

MATERIALS AND METHODS

Experimental Design. The changes in energy metabolism (measurement of actual REE and determination of predicted REE and caloricintake) and substrate hormone profiles were prospectively studied in 31patients with newly diagnosed SCLC. All patients in Toronto, Ontario,Canada, were part of a multiinstitutional trial supported by the NutritionProgram of the Division of Cancer Treatment, the National CancerInstitute. The aim of the trial was to evaluate the efficacy of TPN as anadjunct to chemotherapy in measurable SCLC.

Upon entry to the study, all patients had standard nutritional assessment and tumor staging performed. Patients were stratified according tothe extent of disease (limited versus extensive), the degree of weightloss over the 3 months preceding their study (less than 5% and greaterthan 5%), their performance status (Eastern Cooperative OncologyGroup), and institution. After stratification, patients were randomized into2 groups by a central randomization procedure at the National CancerInstitute; a TPN group which received in-hospital TPN for 4 weeks anda control group which continued to consume a self-regulated p.o. diet.

During the 4 weeks of TPN, p.o. intake was restricted to noncaloricfluids. In nondepleted patients (<5% body weight loss Â¡nthe 3 monthsprior to diagnosis), the TPN provided between 1 and 1.25 g/kg bodyweight/day of crystalline amino acids (Travasol; Baxter-Travenol Labo

ratories of Canada) and a nonprotein calorie intake of between 32 and40 kcal/kg body weight/day given as an equicaloric mixture of dextroseand lipid (Nutralipid; Pharmacia, Canada). Depleted patients (>5% bodyweight loss Â¡nthe 3 months prior to diagnosis) received an amino acidintake of between 1.50 and 2.0 g/kg body weight/day and a nonproteincalorie intake of 48 to 64 kcal/kg body weight/day. Both the protein andcalorie intake were reassessed each week, and minor adjustments weremade depending on clinical assessment of the nutritional status. Allpatients received electrolytes, vitamins, and trace elements in similaramounts (21).

Chemotherapy started in the control group after completion of theinitial nutritional evaluation, and in the TPN group after 7 days ofparenteral nutrition. All patients received CAV consisting of high-dose

cyclophosphamide (1200 mg/sq m), doxorubicin (Adriamycin, 70 mg/sqm; Adria Laboratories of Canada, Ltd.), and vincristine (2 mg) for 2 cycles3 weeks apart, provided that it was well-tolerated, that there was no

1706 CANCER RESEARCH VOL. 44

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bleeding or infection, and that there were adequate granulocyte andplatelet counts. All patients were given prophylactic trimethoprim-sulfa-methoxazole, 2 tablets twice daily, from Days 8 to 18 during each cycleof CAV. At 6 weeks, all patients were reevaluated and classified asresponders (partial or complete response) or nonresponders (stablediseaseor progression).Respondersthen received2 cyclesof moderate-dose CAV (calledCAV1):cyclophosphamide(1000 mg/sq m),doxorubicin

(50 mg/sq m), and vincristine (2 mg) and prophylactic cranial irradiationafter the second cycle of CAV1(2000 rads in 5 fractions over 1 week).

Partial responders with limited disease were also given locoregionalradiotherapy (2500 rads in 10 fractions over 2 weeks). At this point,responders were switched to VP-16-213 (Etoposide; 100 mg/sq m dailyfor 3 days), methotrexate (50 mg/sq m), and p.o. folinic acid (10 mgevery 6 hr for 6 doses, beginning at 36 hr after methotrexate) for 5cycles at 3 weekly intervals, after which they crossed back to CAV1.

This was continued until they reached a total cumulative dose of doxorubicin of 450 mg/sq m. They then received VP-16-213, Methotrexate,and folinic acid for 5 further cycles to complete 1 year of therapy.

Nonresponders at 6 weeks received VP-16-213 (100 mg/sq m dailyfor 3 days), Methotrexate (50 mg/sq m), and folinic acid (10 mg every 6hr for 6 doses beginningat 36 hr after Methotrexate)every 3 weeks untilprogression. Complete response was defined as complete disappearance of all tumor lesions, assessed clinically and by chest radiographyand liver and bone scans. Partial response was defined as a decreaseof >50% in the product of the cross-sectional diameter of the primarylung lesion without progression of mÃ©tastases.

Patients. All patientshad histologicallyor cytologicallydocumentedtumor, and none had been previously treated with either chemotherapyor radiotherapy. All patients had Ã©valuableor measurabledisease and alife expectancy of greater than 8 weeks. On entry to the study, allpatients had adequate bone marrow, hepatic and renal function (WBC,>3000 cu mm; platelets, >100,000 cu mm; bilirubin, <2 mg/dl; serumcreatinine,<2 mg/dl; and blood urea nitrogen, <30 mg/dl). The protocolwas approved by the Human ExperimentationCommittee of the University of Toronto, and written consent was obtained from all patients.Patientswere excluded from the study accordingto the following criteria:(a) recent myocardial infarction (<3 months from the date of diagnosis),congestive cardiac failure, or cardiac arrhythmia; (b) documented centralnervous system mÃ©tastases;(c) superior vena cava obstruction precluding central venous catheterization for TPN; (d) inappropriate antidiuretichormone syndrome; (e) other comorbid disease which rendered treatment inappropriate; (f) performance status of 4 on the Eastern Cooperative Oncology Group scale.

There were 16 patients in the control group and 15 in the TPN group.There were 10 females and 21 males with a mean age of 55.8 years(range, 45 to 75 years). There were 9 males in the TPN group and 12 inthe control group. Twenty-one patients had limited disease, and 10patients had extensive disease (5 patients in each group with extensivedisease).Fifteen patients had lost more than 5% of body weight in the 3months prior to diagnosis (9 in the TPN group and 6 in the control group).

Energy Metabolism. The actual REE was determinedby indirectcalorimetry. After an overnight fast, and while at complete rest, thepatient's expired air was collected in a Douglas bag through a mouth

piece over a period of 5 to 10 min. Collection of air started only after aperiod of adaptation to the mouthpiece. The volume of the expired gaswas measured with a Wright spirometer (Ohio Medical Products, Madison, Wl). The spirometer was calibratedregularlyand was alsocomparedwith a Tissot spirometer. Oxygen concentration in expired air wasmeasuredwith a polarographicO2analyzer(BeckmanOM-11; BeckmanInstruments, Inc., Fullerton, CA). The carbon dioxide content of theexpired air was measured with an IR CO2 analyzer (Beckman LB-2).After correction of expired gas volumes to standard temperature pressure dry conditions, the energy expenditure was calculateddirectly fromoxygen consumption (liters of oxygen consumed in 24 hr, VO2),CO2production (liters of carbon dioxide produced in 24 hr, VCO;-),and totalurinary nitrogen in 24 hr (Un)measured from a 24-hr urine collection by

Metabolic Derangements in SCLC

the micro-Kjeldahlmethod, according to the formula of Weir (24):

REE = 3.94 V02 + 1.106 VCO2- 2.17 Uâ€ž

The predicted REE was calculated by the Harris-Benedict formula (7).The nonprotein RQ was also calculated using the oxygen consumption,carbon dioxide production, and total urinary nitrogen.

The actual REE,predicted REE,and RQwere determinedin 20 normalsubjects and in the 31 patients with SCLC on admission and at 1, 2, 3,4 (TPN group only), 7, 10, and 26 weeks.

Calorie Intake. The calorieintakefor patientstakinga p.o. diet wasdetermined from 3-day diaries prepared by the patients at home. Thecaloric equivalent of foodstuffs was obtained from tables of the Department of Agriculture (1). The daily calorie intakes were recorded at thesame intervals as the REE, so that net energy intake above restingrequirementscould be calculated. For patients receivingTPN, the calorieintake was preciselydefined by the amount infused.

Substrates-Hormones.Bloodfordeterminationofsubstrate-hormoneprofiles was drawn, after an overnight fast, following the collection ofexpired air. Plasmacortisol was determined by radioimmunoassay(25)and plasma catecholamines by a radioenzymatic technique (22). Bloodglucose, lactate, /3-hydroxybutyrate,plasma FFAs, immunoreactive insulin, and immunoreactive glucagon were determined by methods described elsewhere (10).

StatisticalAnalysis.Resultsof measurementsare reportedas meanÂ±S.E. Standard f tests, paired and unpaired as appropriate, were usedto examine the significanceof differences between means.

RESULTS

Energy Metabolism

In the 20 normal subjects (10 male and 10 female; mean age,32.8 years; range, 21 to 59 years), who were hospital employeeswithout any clinical abnormalities, the mean actual REE measured after an overnight fast by indirect calorimetry was 1513 Â±52 kcal/day, not significantly different from the predicted REE of1501 Â±33 kcal/day, calculated by the Harris-Benedict formula.In this group, the RQ was 0.79 Â±0.011. In 4 additional patientswith a mean age of 68 years, admitted for elective surgery andasymptomatic at the time of study, the mean RQ was 0.79 Â±0.026, and the measured and predicted REE were 1235 Â±102and 1414 Â±102, respectively. In contrast, in the 31 patients withSCLC, studied under the same conditions as the patients inelective hospital admissions, the mean base-lineactual REE was1804 Â±86 kcal/day, significantly higher than the mean predictedREE of 1374 Â±27 kcal/day (p < 0.001). This demonstrates thatpatients with SCLC are hypermetabolic, with a 31% increase inREE above the predicted normal even when compared withcontrols in the same age range. The percentage increase inpatients with metastatic disease (39.5 Â±7.9%) was not statistically different (p < 0.30) from those with limited disease (25.7 Â±6.2%).

Table 1 outlines the calorie intake and REE in the control andTPN patients at base line, during the period of TPN (Weeks 1 to4) and during follow-up (Weeks 7 to 26). The base-line calorieintake, REE, and net energy intake above resting requirementswere not significantly different between the 2 groups. However,the net positive energy intakes above resting requirements werewell below the normal required for the energy expenditure ofdaily activity. The calorie intake was clearly inappropriately lowin these patients who are hypermetabolic.

1707



D. M. Russell et al.

Table 1Energy metabolismin small cell lung cancer

Table 2Effect of response to therapy on energy metabolism

Control patients (n = 16)BaselineWK1-3Wk

7-26TPN

patients (n = 15)BaselineWk

1-4 (TPN)Wk 7-26Calorie

intake(kcal)1971

Â±140Â°1996

Â±1041918Â±882020

Â±1742821Â±103

1524 Â±104Resting

energy expendi

ture(kcal)1832

Â±791727Â±561677Â±521783

Â±1671848Â± 69

1534 Â± 50Net

energy intakeaboveresting

requirements(kcal)+138

Â±135+268Â±91+241Â±79+236

Â±201+973+87

-9Â±116'

Mean Â±S.E.

Effect of Chemotherapy. There were no significant short-

term effects of chemotherapy (base line compared with Weeks1 to 3) on either calorie intake or REE in the control patients(Table 1).

Effect of TPN. The 4 weeks of TPN resulted in a significantincrease in calorie intake compared with the base-line p.o. calorie

intake (p < 0.001), and a significant positive net energy intakeabove resting requirements (p < 0.001) (Table 1). After 1 weekof TPN and before the first course of chemotherapy, the meanactual REE increased by 8.5% from 17873 Â±167 kcal/day to1933 Â±132 kcal/day (p < 0.05). This increase represents thespecific dynamic action of TPN (comparable to the specificdynamic actions of p.o. feeding), since the REE measurementswere performed while the TPN solutions were being infused. Inthe follow-up period (Weeks 7 to 26), there were no significant

changes in the metabolic parameters compared with the baseline in the control patients, while the TPN patients showed asignificantly lower calorie intake (p < 0.001) and a negative netenergy intake above resting requirements. During this follow-up

period, the mean daily p.o. calorie intake after cessation of TPNwas not significantly different in the patients who obtained acomplete clinical response (1520 Â±228 kcal/day; n = 4) compared with the non-responders (1556 Â±101 kcal/day; n = 11).

Effect of Response to Therapy. Twelve patients had a complete clinical response to therapy between 10 and 26 weeksafter induction chemotherapy. On the initial assessment of these12 patients, 7 had limited disease and 5 had extensive disease,while 8 patients were in the control group and 4 Â¡nthe TPNgroup. At base line in these 12 patients, there was a 27.6 Â±4.5% increase in the actual REE above predicted while, followinga complete clinical response to therapy, there was a significantreduction in the REE to only 7.5 Â±4.5% above predicted (p <0.01). In the partial responders and the nonresponders, therewas no significant change in the REE.

Table 2 compares these changes in energy metabolism in thepatients who obtained a complete clinical response to therapycompared with nonresponders. The significant reduction in REEin the responders (p < 0.01) and maintainance of calorie intakeresulted in a positive net energy balance (+451 Â±137 kcal). Incontrast, the nonresponders had a significant reduction in calorieintake (p < 0.05) and no reduction in REE such that they wentinto a negative net energy balance (-93 Â±144 kcal). Clearly, the

energy balance was significantly higher in patients at the time ofcomplete response to therapy compared with the energy balancein the nonresponders (p < 0.02).

Respondersfn = 12)Base lineResponseto therapyP

Nonresponders(n = 14)Base lineWk 10 (nonresponse)PCalorie

intake(kcal)1988

Â±146a2020 + 141NSÂ°2034

Â±1751656 Â±145

<0.05Resting

energy expendi

ture(kcal)1835

Â±1281568+ 56<0.011802

Â±1191749+ 75NSNet

energy intake aboveresting requirements(kcal)+153

Â±145+451 Â±137NS+232

Â±194-93 Â±144

NS"Mean Â±S.E.

6 NS, not significant.

Substrate-Hormone Profile

Table 3 outlines the base-line substrate-hormone profile in the

31 patients with SCLC. There was a significant increase in fastingcatecholamines (norepinephrine, epinephrine, and dopamine; p< 0.05), whereas base-line plasma insulin, glucagon, and cortisol

were normal. While the FFA were raised in the fasting state ascompared with controls, there was no hyperglycemia. There wasa significant increase in fasting blood lactate compared withnormal (p < 0.01), suggesting increased tumor or tumor-me

diated production of lactic acid. There was evidence of increasedoxidation of fat and ketone body production with increasedfasting plasma FFAs (p < 0.01) and /3-hydroxybutyrate (p <0.05). Preferential fat oxidation was noted by a low mean non-

protein RQ, 0.73 Â±0.03, compared with 0.79 Â±0.01 in bothyoung and elderly controls (p, not significant).

Effect of Chemotherapy. There were no significant acuteeffects of chemotherapy on the substrate-hormone profile in the

2 weeks following induction chemotherapy in the control patients. Fasting blood lactate remained elevated (984 Â±63 MM)and fasting plasma FFAs and blood /3-hydroxybutyrate were also

elevated (691 Â±39 and 127 Â±46 MM,respectively). Fat oxidationcontinued as evidenced by a low RQ of 0.72 Â±0.02.

Effects of TPN. Table 4 outlines the effect of 1 week of TPNon the substrate-hormone profile prior to chemotherapy, Therewas almost complete suppression of the blood /3-hydroxybutyr-

ate, which fell from 90.7 Â±26.4 to 13.3 Â±2.7 MM (p < 0.02),while there was a marked increase in plasma immunoreactiveinsulin from 0.54 Â± 0.05 to 5.07 Â± 1.67 ng/ml (p < 0.01).However, the plasma FFA level continued to be elevated (880 Â±127 MM)despite this marked increase in plasma insulin, and theRQ remained low at 0.76 Â±0.16 even after 4 weeks of TPN inwhich at least 50% of calories were given as glucose. The RQwas not significantly higher than in the control patients withSCLC (0.70 Â±0.09; p, not significant), who were not receivingadditional nutritional support.

Effect of Response to Therapy. Tables 5 and 6 compare thesubstrate-hormone profiles in responders compared with non-

responders. In the responders, there was a significant reductionin fasting blood lactate from 1059 Â±10 to 595 Â±82 MM (p <0.001 ). Response to therapy was not associated with a significant change in substrate use, since FFA remained elevated inboth responders (824 Â±105 MM)and nonresponders (878 Â±70MM)and RQ low in both responders (0.76 Â±0.03) and nonresponders (0.76 Â±0.03). Preferential fat oxidation appears obligatory despite a complete clinical response to therapy.




Metabolie Derangements in SCLC

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DISCUSSION

Energy Metabolism. The results of this study showed thatpatients with SCLC were hypermetabolic. In addition, prior toany therapy, their mean calorie intake exceeded mean restingrequirements by only 138 and 236 kcal/day in controls and TPNpatients, respectively. This excess of calorie intake over restingrequirements is clearly insufficient to meet the energy needs ofday-to-day activity, and it is, therefore, not surprising that 15

patients had lost more than 5% body weight on admission.Hence, weight loss in these patients represents a combinationof hypermetabolism and a relative anorexia.

The administration of TPN for 4 weeks placed these patientsin a markedly positive energy balance compared with controlswho continued to eat as before. We have already reported thatthis increase in calorie intake was associated with a rise in bodyweight, total body potassium, and body fat.5 The interesting

finding is that this gain in body weight was followed by profoundanorexia in TPN patients compared with controls at the samestage of their disease. In consequence, after 4 weeks of TPN,the observed calorie intake over a 19-week period was below

the resting metabolic requirements. The characteristics of thisanorexia were that it was not transient, but lasted several monthsafter TPN was discontinued, and that it was not due to diseaseprogression, since both responders and nonresponders had asimilar reduction in p.o. intake following cessation of TPN. Hence,we are left with the interesting conclusion that changes in bodycomposition and weight gain were associated with appetitesuppression. In other words, appetite control was set to maintainsubnormal weight. The reduced p.o. calorie intake following TPNresulted in a sharp decline in body weight, total body potassium,and total body nitrogen such that, after 32 weeks, there wereno significant differences in body weight and body compositionbetween the TPN and control patients.

It is of interest that chemotherapy had little overall effect oncalorie intake or metabolic expenditure, whereas response totherapy reduced energy expenditure and improved intake. Thecontrary was true in nonresponders. The reduced intake inresponders is unlikely to be due to prior TPN, as it was observed6 weeks after TPN had been discontinued. These findings indicate the dominant nature of tumor activity in controlling appetiteand hypermetabolism. The mechanisms involved need furtherstudy.

Substrate Use and Hormone Profile. In patients with SCLC,the dominant fuel used for energy is fat. Fasting plasma FFAlevels were high (880 Â±127 ^M). This could be due to the tumor,or the relative insulin resistance of age. However, in other patients with nonmalignant conditions studied by Nordenstrom efal. (19) using a comparable TPN regimen, the FFA levels werenot similarly raised, being 397 Â±17 and 373 Â±35 UM in acutelyill and depleted patients, respectively. By comparison, theirhealthy controls had a mean FFA level of 543 Â±165 MM,resultscomparable to our own controls. Furthermore, in our patients,even during TPN, the high FFA levels were unsuppressed despitea high circulating level of insulin (5.07 Â±1.66 ng/ml or 126.79 Â±41 .5 itunits/ml). This finding was in contrast to Nordenstrom's

5M. Shike, D. M. Russell, A. S. Detsky, J. E. Harrison, K. G. McNeill, F. A.Shepherd, R. FekJ,W. K. Evans, and K. N. Jeejeebhoy, Changes in body composition in patients with small cell lung cancer: the effect of total parenteral nutritionas an adjunct to chemotherapy, submitted for publication.

APRIL 1984 1709



D. M. Russell et al.

Table 4Effect of TPNon substrate-hormoneprofile

Substrates Hormones

Initial valueWk 1(TPN)SignificanceBlood

glucose(mg/dl)106

Â±7.1a

122Â±9.7NS"Blood

lactate(Â¿imol/liter)1151

Â±1561272 Â±128NSBlood

pyruvate(^mol/liter)75.4

Â± 8.4100.9 Â±14NSBlood

0-hy-droxybutyrate(>imol/liter)90.7

Â±26.413.3 Â±2.7p

< 0.02Plasma

FFAs(iimol/liter)860

Â±107880Â±127NSPlasma

immune-reactive insulin(ng/ml)0.538

Â±0.0535.07Â±1.166p

< 0.005Plasma

im-munoreac-tive gluca-gon(pg/mi)315

Â±49301 Â±47NSPlasma

cortisol(M9/dl)18.27

Â±2.5716.97Â±1.82NS

Â°Mean Â±S.E. (n = 15)." NS, not significant.

TablesEffect of response to chemotherapyon substrate-hormoneprofile

InitialvalueValue at complete responseBlood

glucose(mg/dl)111

Â±3.5a

118 + 7.9Blood

lac-

liter)1059

Â±10595 Â±82SubstratesBlood

pyru-vate (fimol/liter)89.2

Â±7.971.7 Â±7.13Blood

/3-hy-droxybutyrateOimol/liter)100.7

Â±33.555.9 Â±11.0Plasma

FFAs iÃŸtnct/liter)716

Â± 71824 Â±105Plasma

immuno-reactive insulin(ng/ml)0.498

Â±0.0590.570 Â±0.118HormonesPlasma

immu-noreactive glu-cagÃ³n(pg/ml)278.4

Â±45.3319 Â±88.4Plasma

cortisol14.65

Â±1.1516.93 Â±2.09

Significance NS6 p < 0.001 NS NS NS NS NS NSa Mean Â±S.E. (n = 12)." NS, not significant.

TableÃ³Effect of no response to chemotherapyon substrate-hormoneprofile

Substrates Hormones

Plasma Plasmaim-Blood lac- Blood pyru- Blood /3-hy- FFAs Plasmaimmu- munoreac- Plasma

Blood glucose tate (/imol/li- vate Ornol/li- droxybutyrate (^mol/li- noreactive in- live gluca- cortisol<mg/dl) ter) ter) (^mol/liter) ter) sulin (ng/ml) gon (pg/ml) Oig/dl)

Initial value 106.7Â± 4.6a 1157Â±159 83.14 Â±8.70 112.1 Â±46.7 852 Â±92 0.592 Â±0.079 245 Â±14.0 20.58 Â±2.6

ValueatlOwk 121.6 Â±21.1 1136Â±129 76.48 Â±5.55 94.88 Â±34.0 878 Â±70 0.703Â±0.162 245Â±12.0 17.11Â±2.20

Significance NS" NS NS NS NS NS NS NS" Mean Â±S.E. (n = 14)." NS, not significant.

observation in patients on a comparable regimen of TPN wherethe FFA levels were only 373 Â±35 /Â¿mol/literwith much lowerlevels of insulin (8 Â±3 /Â¿units/ml)(19). In previous studies, wehad similarly observed comparably low FFA and insulin levels inpatients without cancer on a comparable regimen of TPN containing lipid (9).

These findings indicated that there was continuing fat mobilization unsuppressed by insulin in patients with SCLC, not seenin other patients on a comparable lipid regimen of TPN. Furthermore, associated with fat mobilization, the RQ was low, indicating that fat was oxidized in preference to carbohydrate. Datacalculated from MacFie ef al. (17) indicated that the mean startingRQ in 7 patients without cancer on TPN using a lipid systemwas 0.79 Â±0.05, but rose to over 0.92 on TPN using a comparable glucose-lipid regimen. In contrast, the RQ of our patients

remained at 0.76 Â±0.168. Thus, the higher fatty acid levels andlower RQ observed are not due to lipid infusions, since theywere not observed in several different studies in patients receiving equivalent or higher glucose-fat ratios in TPN. Increased fat

oxidation seemed to continue despite tumor response. In contrast, the increased blood lactate levels fell in the responders.These findings suggest that fatty acid mobilization is likely to be

an indirect effect of the tumor. In contrast, since the lactateproduction fell when the tumor responded, it is likely to be theresult of tumor-mediated glycolytic activity. Such an effect couldbe due to the action of tumor-specific lactic acid dehydrogenase.

In part, the continued fatty acid mobilization is due to insulinresistance and elevated catecholamines, as evidenced by thefact that the marked increase Â¡ninsulin levels during TPN failedto reduce circulating FFAs. The only increase in counterregula-

tory hormones was in the catecholamine levels, but other causesof insulin resistance, particularly related to tumor activity, arealso possible.

Finally, the administration of TPN, a forced intake of excesscalories, resulted in net fat synthesis and weight gain, but withconcurrent hypercatabolism and fat mobilization.

In conclusion, patients with SCLC are hypermetabolic, preferentially use fat stores, and are also relatively anorexic. A forcedincrease in calorie intake reduced neither hypercatabolism norfat mobilization. Weight gain imposed by artificial means increased anorexia, so that weight loss was even more rapid thanusual when nutritional support was discontinued. The single mosteffective way of improving the balance between intake andcatabolism is to achieve tumor response to therapy.




ACKNOWLEDGMENTS

We would like to thank nurses Mame Clark, Linda Millband, Betty MullÃs.SandraStewart, and Diane Taylor for all of their hard work on the study; and nutritionistsKaren Paul and Sandra Mitchell for preparing diet diaries. Special thanks go toJocelyn Whitwell and Dr. A. Bruce-Robertson for their help in preparing the

manuscript.

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APRIL 1984 1711



1984;44:1706-1711. Cancer Res David McR. Russell, Moshe Shike, Errol B. Marliss, et al. Metabolic Derangements in Small Cell Lung CancerEffects of Total Parenteral Nutrition and Chemotherapy on the

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