Abnormalities in Glucose and Protein Metabolism in Noncachectic Lung Cancer Patients David Heber, Rowan T. Chlebowski, Debra E. Ishibashi, et al. Cancer Res 1982;42:4815-4819. Published online November 1, 1982.
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[CANCER RESEARCH 42, 4815-4819, November 1982] 0008-5472/82/0042-0000$02.00
Abnormalities in Glucose and Protein Metabolism in Noncachectic Cancer Patients1
Lung
David Heber,2 Rowan T. Chlebowski, Debra E. Ishibashi, Joyce N. Herrold, and Jerome B. Block General Clinical Research Center and Department of Medicine, University of California, Los Angeles, School of Medicine, Harbor-UCLA California 90509
Medical Center, Terranee,
malnutrition associated with non-oat cell bronchogenic carci noma, we studied lung cancer patients under conditions of To determine whether metabolic abnormalities occur as part constant nitrogen and calorie intake and measured total body of the process of malnutrition in cancer, we studied 12 patients protein turnover, total body glucose production, muscle catab with non-oat cell lung cancer and 6 age-matched healthy olism, nitrogen balance, and basal metabolic rate. Since ec controls under metabolic ward conditions. Under conditions of topie adrenocorticotropic hormone syndrome has been re constant caloric and nitrogen intake, total body protein turnover ported in lung cancer (11) and could affect the metabolic measured by the continuous infusion of [14C]lysine was signifi variables being measured, 24-hr urinary-free cortisol excretion cantly increased (p < 0.05) in lung cancer patients [3.15 ± was measured in all subjects. Insulin resistance has also been 0.51 (S.D.) g/kg/day] compared to that of controls [1-87 ± reported in cancer patients (13) and could affect both protein 0.32 g/kg/day]. Increased protein recycling characterized by and glucose metabolism. Both serum insulin and plasma glu both increased synthesis and breakdown of body proteins in cose were measured before and 2 hr after a standard p.o. the lung cancer patients was inversely correlated with per glucose load. centage of ideal body weight at the time of study (r = —¿0.69; ABSTRACT
p < 0.05). Muscle catabolism rates determined by quantitating urinary 3-methylhistidine-creatinine excretion rates were in creased in lung cancer patients (106 ±11 /¿mol/gcreatinine) compared to those of controls (71 ±8 /¿mol/creatinine; p < 0.05). Glucose production rates assessed by the continuous infusion of [6-3H]glucose were increased in lung cancer pa tients (2.84 ±0.16 mg/kg/min) compared to those of controls (2.18 ±0.06 mg/kg/min; p < 0.05). There was no evidence of ectopie adrenocorticotropic hormone production in these patients, and 24-hr, urinary-free cortisol excretion in these patients was not increased compared to that of controls. Serum insulin and plasma glucose levels measured before and 2 hr after a standard p.o. glucose load were not different in patients and controls. Thus, increases in protein turnover, glucose production, and muscle catabolism were evident metabolic abnormalities in patients with non-oat cell lung cancer. The identification of these metabolic abnormalities as an integral part of the non-oat cell lung cancer disease process permits further evaluation of therapies designed to prevent cancer cachexia. INTRODUCTION Protein-calorie malnutrition is a commonly occurring morbid and mortal complication of advanced cancer (21). Both de creased food intake secondary to anorexia (5) and metabolic abnormalities in the tumor-bearing host (10, 25) have been proposed as contributing to progressive malnutrition in certain groups of patients with metastatic cancer. Weight loss occurs commonly in metastatic non-oat cell bronchogenic carcinoma and significantly affects survival (6, 7). In order to determine whether metabolic abnormalities are an integral part of the 1 Supported by NIH Grant CA-26563, by the General Clinical Research Center Grant RR-00425, and in part by a grant from Mead Johnson and Co., Evansville, Ind. 2 To whom requests for reprints should be addressed, at Clinical Research Center, Harbor-UCLA Medical Center, 1000 West Carson Street, Terranee, Calif. 90509. Received January 4, 1982; accepted July 26, 1982.
MATERIALS
AND METHODS
Cancer Patients and Control Subjects. Twelve patients 54 to 74 years old (mean age, 63 years), with documented non-oat cell bron chogenic carcinoma, and 6 healthy age-matched controls, 52 to 68 years old (mean age, 59 years), were admitted to the Clinical Research Center after consenting to the studies described below. The clinical data and nutritional parameters of the patients and control subjects studied are detailed in Tables 1 and 2. All lung cancer patients received a standardized chemotherapy regimen consisting of monthly doxorubicin (50 mg/sq m), vincristine (1.4 mg/sq m), cyclophosphamide (500 mg/sq m), and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (50 mg/ sq m). All patients were studied prior to therapy or at least 3 weeks after receiving chemotherapy to minimize the effects of this therapy on the variables studied. In addition, none of the patients had bronchopulmonary infections, bronchitis, or emphysema prior to study, based on routine pulmonary function testing and clinical assessment. Study Protocol. Twenty-four-hr dietary recalls and dietary histories were obtained on all patients at the timo of admission utilizing plastic food models (Iwasaki Images, Terranee, Calif.) to aid in estimating food portion sizes. Body weights were monitored with a calibrated-printing Toledo Scale, triceps skinfold thicknesses were measured with Lange calipers, and arm circumferences were measured with a flexible tape measure. All patients received a flesh-free diet at a level of 30 kcal and 1 g protein per kg of ideal body weight for 5 days in the Clinical Research Center. A constant caloric composition of 40% fat, 40% carbohydrate, and 20% protein was maintained. All patients consumed >98% of administered calories and protein with no consistent prefer ence of omitted portions of food. On Days 4 and 5, 24-hr urine collections for nitrogen, creatinine, lysine, and 3-methylhistidine were obtained. Glucose production rate was determined on Day 4; total body protein turnover was determined on Day 5 as described below. Basal metabolic rate was determined in the fasting state on Days 4 and 5 using a closed-circuit Douglas bag method (20). A Collins gas meter calibrated with a Tissot spirometer was used to determine volumes of expired air. A Perkin-Elmer mass spectrometer was used to determine percentages of oxygen and carbon dioxide in air samples withdrawn from the Douglas bag with oil-sealed, 50-ml glass syringes. Dietary nitrogen intake was monitored by analyzing food aliquots in a Cole-Parmer automated nitrogen analyzer. Urinary and stool nitrogen
NOVEMBER 1982
4815
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D. Heber et al. Table 1 Clinical parametersCancer patientsPatientM. study(days)18511336705713833012034442101761 to (days)45516755158344(Alive
(yr)70535863666860597275516563 F.L S.M.B.C. J.M. 0.C. R.J. K.F. S.C.W.E. S.J. P.1. O.Mean indicesAge
métastasesAdenocarcinoma, no métastasesSquamous bone métastasesAdenocarcinoma, cell, no visceral métas tasesSquamous métastasesAdenocarcinoma, cell, bone visceral métas tasesUndifterentiated carcinoma.bonelung métastasesSquamous métastasesAdenocarcinoma, cell, no métastasesAdenocarcinoma, bone viscéralmétas tasesSquamous métastasesSquamous cell, no cell, no métastasesKPSa100709080808080806060607076 ±2"SexFMFMFMMMMMMMDiagnosisAdenocarcinoma, ±3Hematocrit38393238323836403334464538 ±1Time 54Control 20 ± 27Survival
3/82)720319150210381420307
±
subjectsMean (yr)67575368555259 R.S. L.B. R.M. C.M. N.D. B.Age
indicesSubjectR.
±3SexMFFFFFHematocrit41384143414241
± 1
a KPS, Karnofsky performance score. ^ Mean ±S.D. Table 2 Nutritional parameters PatientCancer
body wt of ideal (kg)54.961.252.369.252.770.462.263.668.278.372.576.665.2 (kg)63.662.755.068.957.564.355.147.258.360.055.459.458.9 wt wt1161039899.1109.19186748677767891 body loss0071924171129231210313 Of Wt (g/dl)3.84.23.73.63.93.63.24.0•4.13.53.84.23.8
patientsM. F.L. S.M. B.C. J.M. Q.C. R.J. K.F. S.C. W.E. S.J. P.I. 0.Mean indicesControl
2.6a66.558.758.055.060.265.960.7 ± 41001141119711499106 ± .666.367.064.053.468.765.664.2 ±1 30000061 ±
0.14.04.34.54.24.34.04.2 ±
subjectsR. R.S. L.B. R.M. C.M. N.D.B.Mean indicesIdeal
±1.9Actual
±2.2%
±3%
±1Albumin
± 0.1
Mean ±S.D.
excretion rates were determined using the automated nitrogen ana lyzer. Carmine red was used as a visible marker on Days 4 and 5 to obtain pooled 24-hr stool collections. Nitrogen balance was calculated as the difference between measured nitrogen intake and the sum of urinary, stool, and unmeasured (estimated as 0.5 g/day) nitrogen losses. Total body protein turnover was determined in the fasting state by administering a loading bolus of 5 jiCi of [/»-"CJIysine followed by a constant infusion of [MC]lysine, 2 juCi/hr, for 5 hr. This method of determining
whole-body
protein turnover,
based on the turnover
of
lysine, has been validated by Waterlow (23) and Bier and Christopherson (2). Lysine concentrations were measured in sulfosalicylic acidprecipitated plasma samples using a Beckman amino acid analyzer. The [1"C]lysine concentration the same samples by measuring total acid-soluble a Beckman /> scintillation counter. At equilibrium, lysine flux (Q) was calculated from the formula O
119CL automated was determined in radioactivity
using
reached after 3 hr,
q x SA, SAS
CANCER
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RESEARCH
VOL. 42
Abnormal where O is lysine flux in /¿mollysine per hr, SA is.specific activity of infúsate in cpm per ml, SA., is specific activity of plasma at equilibrium in cpm per /xmol, and q is infusion rate in ml per hr. Total body protein turnover (g protein per day) was then equal to O x 0.0042, assuming 6.25 g protein per g nitrogen and 3.6 mol lysine per mg nitrogen. The data were finally expressed as protein turnover in g/kg/day. Pooled aliquots of supernatants of acid-precipitated plasma samples were concentrated by evaporation and analyzed using a stream splitter attached to a Beckman 119CL automated amino acid analyzer. This method was also applied to aliquots of infused [""CJlysine. Both the infusâtes and plasma supernatants contained over 90% of the detected radioactivity in lysine, and there was no significant conversion of lysine to other circulating metabolites during the infusion of [14C]lysine. Total body glucose production was determined by infusion of [63H]glucose in the fasting state, using a loading bolus of 25/iCi followed by a 5-hr infusion of 16 fiCi/hr
(1). At equilibrium,
sulfosalicylic
acid-
precipitated plasma supernatants were sequentially passed through anión- and cation-exchange columns and evaporated to dryness to remove labeled by-products of glucose metabolism and to eliminate any tritiated water formed by glucose metabolism (13). Production rate (fl*) was calculated from the formula _ q x SA
RA
Metabolism
in Lung Cancer
With constant calorie and nitrogen intake, basal metabolic rates were not different in non-oat cell lung cancer patients (37.1 ±1.4 kcal/hr/sq m) and in healthy controls (35.7 ±1.3 kcal/hr/sq m). Conditions of constant nitrogen intake based on ideal body weight were confirmed by nitrogen analysis of food aliquots. There was no difference between the nitrogen intake of cancer patients (10.4 ±0.7 g/day) and that of healthy controls (9.6 ±0.4 g/day). Total excretion of nitrogen on Days 4 and 5 was not significantly different in any of the patients or controls studied, and these data were averaged to yield estimates of nitrogen balance. There was no difference between the nitro gen balance of cancer patients ( + 1.4 ±1.1 g of nitrogen per day) and that of healthy controls (+1.3 ±0.4 g nitrogen per day). Total body protein turnover in the fasting state on Day 5 of constant nitrogen and calorie intake was significantly increased in lung cancer patients compared to that of healthy controls (see Table 4). Total body protein turnover was inversely cor related with percentage of ideal body weight in cancer patients (r = -0.69; p < 0.05) (Chart 1). There were no significant
SA
correlations of percentage of weight loss from preillness weight or age with protein turnover in these patients (p > 0.2). Muscle catabolism, measured by 3-methylhistidine excretion, ex where RA is glucose production rate in mg/min, Q is infusion rate in ml/min, SA is specific activity of the infúsate in cpm/jumol, and SA ¡s pressed per g creatinine excreted in the urine per day on a flesh-free diet on Days 4 and 5, was increased in lung cancer specific activity of glucose at equilibrium in cpm/¡umol. The data were expressed as glucose production rate in mg/kg/min. patients compared to that of healthy controls (see Table 4). 3The 24-hr urinary 3-methylhistidine excretion on a flesh-free diet, Methylhistidine excretion rates did not correlate with weight measured using automated amino acid analysis, was used as an index loss, percentage of ideal body weight, or age in the lung cancer of skeletal muscle catabolism as described by Young et al. (26). patients studied. Creatinine excretion on this diet, measured using standard enzymatic Creatinine excretion was decreased in proportion to the analysis, was used as an index of muscle mass. The 24-hr 3-methyl reduction in body weight in some cancer patients, but for the histidine excretion was normalized by dividing by the amount of creatgroup overall it was not significantly lower than that in ageinine excreted per 24 hr in g. matched controls (Table 3). There was no difference in urinary Plasma glucose and serum insulin were measured before and 2 hr lysine excretion in lung cancer patients (68 ± 7 after administration of dextrose, 40 g/sq m p.o. Plasma glucose levels were measured using a Beckman glucose analyzer. Serum insulin was compared to that in controls (48 ±8 /¿mol/day). measured using a standard double-antibody radioimmunoassay method. Urinary-free cortisol was measured in aliquots of 24-hr urine collections using a radioimmunoassay ratory, Torrance, Calif).
kit (Radioassay
Systems Labo
Table 3 dataPatientCancer
in cir take ofbasal (% skin-fold cumference(% en Creati thick of pre ergy ex (g/day).1.10.9.2.2.00.91.10.81.10.81.11.02 nine ness2817181124177518810914.3 dicted)9191889110192817410075818387 penditure)11816312916281117
RESULTS Two of the 12 lung cancer patients studied had no prior weight loss and were above their ideal body weight for height at the time of study. The remaining patients had lost between 3 and 29% of their pre-illness weight. The actual body weight, percentage of ideal body weight for height, triceps skinfold thickness, and mid-arm muscle circumference were signifi cantly decreased in patients compared to those of controls (p < 0.05) (Tables 2 and 3). Serum albumin levels were lower in cancer patients [3.8 ± 0.1 g/dl (S.D.)] than in controls [4.2 ±0.1 g/dl; p < 0.05], but were within the usually accepted normal range of values. Hematocrits were also slightly lower in patients (38 ± 1%) than in controls (41 ± 1%; p < 0.05). Caloric intakes by history were not different in the cancer patients (1735 ± 220 kcal/day) and healthy controls (1622 ±107 kcal/day). This was also true when caloric intake was calculated as a percentage of basal energy expenditure, de termined on the basis of the Harris-Benedict formula (3) (Table 3). NOVEMBER
Anthropométrie
patientsM. F.L. S.M. B.C. J.M. Q.C. R.J. K.F. S.C. W.E. S.J. P.I. O.Mean indicesControl
0.04a0.71.11.00.70.91.00.91 ± 2.110313521323327 ± 2.587105104911109398 ± 12113107144171125125131 ±
subjectsR. R.S. L.B. R.M. C.M. N.D. B.Mean 10a indicesUrinary ±0.07Triceps ±4Mid-armmuscle ±4Caloric Mean ±S.D.
1982
±
4817
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D. Heber et al. Glucose production rates measured via a constant infusion of [6-3H]glucose in the fasting state were markedly increased in lung cancer patients (2.84 ±0.16 mg/kg/min) compared to healthy controls (2.18 ± 0.06 mg/kg/min; p < 0.05). Changes in glucose production rates in the cancer patients studied did not correlate with weight loss, percentage of ideal body weight, or age (p > 0.2). There was no significant increase in glucocorticoid hormone secretion in the cancer patients compared to controls, as assessed by 24-hr urinary-free Cortisol (Table 5). There were no statistically significant differences in fasting plasma glucose or serum insulin between the cancer patients and controls. Two hr following a glucose load of 40 g/sq m p.o., there were no differences in plasma glucose or serum insulin between the cancer patients and healthy controls (Table 5). DISCUSSION The present studies have documented metabolic abnormali ties in patients with lung cancer and, in most cases (10 of 12), weight loss from preillness weight. Weight loss and malnutrition can occur in lung cancer patients for a number of reasons and Table 4 Metabolic
studiesGroupControl
dine excretion (/imol/g creatiproduc tion (mg/kg/min)2.18 nine/day)71
turnover (g/kg/day)2.12
±0.38 ±0.06 8106± 2.84 ±0.16a3-Methylhisti±11a Lung cancerProtein 3.15 ±0.51s' 'Glucose a p < 0.05 versus control subjects. Mean ±S.D. 6.0 -5.0 ed0)a«0C5C00i7.0 \\
-4.0
\\r-0.69\•
-3.0 \'
-2.0
"
\\
*\\ n D\•
-1.0 \
70
ü
\\
-\N\ .N\_i
\
1
1
1
80
90
100
Ûk
110
120
% Ideal body weight
Chart 1. Whole-body protein turnover determined by [U-"C]lysine infusion in the fasting state in g/kg/day versus percentage of ideal body weight for height in non-oat cell lung cancer patients (•) and age-matched healthy controls (.-'). The correlation coefficient of the linear regression drawn ( r(p
