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Ann Thorac Surg 2001;72:348-351
© 2001 The Society of Thoracic Surgeons

Original article: general thoracic

Do patients with nonmetastatic non-small cell lung cancer demonstrate altered resting energy expenditure?

Aminah Jatoi, MDa,b, Benedict D.T. Daly, MDc, Virginia A. Hughes, MSd, Gerard E. Dallal, PhDe, Joseph Kehayias, PhDf, Ronenn Roubenoff, MD, MHSa,d

a Division of Clinical Nutrition, The New England Medical Center, Tufts University, Boston, Massachusetts, USA
b Division of Hematology/Oncology, Department of Medicine, The New England Medical Center, Tufts University, Boston, Massachusetts, USA
c Division of Cardiothoracic Surgery, Department of Surgery, The New England Medical Center, Tufts University, Boston, Massachusetts, USA
d Nutrition, Exercise Physiology, and Sarcopenia Laboratory, The Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, USA
e Biostatistics Section, The Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, USA
f Body Composition Laboratory, The Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, USA

Accepted for publication May 14, 2001.

Address reprint requests to Dr Jatoi, Division of Medical Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55905
e-mail: jatoi.aminah{at}mayo.edu


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Comment
 Acknowledgments
 References
 
Background. The cancer cachexia syndrome occurs in patients with non-small cell lung cancer (NSCLC) and includes elevated resting energy expenditure (REE). This increase in REE leads to weight loss, which in turn confers a poor prognosis. This study was undertaken to determine whether the cancer cachexia syndrome occurs in patients with nonmetastatic NSCLC.

Methods. In this case-control study, 18 patients with nonmetastatic NSCLC (stages IA to IIIB) were matched to healthy controls on age (± 5 years), gender, and body mass index (± 3 kg/m2). Only 4 cancer patients had experienced > 5% weight loss. Cancer patients and controls were compared on the basis of: (1) unadjusted REE, as measured by indirect calorimetry; (2) REE adjusted for lean body mass, as measured by dual x-ray absorptiometry; (3) REE adjusted for body cell mass, as measured by potassium-40 measurement; and (4) REE adjusted for total body water, as measured by tritiated water dilution.

Results. We observed no significant difference in unadjusted REE or in REE adjusted for total body water. However, with separate adjustments for lean body mass and body cell mass, cancer patients manifested an increase in REE: mean difference ± standard error of the mean: 140 ± 35 kcal/day (p = 0.001) and 173 ± 65 kcal/day (p = 0.032), respectively. Further adjustment for weight loss yielded similarly significant results.

Conclusions. These results suggest that the cancer cachexia syndrome occurs in patients with nonmetastatic NSCLC and raise the question of whether clinical trials that target cancer cachexia should be initiated before weight loss.


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Comment
 Acknowledgments
 References
 
The cancer cachexia syndrome has been described in patients with non-small cell lung cancer (NSCLC) and includes increased resting energy expenditure (REE) [1]. Energy deficits result from this increase in REE and lead to weight loss. Occurring in over 60% of advanced NSCLC patients at diagnosis, this weight loss confers a poor prognosis independent of tumor stage [2].

Earlier studies that have examined REE in patients with NSCLC have usually focused on patients with metastatic disease. These earlier studies have often omitted control groups of noncancer subjects and have failed to adjust for lean body mass (LBM), a major determinant of REE, or for one of its subcomponents [3–8]. To our knowledge, no prior study has examined REE in patients with nonmetastatic NSCLC (stages IA to IIIB) both with the use of a control group and with accurate measurement of and adjustment for LBM or one of its subcomponents. Because an increase in REE leads to weight loss and because the latter predicts a poor prognosis for patients with NSCLC, our improved understanding of energy utilization among NSCLC patients might lead to novel approaches in cancer treatment. The present study was undertaken with these issues in mind.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Comment
 Acknowledgments
 References
 
Recruitment of cancer patients and control participants
This study was approved by the Human Investigation Review Committee at Tufts-New England Medical Center, and all research participants provided written informed consent before participation. Lung cancer patients were recruited from the Lung Tumor Evaluation Center at New England Medical Center. Only patients with either a tissue-confirmed diagnosis of NSCLC or a high clinical suspicion for NSCLC were approached for recruitment. All had undergone clinical staging, and surgical staging of the mediastinum was undertaken if lymph nodes appeared enlarged on computed tomography. Mountain’s criteria were used to establish tumor stage [9]. No patients had evidence of metastatic cancer at the time of study entry.

Exclusion criteria for patients were determined a priori and included the following: (1) no histologic evidence of NSCLC at the time of surgical resection if no tissue-confirmed diagnosis had been made prior; (2) abnormal thyroid function tests on the day of enrollment; (3) temperature greater than 38°C on the day of study participation; (4) other evidence of infection on the day of study participation; and (5) renal failure, requiring dialysis.

Data on control subjects were obtained through The Jean Mayer Human Nutrition Research Center on Aging at Tufts University. All subjects had undergone a history and physical examination and were found to be in good health with no clinical evidence of infection, fever, thyroid disease, or malignancy at the time of study participation. Control subjects underwent similar testing as cancer patients and were chosen for their ability to match cancer patients by gender, age (± 5 years), and body mass index (BMI) ± 3 kg/m2. Each control subject was specifically chosen to match a given cancer patient on each of these parameters.

Research methods
Both cancer and control subjects followed the same protocol and underwent testing that began at 8:00 AM. Participants were asked to undergo a 12-hour fast the night before their testing. All testing was performed before the initiation of any antineoplastic treatment, including surgical resection.

REE was measured by indirect calorimetry (Deltatrac; Sensorimedics Corporation, Yorba Linda, CA), a well-accepted method for measuring REE. The calorimeter was calibrated on the morning of testing and the machine was checked monthly with a standardized alcohol burn procedure. Participants rested quietly on a cot for 30 minutes before REE measurements and were asked to remain awake and still during the actual measurement period. Measurements were obtained on all subjects for at least 15 minutes. The Weir equation was then used to calculate REE for each subject [10]. The coefficient of variation for this technique in our hands, as determined by paired sequential measurements of healthy subjects, is 2.5% (personal communication, Virginia A. Hughes).

LBM was measured with dual x-ray absorptiometry (DEXA), Hologic 2000 (Hologic Corporation, Waltham, MA), using the array scanning mode. Software was provided by Hologic Corporation. We have previously shown that the correlation between this instrument and in vivo neutron activation analysis is 0.87 (p < 0.0001) for whole-body fat mass and lean mass. DEXA is therefore considered an acceptable method for assessing lean tissue. Body cell mass (BCM), the most abundant component of LBM, was measured with potassium-40 whole-body counting. This technique relies on the ability of a scanner to detect potassium-40, which is found naturally in the body in small amount; the coefficient variation for total-body potassium measurement in our laboratory is less than 3% [11]. Finally, total body water (TBW), an estimate of fat-free mass and a correlate of LBM, was measured by tritium dilution, as previously described [11]. The coefficient of variation for this technique in our hands is 2%.

Cancer patients were questioned at the time of their metabolic assessment about whether they had suffered weight loss in the preceding 6 months. Responses were recorded on standardized data sheets.

Statistical analyses
Data are expressed as mean values ± standard deviations or as mean values ± standard errors of the mean, as indicated in the text. A paired t-test was used to compare REE and body composition measurements between matched cancer patients and control subjects. Bland and Altman have recommended this approach when controls and cases are matched in this manner [12]. The mean REE between cancer and control subjects was compared and an analysis of covariance was used to make adjustments for LBM, BCM, TBW, and prior weight loss. A p value less than 0.05 was considered statistically significant. All analyses were performed with Systat 5.2.1 for Macintosh (SPSS, Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Comment
 Acknowledgments
 References
 
A total of 24 consecutive cancer patients were recruited. Of these, 6 were excluded for one of the following reasons: benign diagnosis after surgical resection (2), tumor other than NSCLC diagnosed after surgical resection (1), hyperthyroidism (1), fever at the time of REE measurement (1), or inability to be matched to control subjects on the basis of BMI, gender, or age (1). The remaining 18 cancer patients were included in the study.

All 18 of these patients underwent measurement of REE and LBM, as determined by DEXA. TBW was measured in all except 3 cancer patients, who were unable to participate because of scheduling problems. BCM, as measured by potassium-40 assessment, was determined in 9 cancer patients, with the other 9 unable to participate because of either machine malfunction or scheduling problems.

Baseline characteristics of these 18 patients and their matched controls are shown in Table 1. Among the cancer patients, 4 reported weight loss of more than 5% of their premorbid weight during the preceding 6 months. Tumor stages among the cancer patients included 6 with stage IA disease, 3 with stage IB disease, 3 with stage IIB disease, 4 with stage IIIA disease, and 2 with stage IIIB disease.


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  		Table 1. Characteristics of Research Participants

 
Without adjustment for LBM, BCM, and TBW, there was no significant difference in REE between cancer patients and control subjects. Cancer patients had an REE of 1,546 kcal/day, and control subjects had an REE of 1,476 kcal/day (p = 0.221). However, after adjusting for LBM, as determined by DEXA, a statistically significant difference in REE was observed between the cancer patients and their matched healthy controls. Cancer patients had a mean REE of 1,581 kcal/day as compared with 1,441 kcal/day in control subjects (p = 0.001) after adjustment for LBM. Similarly, adjustment for BCM, as determined by potassium-40 measurement, yielded a significantly greater mean REE in cancer patients of 1,621 kcal/day in contrast to that seen in control subjects of 1,449 kcal/day (p = 0.032). In contrast, adjustment for TBW yielded no significant difference in REE between the cancer patients and control subjects. Cancer patients had a mean REE of 1,550 kcal/day, and controls had a mean REE of 1,468 kcal/day (p = 0.103) (see Table 2 for summary of results). Additional adjustments for a history of weight loss yielded results similar in significance to those reported above.


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  		Table 2. Amount by Which Resting Energy Expenditure of Cancer Patients Exceeds That of Control Subjects With Adjustments for Body Composition

 

   Comment
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Comment
Acknowledgments
 References
 
To our knowledge, this study is the first to examine critically the issue of REE in patients with nonmetastatic (stages IA to IIIB) NSCLC. Our results suggest that after adjustment either for LBM, as determined by DEXA, or for BCM, as determined by total-body potassium measurement, patients with nonmetastatic NSCLC are hypermetabolic when compared with matched control subjects. Our results also suggest that the cancer cachexia syndrome is not confined to patients who experience weight loss; when prior weight loss was added as a covariate, we continued to observe similar significant differences in REE between cancer and control patients. We conclude that the cancer cachexia syndrome, as defined by the presence of metabolic changes that lead to eventual weight loss, appears to occur even in patients with nonmetastatic NSCLC.

Our results raise questions as to what causes patients with nonmetastatic NSCLC to manifest this increase in REE. Although mechanisms have remained unexplored for the most part, recent data have implicated inflammatory cytokines. A large body of evidence suggests that these cytokines are involved in several aspects of the cachexia syndrome including loss of appetite and wasting of lean tissue [1]. With regard to REE, mononuclear cells that infiltrate the tumor produce tumor necrosis factor (TNF{alpha}), and prior studies suggest that this cytokine may drive these metabolic alterations [4].

Our study results also might have important implications for the treatment of cancer cachexia. Until recently, most studies have focused on the palliation of cancer-associated anorexia [13–15]. Although decreased caloric intake does account for some of the weight loss in patients with cancer, caloric repletion benefits only a subset of cancer patients, not the vast majority [1]. The results presented here suggest that other treatment modalities targeted at slowing REE or at compensating for this increase in REE may be worth investigating as a means of retarding weight loss and perhaps improving prognosis for lung cancer patients. For example, Gambardella and others demonstrated that propranolol administration decreases REE and suggested that cancer patients may maintain their weight with this intervention [16]. In addition, preliminary investigations suggest that infusions of adenosine 5'-triphosphate may be worthy of further investigation in the treatment of cancer cachexia as a means to compensate for the seemingly wasted energy associated with the presence of lung cancer [17–20]. Because patients with nonmetastatic NSCLC appear to manifest such alterations in REE, such agents may be worthwhile studying even in patients who lack evidence of metastatic disease or are not losing weight.

Somewhat unexpected in our study is the finding that adjustment for TBW, a correlate of LBM, did not yield significant differences in REE between cancer patients and control subjects. One explanation for this finding is that although TBW is a correlate of LBM, it may not be as sensitive as DEXA determination of LBM and may not be as predictive of metabolically active tissues as BCM measurements with potassium-40. One of the strengths of our study is that by utilizing multiple different methods for body composition measurement, we were able to draw conclusions that were verified with the use of more than one technique.

In summary, the results of our study suggest that the cancer cachexia syndrome is present even in nonmetastatic NSCLC patients. Our results might raise the questions of whether interventions for the experimental treatment of cachexia should begin before weight loss occurs and of what clinical and biochemical mediators might be leading to this increase in REE.


   Acknowledgments
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Comment
 Acknowledgments
References
 
This work was supported by grants F32CA69742 (AJ) and M01RR00054-36A1 from the National Institutes of Health and USDA contract 53-3K06-5-10.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Comment
 Acknowledgments
 References
 

  1. Jatoi A., Loprinzi C.L. Current management of cancer associated anorexia and weight loss. Oncology 2001;15:1497-1502.
  2. Dewys W.D., Begg C., Lavin P.T., et al. Prognostic effect of weight loss prior to chemotherapy in cancer patients. Am J Med 1980;69:491-497.[Medline]
  3. Staal-van den Brekel A.J., Schols A.M., Dentener M.A., et al. Metabolism in patients with small cell lung carcinoma compared with patients with non-small cell lung carcinoma and healthy controls. Thorax 1997;52:338-341.[Abstract]
  4. Staal-van den Brekel A.J., Dentener M.A., Schols A.M., et al. Increased resting energy expenditure and weight loss are related to a systemic inflammatory response in lung cancer patients. J Clin Oncol 1995;13:2600-2605.[Abstract]
  5. Staal-van den Brekel A.J., Schols A.M., ten Velde G.P., et al. Analysis of the energy balance in lung cancer patients. Cancer Res 1994;54:6430-6433.[Abstract/Free Full Text]
  6. Fredrix E.W., Soeters P.B., Wouters E.F., et al. Effect of different tumor types on resting energy expenditure. Cancer Res 1991;51:6138-6141.[Abstract/Free Full Text]
  7. Fredrix E.W., Wouters E.F., Soeters P.B., et al. Resting energy expenditure in patients with non-small cell lung cancer. Cancer 1991;68:1616-1621.[Medline]
  8. Nixon D.W., Kutner M., Heymsfield S., et al. Resting energy expenditure in lung and colon cancer. Metabolism: Clinical and Experimental 1988;37:1059-1064.
  9. Mountain C.F. Revisions of the international system for staging lung cancer. Chest 1997;111:1710-1717.[Abstract/Free Full Text]
  10. Weir J.B. New methods for calculating metabolic rate with special reference to protein metabolism. J Physiol 1949;109:1-12.
  11. Roubenoff R., Roubenoff R.A., Cannon J.G., et al. Rheumatoid cachexia: cytokine driven hypermetabolism accompanying reduced body cell mass in chronic inflammation. J Clin Invest 1994;93:2379-2386.
  12. Bland J.M., Altman D.G. Matching. Br Med J 1994;309:1994.
  13. Loprinzi C.L., Kugler J.W., Sloan J.A., et al. Randomized comparison of megestrol acetate versus dexamethasone versus fluoxymesterone for the treatment of cancer anorexia/cachexia. J Clin Oncol 1999;17:3299-3306.[Abstract/Free Full Text]
  14. Loprinzi C.L., Michalak J.C., Schaid D.J., et al. Phase III evaluation of four doses of megestrol acetate as therapy for patients with cancer anorexia and/or cachexia. J Clin Oncol 1993;11:762-767.[Abstract]
  15. Loprinzi C.L., Ellison N.M., Schaid D.J., et al. Controlled trial of megestrol acetate for the treatment of cancer anorexia and cachexia. J Natl Cancer Inst 1990;82:1127-1132.[Abstract/Free Full Text]
  16. Gambardella A., Tortoriello R., Pesce L., et al. Intralipid infusion combined with propranolol administration has favorable effects in elderly malnourished cancer patients. Metabolism 1999;48:291-297.[Medline]
  17. Haskell C.M., Mendoza E., Pisters K.M.W., et al. Phase II study of intravenous adenosine 5'-triphosphate in patients with previously untreated stage IIIB and stage IV non-small cell lung cancer. Investigational New Drugs 1998;16:81-85.[Medline]
  18. Haskell C.M., Wong M., Williams A., Lee L.-Y. Phase I trial of extracellular adenosine 5'-triphosphate in patients with advanced cancer. Med Pediat Oncol 1996;27:165-173.[Medline]
  19. Agteresch H.J., Dagnelie P.C., van Der Gaast A., Stijnen T., Wilson J.H. Randomized clinical trial of adenosine 5'-triphosphate in patients with advanced non-small cell lung cancer. J Natl Cancer Inst 2000;92:321-328.[Abstract/Free Full Text]
  20. Jatoi A., Loprinzi C.L., Sloan J., Goldberg R.M. Is ATP (adenosine 5'-triphosphate), like STP, a performance-enhancing additive for the tanks of cancer patients?. J Natl Cancer Inst 2000;92:290-291.[Free Full Text]



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