Longitudinal study of resting energy expenditure, body cell mass and the inflammatory response in male patients with non-small cell lung cancer

doi:10.1016/S0169-5002(00)00244-0

Lung Cancer

Volume 32, Issue 3, June 2001, Pages 307-312

https://doi.org/10.1016/S0169-5002(00)00244-0 Get rights and content

Abstract

The aim of this study was to examine the inter-relationship between the inflammatory response and resting energy expenditure in patients with non-small cell lung cancer (NSCLC) before and after the onset of weight loss. Healthy subjects (n=7) and patients with NSCLC without weight loss (n=12) were studied. Resting energy expenditure adjusted for metabolically active tissue, as measured by total body potassium, was approximately 15% higher in the NSCLC group (P<0.01). Moreover, the resting energy expenditure, correlated with the magnitude of the inflammatory response (r=0.753, P<0.01). Six cancer patients subsequently lost weight and the relationship between resting energy expenditure and the inflammatory response was maintained. These results highlight the impact of the inflammatory response on the increase in the resting energy expenditure which precedes the onset of weight loss in patients with NSCLC.

Introduction

Weight loss affects approximately a third of patients presenting with non-small cell lung cancer (NSCLC) and is associated with a worse prognosis [1], [2], [3]. It has previously been reported that the resting energy expenditure is inappropriately elevated in those lung cancer patients who lose weight [4], [5] and this is associated with an ongoing inflammatory response [6], [7]. If the relationship between the inflammatory response, increased resting energy expenditure and weight loss was causal then the inflammatory response and the increase in resting energy expenditure should precede weight loss. To date it would appear that only one longitudinal study of resting energy expenditure in patients with NSCLC has been carried out. Fredrix and colleagues [8] reported that there was a reduction in resting energy expenditure and weight gain following curative surgery for NSCLC. However, there was no information on the systemic inflammatory response and its relationship with resting energy expenditure.

There is continuing controversy over the contribution of hypermetabolism to the weight loss of lung cancer patients [9], [10], [11]. Part of the difficulty in interpreting the results of previous studies is that the estimates of metabolically active tissue have conventionally been based on lean body mass as measured by total body water. However, we have recently reported that as weight loss increases this approach progressively overestimates metabolically active tissue compared with body cell mass as measured by total body potassium [12].

The aim of the present study was to examine the inter-relationship between the inflammatory response and resting energy expenditure adjusted for metabolically active tissue, as measured by total body potassium, in patients with NSCLC before and after the onset of weight loss.

Section snippets

Study design

Healthy male subjects (n=7) and weight-stable male patients (n=12) with cytologically or histologically confirmed locally advanced NSCLC were studied. The patients studied did not have sufficient cardiorespiratory reserve for surgical intervention or high dose radiotherapy and therefore, staging was limited to biopsy of the primary tumour combined with a computed tomography scan. On this basis, the patients were considered to have stage III disease [13]. No patient had evidence of infection or

Results

At baseline, the cancer group were older (<0.001), had higher C-reactive protein (P<0.001) and lower albumin concentrations (P<0.05) compared with controls (Table 1). Resting energy expenditure and total body potassium were both lower in the cancer group (<0.05 and 0.001, respectively) as compared with controls.

In the control group, measured resting energy expenditure and total body potassium values were similar to the predicted values. In contrast, in the cancer group, measured resting energy

Discussion

Resting energy expenditure is conventionally adjusted for metabolically active tissue measured using the total body water. However, it has been known for some time that the intra and extra-cellular water components may vary widely in pathological states [17]. In contrast, body cell mass derived from the total body potassium, which is mostly intracellular, is not affected by such changes [18], [19], [20] and is, therefore, a better predictor of metabolically active tissue in weight-losing cancer

Acknowledgements

The authors gratefully acknowledge the statistical advice of Dr W.J Angerson and encouragement of Professor T.G. Cooke. Thanks are also due to the staff of the Nuclear Medicine Department, Southern General Hospital.

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Development and validation of a host-dependent, PDL1-independent, biomarker to predict 6-month progression-free survival in metastatic non-small cell lung cancer (mNSCLC) patients treated with anti-PD1 immune checkpoint inhibitors (ICI) in the CERTIM Cohort: The ELY study
2021, EBioMedicine
Immune checkpoint inhibitors (ICI) are dramatically active in a minority of non-small cell lung cancer (NSCLC) patients. We studied here the relationship between patients's metabolism and outcome under ICI.
Metastatic NSCLC patients underwent a nutritional assessment prior to initiating immunotherapy. Resting energy expenditure (REE) was measured (mREE) using ambulatory indirect calorimetry and compared with the theoretical value (tREE) provided by the Harris and Benedict formula. The primary endpoint was 6-month progression-free survival (PFS). Secondary endpoints included objective response rate (ORR) and disease control rate (DCR) based on investigator review per RECIST v1.1. and overall survival (OS). The association of patient's metabolism with 6-month PFS was first explored in a single-center training cohort to estimate the effect size. The relationship between patient's metabolism and 6-month PFS was then tested in an independent non interventional observational prospective cohort (ELY) of 100 patients recruited in two tertiary university centers.
In the entire cohort, the ORR was 14% for the hypermetabolic group (n = 10/74) vs 38% for the normometabolic group (n = 26/68), respectively (estimated difference 25%, 95CI 9–40%, p = 0.001). The DCR was 28% for the hypermetabolic group (n = 21/74) vs 53% for the normometabolic group (n = 36/68), respectively (estimated difference 25%, 95CI 7–42%, p = 0.005). In the validation cohort (100 patients, 2 centers), normometabolic patients (defined as mREE/tREE < 110%) had increased 6-month PFS (57% versus 22%; odds ratio: 4.76; IC95 [1.87 – 12.89]; p<0.001) and improved overall survival (HR 2.20; IC95: 1.41–3.44; p<0.001). The positive and negative predictive values of normometabolism to identify non-progressive patients at 6 months, were 57% and 78% respectively, sensitivity was 72% and specificity was 66%. In multivariate analysis including PD-L1 tumor status, basal metabolism was an independent predictive factor for 6-month PFS.
Normometabolism is a new independent parameter to identify mNSCLC patients who will benefit from ICI, with both improved tumor response, 6-month PFS, and survival.
This work was supported by Baxter (04012016).
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Citation Excerpt :
Change in CRP was a predictor of REE change in our study, after controlling for several variables. At a single time point, markers of systemic inflammation such as CRP have been positively related to REE [16,41] and may predict survival [42,43] in various cancer types. The presence of a tumor induces a chronic inflammatory response associated with the production of T helper 1 cytokines [44] and an ensuing ‘energy appeal reaction’ consumes glucose from the liver, protein from muscle, and lipids from fat tissue, perpetuating high REE [1,45].
Resting energy expenditure (REE) is variable in cancer and might be influenced by changes in tumor burden, systemic inflammation, and body composition. The objective of this study was to assess REE change and the predictors of such in patients with stage III or IV colorectal cancer.
REE was measured via indirect calorimetry and fat mass and fat-free mass (FFM) were assessed using dual X-ray absorptiometry as part of a unique analysis of two studies. C-reactive protein (CRP) was measured as an inflammatory marker. Linear regression was used to assess the determinants of REE at baseline and REE change, with days between baseline and follow-up measures included as a covariate.
One-hundred and nine patients were included at baseline (59.6% male; 67 ± 12 years; body mass index 24.1 ± 4.3 kg/m²); 49 had follow-up data (61.2% male; 65 ± 12 years; body mass index 25.4 ± 4.3 kg/m²), with median follow-up of 119 days (interquartile range: 113–127 days). At baseline, age, FFM, and CRP explained 68.9% of the variability in REE. A wide variability in REE change over time was observed, ranging from −156 to 370 kcal/day, or −13.0 to 15.7%/100 days. CRP change (1.7 ± 0.4 mg/L, p < 0.001) and stage (81.3 ± 38.7, p = 0.042) predicted REE change in multivariate analysis, controlling for age, FFM change, and days between visits (R²: 0.417 ± 88.2, p < 0.001).
Age, FFM, and CRP predicted REE at a single time point. REE change was highly variable and explained by inflammation and stage. Future research should investigate the validity and feasibility of incorporating these measures into energy needs recommendations.
SFNEP oncology nutrition guidelines: Nutritional, energetic and proteinic needs throughout the cancer treatment process
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Cancer cachexia: A systematic literature review of items and domains associated with involuntary weight loss in cancer
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Thus studies that have defined weight loss in comparison to pre-illness weight [10,14,57] without reporting the time period over which the weight loss has occurred may be describing a significantly different patient population to studies that have included patients who have lost a defined amount of weight within a defined time period [19,42,61,62,72,77]. Likewise patients described by absolute weight loss (in kilograms) [37,40,43,46,54,56,62] may be different from patients described by percentage weight loss [14,15,17,19]. Second, the historic definition of the anorexia/cachexia syndrome [5] merits an update [7,8,102,103], which acknowledges its multidimensional nature [10].
The concept of cancer-related anorexia/cachexia is evolving as its mechanisms are better understood. To support consensus processes towards an updated definition and classification system, we systematically reviewed the literature for items and domains associated with involuntary weight loss in cancer.
Two search strings (cachexia, cancer) explored five databases from 1976 to 2007. Citations, abstracts and papers were included if they were original work, in English/German language, and explored an item to distinguish advanced cancer patients with variable degrees of involuntary weight loss. The items were grouped into the 5 domains proposed by formal expert meetings.
: Of 14,344 citations, 1275 abstracts and 585 papers reviewed, 71 papers were included (6325 patients; 40–50% gastrointestinal, 10–20% lung cancer). No single domain or item could consistently distinguish cancer patients with or without weight loss or having various degrees of weight loss. Anorexia and decreased nutritional intake were unexpectedly weakly related with weight loss. Explanations for this could be the imprecise measurement methods for nutritional intake, symptom interactions, and the importance of systemic inflammation as a catabolic drive. Data on muscle mass and strength is scarce and the impact of cachexia on physical and psychosocial function has not been widely assessed.
Current data support a modular concept of cancer cachexia with a variable combination of reduced nutritional intake and catabolic/hyper-metabolic changes. The heterogeneity in the literature revealed by this review underlines the importance of an agreed definition and classification of cancer cachexia.
Influence of Inflammation on Total Energy Expenditure in Hemodialysis Patients
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Citation Excerpt :
Kamimura et al.14 showed that serum IL-6 was associated with an increase of energy expenditure in HD patients. A high REE is also observed in patients with AIDS, rheumatoid arthritis, chronic obstructive pulmonary disease, trauma, sepsis, cancer, and diseases associated with inflammation; however, the mechanisms involved with this increased REE have not been identified.1,31 Indeed, other elements of energy expenditure (i.e., TEM and PAEE) were not determined.
Studies show that inflammation can contribute to an increase in resting energy expenditure in patients with chronic kidney disease; however, findings about total energy expenditure (TEE) have not been reported. The aim of this study was to evaluate the effects of inflammation on TEE and physical activity energy expenditure in hemodialysis (HD) patients.
This was a cross-sectional study.
This study was conducted from Hôpital Edouard Herriot, Lyon, France.
This study included 24 HD patients and 18 healthy subjects.
TEE and step counts were measured over a 7-day period by the SenseWear Pro2 Armband in 24 HD patients (15 patients with C-reactive protein <5 mg/L, aged 67.0 ± 14.7 years, and 9 with C-reactive protein >5 mg/L, aged 69.0 ± 18.0 years) and compared with 18 healthy subjects (62.3 ± 15.3 years).
Mean estimated TEE measured with SenseWear Pro2 Armband was significantly lower (25.5 ± 4.1 kcal/kg/day) in patients with inflammation when compared with those without inflammation (32.0 ± 6.7 kcal/kg/day) and with healthy subjects (31.8 ± 7.0 kcal/kg/day) (P = .012). There was a difference in the physical activity (step counts) between patient groups (P < .05). Healthy subjects and patients without inflammation walked more (8,107 ± 5,419 and 6,016 ± 3,752 steps/day, respectively) as compared with patients with inflammation (2,801 ± 2,754 steps/day, P = .001).
Our findings suggest that patients with inflammation have a lower TEE when compared with healthy subjects and patients without inflammation. TEE is influenced by physical activity because patients with inflammation appear to be less active.
A longitudinal study of leptin and appetite, resting energy expenditure and body fat mass in weight-stable cancer patients
2002, Cytokine
Leptin and its relationship with energy metabolism in male weight-stable patients with colorectal liver metastases (n=14) was assessed at baseline and after 6 weeks. At baseline, median leptin concentration was 5.9 μg/l and the median percentage fat mass was 32.1%. Circulating leptin concentrations were correlated with measured percentage fat mass at baseline (r_s=0.519, P=0.040) and with the changes after 6 weeks (r_s=0.611, P=0.027) but not with insulin, cortisol, C-reactive protein, appetite or resting energy expenditure. Therefore, it would appear that leptin concentrations reflect changes in fat mass in male weight-stable patients with cancer and their role in the regulation of energy metabolism appears more complex than previously proposed.

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Longitudinal study of resting energy expenditure, body cell mass and the inflammatory response in male patients with non-small cell lung cancer

Abstract

Introduction

Section snippets

Study design

Results

Discussion

Acknowledgements

Am. J. Med.

Lung Cancer

Ann. Oncol.

Lung Cancer

Clin. Nutr.

Metabolism

Am. J. Clin. Nutr.

Nutrition

Nutrition

Lack of improvement of prognostic performance of weight loss when combined with other parameters

Nutrition

The effects on resting energy expenditure of different tumour types

Cancer

The relationship between resting energy expenditure and weight loss in benign and malignant disease

Ann. Surg.

Analysis of the energy balance in lung cancer patients

Cancer Res.

Weight loss and low body cell mass in males with lung cancer: relationship with systemic inflammation, acute phase response, resting energy expenditure and catabolic and anabolic hormones

Clin. Sci.

Energy balance in nonsmall cell lung carcinoma patients before and after surgical resection of their tumours

Cancer