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Beneficial Effects of Adenosine Triphosphate on Nutritional Status in Advanced Lung Cancer Patients: A Randomized Clinical Trial

From the Departments of Internal Medicine and Medical Oncology, Erasmus University Medical Center, Rotterdam, and Department of Epidemiology, Maastricht University, Maastricht, the Netherlands.

Address reprint requests to P.C. Dagnelie, PhD, Department of Epidemiology, Maastricht University, PO Box 616, 6200 MD Maastricht, the Netherlands; email: Dagnelie{at}epid.unimaas.nl

	ABSTRACT

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PURPOSE: In a randomized clinical trial in patients with advanced non–small-cell lung cancer (NSCLC), infusion with adenosine 5'-triphosphate (ATP) inhibited loss of body weight and quality of life. In the present article, the effects of ATP on body composition, energy intake, and energy expenditure as secondary outcome measures in the same patients are reported.

PATIENTS AND METHODS: Patients with NSCLC, stage IIIB or IV, were randomized to receive either 10 intravenous, 30-hour ATP infusions every 2 to 4 weeks or no ATP. Fat mass (FM), fat-free mass (FFM), and arm muscle area were assessed at 4-week intervals for 28 weeks. Food intake, body cell mass (BCM), and resting energy expenditure (REE) were assessed at 8-week intervals for 16 weeks. Between-group differences were tested for statistical significance by repeated-measures analysis of covariance.

RESULTS: Fifty-eight patients were randomized (28 ATP, 30 control). No change in body composition over the 28-week follow-up period was found in the ATP group, whereas, per 4 weeks, the control group lost 0.6 kg of FM (P = .004), 0.5 kg of FFM (P = .02), 1.8% of arm muscle area (P = .02), and 0.6% of BCM/kg body weight (P = .054) and decreased 568 KJ/d in energy intake (P = .0001). Appetite also remained stable in the ATP group but decreased significantly in the control group (P = .0004). No significant differences in REE between the ATP and control groups were observed.

CONCLUSION: The inhibition of weight loss by ATP infusions in patients with advanced NSCLC is attributed to counteracting the loss of both metabolically active and inactive tissues. These effects are partly ascribed to maintenance of energy intake.

	INTRODUCTION

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CANCER-ASSOCIATED cachexia is a syndrome of progressive weight loss associated with extensive wasting of energy stores of fat, skeletal muscle, and liver tissues¹ and with elevated lipolysis,^2,3 protein breakdown,^4,5 and gluconeogenesis.^6-8 Cachexia in cancer patients is associated with increased morbidity and mortality.^9-13 In randomized clinical trials, dietary counseling,^14,15 use of enteral supplements,¹⁵ and pharmacologic approaches^16-20 have failed to reverse cancer-associated cachexia. Treatment with progestogens resulted in attenuation of weight loss or in weight gain, but this was attributed mainly to gain of fat mass (FM).²¹

Two small uncontrolled studies, a phase I study in patients of mixed tumor types and a phase II study in patients with non–small-cell lung cancer (NSCLC), suggested that adenosine 5'-triphosphate (ATP) might inhibit weight loss.^22,23 In the latter study, a nonsignificant trend for weight gain (1.3 kg) was demonstrated after four ATP courses in NSCLC patients.²³ We recently reported results of the first randomized clinical trial with ATP in patients with advanced NSCLC. ATP infusions, given over 30 hours at 2- to 4-week intervals, induced maintenance of body weight, muscle strength, quality of life, and serum albumin levels over a 6-month period. ATP infusions also had beneficial effects on different domains of quality of life, ie, the physical domain, functional domain, and the overall quality-of-life score. Specific quality-of-life items included both lung cancer–related symptoms (shortness of breath) and general symptoms (eg, tiredness, lack of energy, lack of appetite, and constipation), as well as improved performance of activities of daily life (eg, self-care and doing housework).²⁴ In the present article, effects of ATP on body composition, energy intake, and energy expenditure as secondary end points in the same patient population are presented.

	PATIENTS AND METHODS

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Patients
Patients with histologically or cytologically proven NSCLC of stage IIIB or IV²⁵ with a Karnofsky index of 60% or higher²⁶ were eligible for the study. Exclusion criteria were as follows: eligibility for curative treatment, liver failure, renal failure (defined as patients needing limitation of fluid intake), respiratory failure (defined as O₂ dependence), heart failure, angina pectoris, cognitive dysfunction, and psychiatric illness. The study was performed in agreement with Universal Human Subjects requirements and approved by the medical ethics committee of Erasmus University Medical Center Rotterdam. Written informed consent was obtained from all patients before the study.

Study Design, Treatment Allocation, and Treatment Schedule
A randomization list was prepared by the Medical Oncology Trial Office of the Erasmus University Medical Center Rotterdam with the use of block randomization in permutation blocks of four. After baseline measurements, patients were stratified for tumor stage (IIIB v IV), previous treatment (chemotherapy v no chemotherapy), and performance status (Karnofsky index > 70% v 70%); they were then randomly assigned to receive either supportive care and ATP (ATP group) or supportive care alone (control group).

Patients in the ATP treatment arm were admitted to the Clinical Research Unit of the Erasmus University Medical Center Rotterdam to receive a maximum of 10 ATP courses of 30 hours each, ie, the first seven ATP courses at 2-week intervals, followed by three ATP courses at 4-week intervals. ATP infusions (6.1 mg of ATP-Na₂·3H₂O in 1 mL 0.9% NaCl) were started beginning at a dose of 20 µg/kg per minute and were increased by increments of 10 µg/kg per minute every 30 minutes until a maximum dose of 75 µg/kg per minute was reached or until the maximum-tolerated dose, if this was lower, had been reached. Thereafter, ATP was infused at a continuous rate. If any side effects occurred, the dose was reduced to the last given dose or further until side effects disappeared. Follow-up was continued until 28 weeks, ie, 4 weeks after termination of the last ATP course which was given at 24 weeks. Patients in the control arm were followed up in the outpatient department of the Erasmus University Medical Center Rotterdam at 4-week intervals for 28 weeks. Because of possible confounding effects on metabolism and appetite,^27,28 patients who started corticosteroid treatment during the study were excluded from evaluation of appetite, food intake, body cell mass (BCM), and energy expenditure from the time point of starting the medication. Since at 28 weeks, 28 out of 30 control patients had died, were hospitalized, or had used corticosteroids, statistical analysis for BCM, food intake, and energy expenditure was only performed before randomization and after randomization at 8- and 16-week periods.

Anthropometry
Body height was determined to the nearest centimeter. Body weight was measured with an electronic scale (Seca Ltd, Birmingham, United Kingdom) to the nearest 0.1 kg. Skinfold thicknesses were measured in triplicate to the nearest 0.2 mm with a Holtain skinfold caliper (CMS Weighing Equipment Ltd, London, United Kingdom), and the median skinfold thickness was used for further calculations. Total body FM was estimated from the sum of median skinfold thicknesses at four sites (triceps, biceps, subscapula, and suprailiac) using the age- and sex-specific tables from Durnin and Womersley.²⁹ Fat-free mass (FFM) was calculated by subtracting FM from body weight.

Mid-upper-arm circumference of the left arm was measured with a flexible measuring tape. Arm muscle area was derived using the equation: (arm circumference - x triceps skinfold)²/4.³⁰

Throughout the study, anthropometric measurements were performed by one trained observer (H.J.A.).

Deuterium Oxide and Bromide Dilution
After an overnight fast of approximately 12 hours, patients received a oral dose of 15 or 20 grams of deuterium-labeled water (99.9%; Isotec Inc, Miamisburg, OH) at approximately 9:30 AM. After D₂O administration, patients had to abstain from eating and drinking until blood sampling was completed. Venous blood samples were drawn into heparin tubes from the forearm at baseline and after 2.5, 3, and 3.5 hours. Blood samples were immediately placed on ice and then centrifuged for 10 minutes at 1,300 x g at 4°C. Deuterium oxide in plasma was measured by infrared spectrophotometry (Miran 1FF; Foxboro, South Norwalk, MA). Total body water volume was calculated by dividing D₂O dose by D₂O concentration in plasma. FFM was calculated using a constant hydration factor of 73%.³¹ FM was calculated by subtracting FFM from total body weight.

Extracellular water was estimated by bromide dilution. Following the same protocol as used for the deuterium oxide dilution method, patients drank a known dose of sodium bromide dissolved in water. The bromide concentration in plasma ultrafiltrate was determined with high-performance liquid chromatography according to the anion-exchange chromatographic method.³² BCM was defined as (total body water - extracellular water)/0.73, which is the same as intracellular water/0.73.³³

Energy Intake
Before randomization, all participants kept a 7-day food record. Three-day food records were repeated at 8 and 16 weeks. Intake of energy, protein, fat, and carbohydrates was calculated using the Komeet software program (version 2.0; VBS Nutrition Software, Arnhem, the Netherlands).

Appetite was evaluated as a part of the Rotterdam Symptom Checklist, a 39-item validated self-report quality-of-life questionnaire.³⁴ The item "lack of appetite" was rated on a 4-point scale (not at all = 4, a little = 3, quite a bit = 2, very much = 1). The Rotterdam Symptom Checklist, which assesses symptoms over the preceding week, was filled out by the patients before randomization and at 4-week intervals until week 28.

Resting Energy Expenditure
Before randomization and at 8 and 16 weeks, resting energy expenditure (REE) was assessed by indirect calorimetry using a ventilated hood system (Deltatrac MBM-100; Datex Instrumentarium Corp, Helsinki, Finland). After an overnight fast and a resting period of approximately half an hour, CO₂ production and O₂ consumption were measured during a 30-minute period between 9 and 11 AM while the patient was lying down at complete rest. REE was calculated by using the abbreviated Weir formula.³⁵ Measured REE was compared with predicted REE using the Harris-Benedict equations,³⁶ which are age-, height-, weight-, and sex-specific. The equipment was calibrated at the start of each experiment.

Statistical Analysis
The differences over time between FM, FFM, arm muscle area, BCM, appetite, energy intake, and energy expenditure in the two groups were analyzed by repeated-measures analysis of covariance using the linear regression model. To account for the within-patient correlation in the measurements of the dependent variable, and simultaneously for possible nonnormality of the dependent variable, the generalized estimating equations³⁷ approach was followed. These analyses were performed with the SAS Proc Mixed software (version 6.12 for Windows; SAS Inc, Cary, NC), using the independence working correlation structure. Independent variables in the model were the treatment indicator variable, baseline measurement, measurement time, and interaction between time and treatment. This model assumes a linear relationship between measurement and time in both treatment groups, which was checked by adding quadratic time terms. Statistical significance of the treatment effect was assessed by testing the null hypothesis that the coefficients of the treatment indicator and its interaction with time are simultaneously equal to zero. Two sided P values below .05 were considered statistically significant.

	RESULTS

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Patient Characteristics and Treatment
Fifty-eight patients were randomized to the ATP (n = 28) or control group (n = 30). The trial profile is summarized in Fig 1. General baseline characteristics, including age, stage, performance status, and prior treatment, were similar in the ATP and control groups, both for randomized and assessable patients. In both groups, the majority of patients were male (ATP, 71%; control, 60%). Baseline anthropometric parameters of assessable patients are listed in Table 1. Compared with control patients, assessable patients in the ATP group weighed more but had a higher degree of weight loss at time of randomization.

View larger version (28K): [in this window] [in a new window]   Fig 1. Flow diagram. *BCM was not assessable because of a technical reason (one control) or burden (seven controls). REE was not assessable because of technical reasons (two ATP recipients, one control) or burden (seven controls).

Body Composition
As previously reported,²⁴ weight loss over the 28-week study period, expressed as change per 4 weeks, was -1.0 kg (95% confidence interval [CI], -1.5 to -0.5 kg) in control patients (P = .0001), whereas in ATP-treated patients, no weight loss (0.2 kg; 95% CI, -0.2 to +0.6 kg; between-group difference, P = .002) was observed. Changes in FM and FFM for both study groups during the 28-week follow-up period are plotted in Fig 2. In the control group, a significant loss of -0.6 kg (95% CI, -0.9 to -0.3 kg) FM per 4 weeks was observed (P = .0002), which was not seen in the ATP group (+0.1 kg; 95% CI, -0.3 to +0.5 kg; between-group difference, P = .004). FFM of patients in the control group remained relatively stable for the first 16 weeks but then showed a marked drop; during the overall 28-week study period, FFM decreased by -0.5 kg (95% CI, -0.9 to -0.1 kg) per 4 weeks (P = .03), whereas no significant change was observed in ATP-treated patients (+0.1 kg; 95% CI, 0.0 to 0.2 kg; between-group difference, P = .02).

View larger version (16K): [in this window] [in a new window]   Fig 2. Changes in (A) FM and (B) FFM. Graphs represent mean values and bars represent SEM. Two-sided P values shown for differences between the ATP and control groups were determined by repeated-measures analysis of covariance.

View larger version (22K): [in this window] [in a new window]   Fig 3. Changes in arm muscle area are expressed as percentage of baseline values. Graphs represent mean values and bars represent SEM. Statistics are shown in Fig 2.

View larger version (15K): [in this window] [in a new window]   Fig 4. Changes in BCM per kilogram of body weight (BW). Graphs represent mean values and bars represent SEM. Statistics are shown in Fig 2.

View larger version (22K): [in this window] [in a new window]   Fig 5. Changes in appetite (4-point scale; part of the quality-of-life Rotterdam Symptom Checklist). Lower value indicates less appetite. Graphs represent mean values and bars represent SEM. Statistics are shown in Fig 2.

	DISCUSSION

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Weight loss is a frequent phenomenon in cancer patients and particularly in patients with lung cancer.¹¹ The aim of the present randomized clinical trial was to investigate the effects of ATP on body composition, energy intake, and energy expenditure in patients with NSCLC (stage IIIB or IV).

Weight loss is the result of an imbalance between energy intake and energy expenditure. Although not in all studies,^39,40 an elevated REE (> 115% of the predicted Harris-Benedict value) was reported in several studies in patients with NSCLC.^41-44 Because the elevation was more pronounced in weight-losing patients, it was suggested that hypermetabolism might contribute to weight loss. However, results of the present study indicate that the inhibitory effects of ATP on weight loss were not caused by a reduction in REE by ATP.

The progressive weight loss in the control group was attributed to loss in FM and, to a lesser degree, FFM. These results confirm the findings of Heymsfield and McManus,⁴⁵ who demonstrated that weight loss in cancer patients is primarily caused by loss of FM and muscle mass, whereas total FFM seems to decrease to a smaller extent because of maintenance of visceral organ mass and tumor growth.⁴⁵ Our results also showed that ATP significantly inhibited the loss in upper arm muscle area, as an indication of muscle mass.⁴⁶ This finding is consistent with our recent observation that control patients lost approximately one third of their strength in both elbow flexor and knee extensor muscles over the 28-week study period, whereas the muscle strength of ATP-treated patients remained stable.²⁴

A key component of weight loss in cancer cachexia is the loss of BCM, which is the vital compartment containing the oxygen-exchanging, potassium-rich, and metabolically active tissue.⁴⁷ Simons et al⁴⁸ demonstrated a correlation between BCM and Karnofsky performance status in weight-losing lung cancer patients and between decreased BCM and increased systemic inflammatory state. It is remarkable that ATP treatment seems to counteract BCM wasting in patients with advanced lung cancer.

The beneficial effects of ATP not only on FM but also on muscle and BCM as parts of the FFM are noteworthy in view of the lack of positive results from other randomized clinical studies using pharmacologic approaches to treat cachectic cancer patients. Corticosteroids^16,49,50 and the antiseritonergic drug cyproheptadine¹⁷ induced an increase in appetite without, however, positive effects on body weight. The phosphoenolpyruvate-carboxykinase inhibitor hydrazine sulfate had no effect on either appetite or body weight.¹⁸ Anabolic steroids also failed to influence weight in NSCLC patients.²⁰ Administration of medroxyprogesterone acetate or megestrol acetate induced an increase in appetite,^51,52 attenuation of weight loss,⁵² and weight gain.²¹ However, as assessed by dual-energy x-ray absorptiometry⁵³ and deuterium oxide dilution,²¹ this weight gain was attributed to gain in FM and not in FFM. Preliminary results showed that n-3 fatty acid supplementation might inhibit weight loss in cancer patients. It was speculated that these beneficial effects could be related to modulation of the acute-phase response.⁵⁴

The mechanisms underlying the positive effects of ATP on nutritional status are not clear. The scores on the item "lack of appetite," which was part of the quality-of-life questionnaire, revealed a significant difference in appetite appearing over time between the ATP and control groups. Although interpretation of this subjective finding is difficult because of lack of a blinded control group, the measured difference in appetite between the ATP and control groups is supported by the progressive difference in energy intake as calculated from objective food records that were kept by the patients. The latter showed a sharp decline in energy intake in the control group but not in the ATP group. This would suggest that ATP may have appetite-regulatory effects contributing to increased food intake. However, approximate calculations of differences between the ATP and control groups with regard to energy intake (10,000 kJ over 4 weeks) and energy expenditure from both fat and fat-free body mass wasting (22,000 kJ over 4 weeks) indicate that differences in food intake cannot entirely account for the observed differences in body composition between the two groups. Moreover, the appetite stimulator megestrol acetate was shown only to increase FM but not FFM.²¹ Therefore, it is unlikely that the inhibitory effects of ATP on loss of BCM and skeletal muscles would be solely caused by appetite-stimulating effects of ATP. This would suggest that ATP may also influence specific metabolic pathways involved in loss of weight and muscle mass.

In experimental cancer models, depletion of ATP levels in liver^1,55,56 and skeletal muscle¹ was reported to be significantly reduced. Recently, reduced liver ATP levels were also demonstrated in advanced lung cancer patients,⁵⁷ particularly in weight-losing patients.⁵⁸ Intraperitoneal ATP administration doubled hepatic ATP pools and inhibited weight loss in tumor-bearing mice.⁵⁹ It is noteworthy that ATP infusion leads to a significant rise in liver ATP pools in weight-losing lung cancer patients.⁶⁰ Rapaport⁶¹ suggested that ATP may inhibit Cori cycle activity (ie, conversion of glucose to lactate in peripheral tissues followed by gluconeogenesis from lactate in the liver). Studies in isolated hepatocytes showed that extracellular ATP evoked Ca²⁺ mobilization and influx by stimulation of surface purinergic P2 receptors,⁶² which are involved in the control of gluconeogenesis⁶³ and glycogenolysis.⁶⁴ It is speculated that these ATP-induced effects might attenuate energy-consuming catabolic processes such as gluconeogenesis, which could contribute to maintenance of body fat and cell mass in cancer patients.

In conclusion, the inhibitory effects of ATP on weight loss are attributed to counteracting the loss of both metabolically active (skeletal muscle and BCM as parts of FFM) and inactive (FM) tissues in cachectic patients with advanced NSCLC. The beneficial effects of ATP on body composition are associated with maintenance of energy intake but not with reduced REE. Clearly, the ideal method for assessing treatment effects would be a double-blind, placebo-controlled study. In the present study, this was not possible because of the transient side effects of ATP during individual dose optimization at the maximum-tolerated dose. Therefore, appropriately powered additional clinical trials with ATP are warranted. Further studies should also address potential differences by sex and mechanisms underlying the observed clinical effects of ATP in metabolically active tissues.

	ACKNOWLEDGMENTS

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Supported by the Netherlands Organization for Scientific Research, The Hague, the Netherlands.

We thank Prof. Th. Stijnen, PhD, Department of Epidemiology and Biostatistics, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands, for statistical advice.

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Submitted January 7, 2000; accepted September 7, 2001.

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