Affiliations of authors: H. J. Agteresch, J. H. P. Wilson (Department of Internal Medicine), T. Stijnen (Epidemiology and Biostatistics), Erasmus University Medical Center Rotterdam, The Netherlands; P. C. Dagnelie, Department of Epidemiology, Maastricht University, The Netherlands, and Department of Internal Medicine, Erasmus University Medical Center Rotterdam; A. van der Gaast, Department of Medical Oncology, Rotterdam Cancer InstituteDr. Daniel den Hoed Cancer Center and University Hospital RotterdamDijkzigt.
Correspondence to: Pieter C. Dagnelie, Ph.D., Department of Epidemiology, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands (e-mail: dagnelie{at}epid.unimaas.nl ).
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ABSTRACT |
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INTRODUCTION |
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Adenosine 5'-triphosphate (ATP) is a naturally occurring nucleoside triphosphate that plays a central role as an energy source in every cell of the human body. In addition, extracellular ATP is involved in the regulation of a variety of biologic processes, including neurotransmission, muscle contraction, and liver glucose metabolism, by stimulation of purinergic receptors (16). Intravenous ATP may offer a novel palliative approach in the treatment of NSCLC. ATP given by daily intraperitoneal injection for 10 days to mice with colon tumors significantly inhibited weight loss (17). Recently, in the United States, a small open phase II trial in 15 patients with NSCLC (stage IIIB or IV) (18) demonstrated maintenance of weight, QOL, and performance status after treatment with two to four intravenous infusions of ATP (50-65 µg/kg per minute) for 96 hours given at 4-week intervals. These results supported earlier findings from a phase I study in 14 cancer patients (19). On the basis of these promising preliminary reports, we conducted a randomized clinical trial to evaluate the effect of ATP infusion on body weight, muscle strength, and QOL in patients with advanced NSCLC (stage IIIB or IV).
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PATIENTS AND METHODS |
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During the period from January 1996 through November 1998, 58 patients were entered in the study. Eligible subjects were patients with histologically or cytologically proven NSCLC of stage IIIB or IV (20) and a Karnofsky index of 60% or higher (21). 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, or psychiatric illness. The study was approved by the Medical Ethical Committee of the Erasmus University Medical Center Rotterdam. Written informed consent was obtained from all patients prior to the study.
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 according to tumor stage (IIIB versus IV),
previous
treatment (chemotherapy versus no chemotherapy), and performance status (Karnofsky index,
>70
versus 70); they were then randomly assigned to receive either supportive care and ATP
(ATP
group) or supportive care alone (control group). Supportive care, provided by the patients'
attending physicians, included analgesics, antibiotics, anticough medication, antiemetics,
bisphosphonates, corticosteroids, and palliative radiotherapy for local control of the primary
tumor or
metastases.
Patients in the ATP-treatment arm were admitted to the Clinical Research Unit of the University Hospital of the Erasmus University Medical Center Rotterdam to receive a maximum of 10 ATP courses. To keep hospitalization at a minimum for ethical reasons, we chose not to use the schedule used by Haskell et al. (18,19) with ATP infusions for 96 hours once every 4 weeks; instead, we gave 30-hour infusions at shorter intervals, i.e., the first seven ATP courses at 2-week intervals, followed by three ATP courses at 4-week intervals. ATP infusions (6.1 mg/mL in 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 maximally 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 lower dose or further reduced until side effects disappeared. Follow-up was continued until week 28, i.e., 4 weeks after the last ATP course that was given at 24 weeks. Patients in the control arm were followed up at the outpatient department of the Erasmus University Medical Center Rotterdam for 28 weeks. In both groups, anthropometry, blood serum albumin levels, muscle strength, and QOL were assessed before treatment randomization and after randomization at 4-, 8-, 12-, 16-, 20-, 24-, and 28-week periods.
Anthropometry and Muscle Strength
Body height was determined to the nearest centimeter. Body weight was measured with an electronic scale (Seca Ltd., Birmingham, U.K.) to the nearest 0.1 kg.
Strengths of two muscle groups (i.e., elbow flexor muscles and knee extensor muscles) were assessed by use of a hand-held Microfet2R dynamometer (Biometrics Europe, Amersfoort, The Netherlands). This technique has been validated in several groups of patients, mostly in those patients who were limited in muscle strength (22,23). The patient while sitting exerted a maximal force with the 90° flexed right elbow, while the examiner pushed with the dynamometer against the patient's thumb pad until the muscle strength was overcome (break test). Similarly, the patient exerted a maximal force with the 90° flexed right knee, while the examiner pushed with the dynamometer against the patient's ankle until the muscle strength was overcome. The strength of both muscle groups was measured three times at an interval of approximately 10 seconds. Muscle strength was expressed in Newtonmeter (Nm) units and was calculated by dividing the measured mean strength (dynamometer reading) by the distance from the dynamometer position point to the humeral epicondylus medialis (elbow) and the femural epicondylus medialis (knee). The same observer (H. J. Agteresch) carried out all measurements.
Quality of Life
QOL was assessed with the use of The Rotterdam Symptom Checklist (RSCL), a 39-item self-report questionnaire (24). The reliability and validity of the RSCL in cancer patients have been confirmed in both cross-sectional (25) and longitudinal (26,27) studies in patients with a wide range of cancers. This questionnaire, which assesses symptoms during the preceding week, was filled out by the patients. The RSCL measures scores on four domains: 1) a physical score (23 items), 2) a psychologic score (seven items), 3) a functional score (eight items), and 4) an overall score (one item). Each item is rated on a 4-point scale. Results per item were transformed into standardized scores, ranging from 0 to 100 with the use of the following formula: 100 - [100 x (item scale score - minimum item score)/(maximum score - minimum score)]. A lower score represents a greater level of distress (24).
Statistical Analysis
Differences over time between body weight, serum albumin levels, muscle strength, and QOL scores in the two groups were analyzed according to the "intention-to-treat" principle by repeated-measures analysis of covariance with the use of the linear regression model. To account for the within-patient correlation in the measurements of the dependent variable and, simultaneously, for possible non-normality of the dependent variable, the Generalized Estimating Equations (28) approach was followed. These analyses were performed with the SAS procedure Proc Mixed (version 6.12-Windows; SAS Inc., Cary, NC), with the use of 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 relation 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. Survival was compared between groups by means of the log-rank test with the use of SPSS (version 6.1.3-Windows; SPSS Inc., Chicago, IL). Two-sided P values less than .05 were considered statistically significant.
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RESULTS |
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Twenty-eight patients were allocated to ATP treatment, and 30 were
assigned to no ATP treatment. The trial design is summarized in Fig.
1. Age, tumor stage, performance status, previous
treatment, and outcome parameters were similar at baseline between the
ATP and control arms. Assessable patients in the ATP group weighed more
and had lost more weight than patients in the control group. In both
groups, the majority were male (Table 1
). However,
when the statistical analyses for all outcome parameters were adjusted
for age, sex, body weight, weight loss, and histologic type, this did
not alter the results in both groups.
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Body Weight
In control patients, the mean weight loss over the 28-week study
period (expressed as change per 4 weeks) was -1.0 kg (95% CI =
-1.5 to -0.5) per 4 weeks, whereas ATP-treated patients
experienced no weight loss (0.2 kg; 95% CI = -0.2 to +0.6;
P for between-group difference = .002; Fig.
2, A). For further analysis, the participants were
stratified according to the presence of cachexia prior to the study
(
5% versus <5% weight loss in relation to weight before the
illness; 16 patients in the ATP group and 13 patients in the control
group versus 9 patients in the ATP group and 12 patients in the control
group). In cachectic patients, progressive weight loss of -1.6 kg
(95% CI = -2.1 to -1.1) per 4 weeks was observed in the control
group, while no additional weight loss occurred in the ATP group (+0.3
kg; 95% CI = -0.5 to +1.1; P for between-group difference
= .0002). In noncachectic patients, statistical significance between
the study groups was not reached (P = .22).
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Serum albumin concentration (g/L) declined by -1.2 (95% CI =
-2.0 to -0.4) per 4 weeks in the control group, whereas no change
was detected in the ATP group (0.0 g/L; 95% CI = -0.3 to +0.3;
P for between-group difference = .006; Fig.
3). The effect of ATP on albumin was highly
significant in patients who were already cachectic at the beginning of
the study (P = .0001) but not in noncachectic patients
(P = .37).
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The strength of elbow flexor muscles declined by -5.5% (95%
CI=
-9.6% to -1.4%) per 4 weeks in the control group, whereas
values remained stable in the ATP group (0.0%; 95% CI =
-1.4%
to
+1.4%; P for between-group difference = .01; Fig. 2, B, top).
A similar pattern was observed for knee extensor muscles: Muscle
strength in control patients decreased by -4.5% (95% CI =
-9.7% to -0.7%) per 4 weeks, whereas muscle strength in
ATP-treated patients showed no significant change with time (+1.4%;
95% CI = -0.2% to +3.1%; P = .02; Fig. 2,
B,
bottom).
The effect of ATP on the strength of elbow flexor and knee extensor
muscles was highly significant in patients who were already cachectic
at the beginning of the study (both P = .0001) but not in
noncachectic patients (P = .38 and P = .44,
respectively).
Quality of Life
During follow-up, patients in the control group showed an impairment
in their physical QOL score of -2.4% (95% CI = -4.1%
to
-0.6%) per 4 weeks, whereas patients in the ATP group showed no
change (-0.2%; 95% CI = -1.1% to +0.7%; P for
between-group difference = .0002; Fig. 4, A). The
functional score deteriorated by -5.5% (95% CI =
-9.6% to
-1.4%) per 4 weeks in patients in the control group, whereas
patients in the ATP group showed no significant change (+0.4%; 95% CI
= -1.8% to +2.6%; P = .02; Fig. 4,
B). The psychologic
score deteriorated by -2.4% (95% CI = -5.9% to
+1.1%) per 4
weeks in patients in the control group but showed no significant change
in patients in the ATP group (-0.7%; 95% CI = -2.0%
to
+0.6%;
P = .11). With regard to the overall score of QOL, patients in
the control group showed a deterioration in QOL by -3.5% (95% CI
=
-6.5% to -0.5%) per 4 weeks, whereas patients in the ATP group
showed no change (+0.1%; 95% CI = -1.8% to +2.0%; P =
.0001; Fig. 4, C). The positive effects of ATP on QOL were similar in
both cachectic and noncachectic patients.
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Concomitant Supportive Treatment
During the 28-week follow-up period, none of the patients underwent surgery. One patient in the control group was treated with chemotherapy, which consisted of five courses of a combination of cisplatin and etoposide given at 3-week intervals, followed by radiotherapy involving all lesions. Palliative radiotherapy was given to seven patients in the control group and to six patients in the ATP group. Thirteen patients in the control group and nine patients in the ATP group used corticosteroids to treat symptoms of brain edema (four patients in the ATP group and one patient in the control group), dyspnea (four patients in the ATP group and 12 patients in the control group), and nausea (one patient in the ATP group and no patients in the control group).
Survival
Twenty-eight weeks after randomization, the median survival time was 5.6 months (95% CI = 1.1-10.1 months) for patients in the ATP group and 4.7 months (95% CI = 2.5-6.8 months) for patients in the control group (P for between-group difference = .51).
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DISCUSSION |
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The aim of our study was to investigate the effect of ATP on body weight and QOL in patients with advanced-stage NSCLC as well as its effect on arm and leg muscle strength as functional and patient-relevant parameters. Since the trial was performed in patients with advanced lung cancer, hand-held dynamometry was chosen because this technique is noninvasive. Clearly, the ideal method for assessing treatment effects regarding QOL would have been a double-blind, placebo-controlled study. However, blinding was not feasible because of the complexity of ATP administration. Some side effects are relatively specific to ATP so that both patients and investigators would have easily recognized that ATP was being given. In addition, there were ethical reasons for not giving 10 placebo infusions to patients with advanced lung cancer with a short life expectancy (3-6 months). Despite these limitations, the remarkably consistent positive effects of ATP on QOL and on objective parameters, such as body weight and serum albumin levels, seem to underline the validity of our results.
During treatment and follow-up, a significant difference in mean weight loss was observed between patients in the ATP group and those in the control group. Patients in the control group lost approximately 1 kg per 4 weeks or 6.5 kg over a 6-month period, whereas patients in the ATP group had an average stable weight over the 6-month period. In cancer patients, loss of body weight is mainly due to loss of fat and of skeletal muscle mass (30). In our study, control patients lost approximately one third of their muscle strength in both arms and legs over a 6-month period, whereas ATP-treated patients lost no muscle strength. The significant difference between patients in the ATP group and those in the control group in concentration of the nutritional parameter albumin provides a biochemical confirmation of the beneficial effects of ATP on the nutritional and functional status of patients with advanced lung cancer. It is noteworthy that the effect of ATP on weight loss, muscle strength, and serum albumin concentration was especially marked in patients who were already cachectic at the start of the study, whereas no statistical significance was reached in noncachectic patients.
Furthermore, a statistically significant difference in overall scores on the QOL instrument evolved between patients in the ATP group and those in the control group. In the control group, the deterioration expected in patients with progressive cancer was seen, whereas this deterioration was not observed in the ATP group. The QOL of the patients in the control group deteriorated significantly both at the physical (2% per 4 weeks) and functional (5% per 4 weeks) levels, whereas these domains remained practically unchanged in patients in the ATP group. The physical and functional scores were significantly different between patients in the ATP group and those in the control group, whereas the psychologic scores were not different. Furthermore, patients in the ATP group showed a significantly better general activity level, including doing housework, climbing stairs, and walking outdoors, which supports the validity of the beneficial effects of ATP on muscle strength. Items contributing to the better physical scores in patients in the ATP group included lung cancer-related (e.g., shortness of breath) as well as general symptoms. It is noteworthy that the items include two of the most common cancer-related symptoms: tiredness and lack of energy (31). Scores for chest pain and coughing did not significantly differ between the two groups (P = .05 and P = .21, respectively).
In both groups of patients, palliative radiotherapy was given to approximately the same number of patients, whereas more patients in the control group than in the ATP group used corticosteroids. None of the patients used corticosteroids as appetite-stimulating drugs or other appetite stimulators, such as cyproheptadine and megestrol acetate. One ATP-treated patient used marihuana tea for nausea; however, in a recent placebo-controlled study in patients with acquired immunodeficiency disease syndrome (32), no significant effect of dronabinol (the active ingredient of marihuana) on body weight was shown. This finding indicates that differences between the patients in the ATP group and those in the control groups were not due to confounding effects of concomitant supportive treatment.
ATP was administered as a constant intravenous infusion without side effects in the majority of courses; if side effects occurred, they disappeared rapidly when the infusion rate was lowered. The reported side effects were mostly of type 1 and sometimes of type 2. Although during the courses some patients showed dyspnea (type 4), this side effect was mild in nature. Since, in addition, no side effects were observed between the ATP infusions, ATP treatment appears to be a nontoxic therapy in patients with advanced lung cancer.
The mechanisms contributing to the effects of ATP on body weight, muscle strength, and QOL are not well understood. It is unlikely that the beneficial effects of ATP on body weight and QOL would be caused simply by appetite-stimulating effects, since appetite stimulators, such as cyproheptadine (6) and corticosteroids (33), did not influence the body weights of cancer patients. Rather, our results would suggest that ATP may also influence specific metabolic pathways. In addition to the well-established role of ATP in cellular metabolism, extracellular ATP appears to be involved in the regulation of a variety of biologic processes, including neurotransmission, muscle contraction, cardiac function, vasodilatation, and liver glycogen metabolism (16). ATP can be released from the cytoplasm of several cell types and interacts with purinergic P1 and, particularly, P2 receptors on the surface of many cells (16). Significantly lower ATP levels have been found in the liver and in the skeletal muscle of tumor-bearing rats (34). Rapaport and Fontaine (17) showed that intraperitoneal ATP administration doubled hepatic ATP pools and inhibited weight loss in tumor-bearing mice. These authors suggested that ATP may inhibit Cori cycle activity (i.e., conversion of glucose to lactate in peripheral tissues followed by gluconeogenesis from lactate followed in the liver). Studies in isolated hepatocytes showed that extracellular ATP induced Ca2+mobilization and influx by stimulation of surface P2 receptors (35) that are involved in the control of gluconeogenesis (36) and glycogenolysis (37). Furthermore, since albumin levels are affected by both nutrition and acute-phase response, it is possible that the stabilization of serum albumin levels by ATP may be caused by inhibition of the acute-phase response. In animals, ATP has been shown to decrease the production of the proinflammatory cytokines interleukin 1 and interleukin 6 (38). This observation is noteworthy, since increased serum levels of these interleukins (39,40) have been found in patients with advanced cancer and were suggested to play a prominent role in progressive weight loss in cancer (41). In addition to the effects described above, ATP may have other benefits in oncology. Preclinical studies showed that ATP administration may potentiate the antitumor effects of cytostatics (42) and radiotherapy (43) and may also have protective effects against radiation tissue damage (44).
In conclusion, our results demonstrate that ATP infusion has marked beneficial effects on the QOL of patients with advanced NSCLC. In patients who are losing weight, ATP prevents further weight loss and maintains muscle strength of both the upper and the lower extremities. ATP can be administered as a constant intravenous infusion without side effects in the majority of courses; if side effects occur, they are mild and transient. In contrast to earlier pharmacologic attempts to reverse cancer cachexia, it appears that ATP might be the first agent with beneficial effects on skeletal muscles of cachectic cancer patients. We conclude that ATP has potential in the palliative management of lung cancer. Further clinical trials using an appropriate placebo control are warranted.
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NOTES |
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We thank J. W. O. van den Berg and A. S. Th. Planting for critical comments on the manuscript and the study design as well as R. Slingerland, G. Stoter, and J. Verweij for critical comments on the study design. We are grateful to L. M. Hanff and A. G. Vulto for coordinating and supervising preparation of ATP infusions. We also thank the following clinicians for their help in patient enrollment: H. van den Berg, J. A. Burgers, J. W. Brouwers, J. A de Goeij, E. C. Groeninx van Zoelen, M. Heysteeg, J. C. E. Meek, J. P. A. M. van Meerbeek, M. J. M. van Mierlo, L. G. W. Kerkhofs, T. C. Kok, S. Leij-Halfwerk, A. Rudolphus, M. J. Samson, S. Senan, K. Y. Tan, R. Slingerland, T. A. W. Splinter, R. van Uffelen, J. C. C. M in't Veen, and O. B. Wijers.
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Manuscript received March 30, 1999; revised November 29, 1999; accepted December 8, 1999.
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