EDITORIALS

Is ATP (Adenosine 5'-Triphosphate), like STP®, a Performance-Enhancing Additive for the Tanks of Cancer Patients?

Aminah Jatoi, Charles L. Loprinzi, Jeffrey Sloan, Richard M. Goldberg

Affiliations of authors: A. Jatoi, C. L. Loprinzi, R. M. Goldberg (Division of Medical Oncology), J. Sloan (Division of Biostatistics), Mayo Clinic, Rochester, MN.

Correspondence to: Richard M. Goldberg, M.D., Division of Medical Oncology, Mayo Clinic, Rochester, MN 55905 (e-mail: goldberg.richard{at}mayo.edu).

Among 1000 patients with advanced cancer, Donnelly and Walsh (1) found that anorexia, weakness, and weight loss (>=10% of premorbid weight) were among the 10 most bothersome signs and symptoms. Despite the impact of the cancer anorexia/cachexia syndrome, relatively few clinical trials target its palliation as their primary end point. Observations that the drugs megestrol acetate, dexamethasone, and cyproheptadine caused unwanted weight gain when they were used to treat other illnesses led to clinical trials in cancer patients with anorexia/cachexia. In this setting, these agents may stimulate appetite and permit some patients to regain weight but do not appear to increase lean tissue mass (2-4). Treatment with megestrol acetate causes a 5% or greater weight gain in only 20% of cancer patients with the anorexia/cachexia syndrome (2). This limited success underscores the need to identify therapeutic alternatives.

In this issue of the Journal, Agteresch et al. (5) describe a randomized, controlled trial studying adenosine 5'-triphosphate (ATP) infusions as therapy for cancer anorexia/cachexia in patients with non-small-cell lung cancer. This trial sought to determine the effect of ATP infusions on body weight change, muscle strength, serum albumin concentration, and quality-of-life scores.

Why might ATP infusion be useful in this setting? Weight maintenance is a balance of energy demand and supply. Illness often increases energy demands. A comparison between a group of healthy individuals and patients with non-small-cell lung cancer found that patients with lung cancer had an increase in basal metabolic rate, as high as 130 kcal/day after adjustment for lean body mass (6). Anorexia or treatment-related toxic effects may also cause a deficit on the supply side of the equation. The administration of ATP, a direct hydrolyzable source of energy, could potentially tip the balance toward weight gain and preservation of lean body mass. Preliminary clinical data supported such a possibility. In a phase I trial, Haskell et al. (7) observed stable weights and Karnofsky scores over a 1- to 3-month period with ATP infusions in eight lung cancer patients. In a subsequent phase II trial, Haskell et al. (8) documented a modest trend toward weight gain, noting a mean increase in weight of 1.3 kg among 15 lung cancer patients receiving ATP. This background clearly justified the current phase III trial.

In the study reported in this issue by Agteresch et al. (5), 58 patients with non-small-cell lung cancer of either stage IIIB or IV were randomly assigned to supportive care with or without ATP infusions. ATP was administered over a 30-hour period at doses tailored to the maximum tolerance of the individual patient; infusions were repeated at 2- to 4-week intervals. When the groups were compared, this treatment appeared to modestly increase weight, improve strength, and slow the decline in quality of life. The authors (5) conclude, "ATP has potential in the palliative management of lung cancer."

Are these results definitive? We agree with the authors that they are not. Supportive care trials present the investigator with multiple methodologic challenges. Some of these challenges are illustrated in this study. First, assessment of many of this study's end points, including strength assessment and quality of life, is potentially tied to the knowledge of whether the patient was receiving ATP. The authors recognized this but believed that a double-blind study was impractical, a conclusion that seems well justified given the inconvenience of ATP infusions. Second, although the mean weight change in the control group of -1.0 kg versus treatment group of +0.2 kg at 4 weeks was statistically significant at a level of P = .002, the clinical significance of this difference is open to question. Moreover, the observed change in the physical domain of the Rotterdam Symptom Checklist (-0.2% for the ATP-treated group versus -2.4% for the control group) is also modest. This checklist has four graded responses for each question that are scored from 0 to 3. The physical function subscale that contains 23 items hence has a potential range of 0 to 69. On average, patients must have rated one or two of the 23 items one category higher in the ATP-treated group in order to generate the observed difference of 2.2% between the mean scores of the two groups. Once again, the clinical significance of such a small change in the quality-of-life scores is open to question.

Finally, in the report's figures, Agteresch et al. display the average results of available data for each time point for both patient groups. As would be expected in a trial of this nature, more than half of the patients dropped out or died by the study's end. However, the curves for both weight change and quality of life appeared to diverge as the number of patients on the trial declined. This observation raises the issue of whether this divergence of curves is an artifact related to patient dropout. The initial stratification between groups did not take weight into account, and the authors noted that the groups differed with respect to weight and change in weight at baseline. Perhaps, at the time of randomization, the two groups were not equally predisposed to weight loss. With respect to quality-of-life assessment, it is possible that the subjects who did not supply data at scheduled reassessments had poorer quality of life than those who did. The divergence of quality-of-life curves may, in fact, represent bias introduced by missing data. Thus, the authors' conclusion is a reasonable one when they describe the "potential" for ATP to be helpful in this setting as opposed to claiming that their results demonstrate a clear efficacy for ATP in the treatment of cancer anorexia/cachexia.

The limitations noted above should not, however, detract from the importance of this provocative study. ATP infusion merits further investigation in the treatment of cancer anorexia/cachexia syndrome. More than 60% of patients with advanced non-small-cell lung cancer report weight loss in the 6 months before diagnosis (9). This weight loss and its associated morbidity are major concerns for cancer patients. Consequently, physicians need to be attentive to this problem and actively conduct research in this field. Agteresch et al. have done just that in their trial.

REFERENCES

1 Donnelly S, Walsh D. The symptoms of advanced cancer. Semin Oncol 1995;22(2 Suppl 3):67-72.

2 Loprinzi CL, Ellison NM, Schaid DJ, Krook JE, Athmann LM, Dose AM, et al. Controlled trial of megestrol acetate for the treatment of cancer anorexia and cachexia. J Natl Cancer Inst 1990;82:1127-32.[Abstract]

3 Loprinzi CL, Kugler JW, Sloan JA, Mailliard JA, Krook JE, Wilwerding MB, et al. Randomized comparison of megestrol acetate versus dexamethasone versus fluoxymesterone for the treatment of cancer anorexia/cachexia. J Clin Oncol1999 ;17:3299-306.[Abstract/Free Full Text]

4 Kardinal CG, Loprinzi CL, Schaid DJ, Hass AC, Dose AM, Athmann LM, et al. A controlled trial of cyproheptadine in cancer patients with anorexia and/or cachexia. Cancer 1990;65:2657-62.[Medline]

5 Agteresch HJ, Dagnelie PC, van der Gaast A, Stijnen T, Wilson JH. Randomized clinical trial of adenosine 5'-triphosphate in patients with advanced non-small-cell lung cancer. J Natl Cancer Inst 2000;92:321-8.[Abstract/Free Full Text]

6 Jatoi A, Daly BD, Hughes V, Dallal G, Kehayias J, Roubenoff R. Do patients with early stage non-small cell lung cancer (NSCLC) suffer cancer cachexia? [abstract]. Proc ASCO 1998;17:171.

7 Haskell CM, Wong M, Williams A, Lee LY. Phase I trial of extracellular adenosine 5'-triphosphate in patients with advanced cancer. Med Pediatr Oncol 1996;27:165-73.[Medline]

8 Haskell CM, Mendoza E, Pisters KM, Fossella FV, Figlin RA. Phase II study of intravenous adenosine 5'-triphosphate in patients with previously untreated stage IIIB and stage IV non-small cell lung cancer. Invest New Drugs 1998;16:81-5.[Medline]

9 Dewys WD, Begg C, Lavin PT, Band PR, Bennett JM, Bertino JR, et al. Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern Cooperative Oncology Group. Am J Med 1980;69:491-7.[Medline]


This article has been cited by other articles in HighWire Press-hosted journals:


             
Copyright © 2000 Oxford University Press (unless otherwise stated)
Oxford University Press Privacy Policy and Legal Statement