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Adenosine Triphosphate: Does It Help Cancer Patients "Get Bigger and Stronger"?

Mayo Clinic, Rochester, MN

"ATP stands for adenosine triphosphate—which to your muscles spells energy, energy, energy!"

—www.netrition.com

TOUTING A PRODUCT that contains 60 mg of adenosine triphosphate (ATP), this advertisement goes on to describe how ATP "helps athletes get bigger and stronger. . . " Unlike so many popular claims for increasing strength and energy, this one may prove true. Agteresch et al,¹ in this issue of the Journal of Clinical Oncology, provide data to suggest that ATP may actually help cancer patients "get bigger and stronger." These investigators observed that ATP seems to impact lung cancer patients favorably by allowing them to maintain body composition and to regain appetite. In an earlier publication from this same trial, these investigators also reported that ATP improves weight, strength, and quality of life.²

These observations are particularly noteworthy because, to date, no intervention has consistently improved weight, strength, quality of life, body composition, and appetite in patients with advanced cancer. Although several agents have been tested for this purpose, the most successful provide modest benefit to only a minority of patients.³ For example, megestrol acetate, although the best studied and arguably the most effective available agent, seems to improve appetite in only approximately 20% of advanced cancer patients independent of a placebo effect, and it does not appear to increase lean body mass.^4,5 The vast majority of patients with advanced cancer continue to suffer from loss of both appetite and weight toward the end of life. In this setting, the current study is provocative and merits scrutiny.

Agteresch et al¹ report on what, to our knowledge, is the first clinical trial to examine ATP for the treatment of cancer-associated wasting. Patients with either stage IIIB or IV non–small-cell lung cancer were randomly assigned in an unblinded fashion to receive either ATP, up to 75 µg/kg/min (as tolerated) for 30 hours intravenously every 2 to 4 weeks, or no ATP. Patients underwent detailed, serial assessments of body composition, appetite, and dietary intake. These investigators report that body composition, appetite, and dietary intake stabilized among the ATP-treated patients, whereas the non-ATP group manifested an erosion of lean tissue and fat, a dwindling of appetite, and a drop in dietary intake.

Why ATP? What provided the impetus for Agteresch et al to test this agent, and what prior information on ATP adds to the plausibility of this study’s positive findings? First, an animal study suggests that intraperitoneal ATP stabilizes weight in tumor-bearing mice.⁶ Next, Asensi et al⁷ observed that ATP may inhibit gluconeogenesis, suggesting that extracellular ATP can cross the cell membrane and effect cellular function. Preliminary human data also exist. In an antineoplastic trial in patients with non–small-cell lung cancer, Haskell et al⁸ found that intravenous ATP was associated with a mean weight increase of 1.3 kg in the absence of a tumor response. It is reasonable to hypothesize that this trend in weight gain occurred as a result of ATP’s salutary effects on lean tissue and fat, rather than from an antineoplastic effect. In addition, because some studies suggest that non–small-cell lung cancer patients lose weight because of hypermetabolic aberrations,^9,10 ATP might provide an alternative to caloric repletion, which has repeatedly been proven unsuccessful in improving clinical outcomes in patients with advanced, incurable cancer.³ Taken together, the foregoing data, including the trial results from Agteresch et al,¹ suggest that ATP might provide a solution to the vexing problem of wasting in cancer patients.

Given the above information, should we prescribe ATP to our emaciated cancer patients? Should we nod when cancer patients ask us about buying and taking ATP-containing supplements? At present, the answer to both questions is no. Designed as a preliminary study to explore whether ATP is worthy of further investigation in the management of weight-losing cancer patients, the current trial requires confirmation. Several aspects of this trial caution us to view these results as being only preliminary. First, although improvements in weight, body composition, quality of life, and appetite may all suggest beneficial effects of ATP, these parameters are not independent of each other. If there had been an imbalance among the two treatment arms, and there might have been given the relatively small sample sizes, then the more robust group may have had improvements in each of these interrelated clinical parameters on the basis of this imbalance alone. Second, improvements were modest. ATP resulted in weight increments in various body compartments of only 0.1 kg, with the overall outcome being one of stable body composition. Had the ATP-treated group manifested greater improvement in body composition, these results would have been more convincing of ATP’s efficacy. Third, this trial was neither blinded nor placebo-controlled. Even so-called objective end points, such as measurement of body composition, may be influenced by patients’ and investigators’ perceptions of intended effects. These perceptions may skew results—and perhaps even skew the interpretation of results—in the absence of double-blinding. As a case in point, a double-blind North Central Cancer Treatment Group study found that 40% of cancer patients reported an improvement in appetite with placebo alone.⁴ In the absence of double-blinding, such "improvement" might be incorrectly credited to a nonplacebo. A double-blind, placebo-controlled trial remains the gold standard for assessing any therapeutic intervention, and it constitutes an optimal study design in testing agents aimed at treating cancer-associated wasting or loss of appetite.

Fourth, dropout bias might have influenced study conclusions. For example, when looking at the data on arm muscle area, one begins to see a divergence of curves at 8 weeks. It is also between 4 and 8 weeks that one sees that 10 of 25 patients dropped out from the ATP-treated group, whereas the non-ATP group remained relatively intact. These high dropout rates are to be expected among patients with advanced cancer and weight loss, and by the trial’s end, roughly the same number of patients had dropped out from each arm. However, one might surmise that dropouts select for healthier patients at different time points in the analysis and might lead to biased conclusions. A challenging quandary in trial design, this problem with dropout bias can be addressed, in part, by using other analysis techniques that adhere more strictly to the intention-to-treat rule or by drawing conclusions based on all patients within each study arm.

Last, from a safety standpoint, ATP should still be viewed as an investigational agent in cancer patients. Approximately one third of ATP infusions were accompanied by side effects. The authors described these side effects as mild and transient in the present publication. However, in their earlier publication from this same cohort,² they provided more detail on the severity of ATP-related toxicity. Although most side effects were of grade 1 severity (according to the National Cancer Institute’s common toxicity criteria), there was one episode of grade 4 dyspnea. This limited safety profile is another reason why ATP should not yet be used as part of routine clinical practice. Thus, when these findings are viewed in aggregate, it becomes clear that further studies are necessary, as explicitly stated by Agteresch et al¹ in their report.

Is it time to study ATP further? Unlike the other two questions posed above, the answer to this question is yes. There is no question that this agent deserves further investigation. Cancer-associated loss of appetite and/or weight occurs in more than 50% of all patients with advanced cancer.¹¹ Weight loss and a decline in functional status are often intimately related.¹² Loss of appetite is one of the most distressing symptoms cancer patients suffer toward the end of life.¹¹ As noted earlier, multiple agents have been tried to reverse or prevent loss of weight and loss of appetite, but all fall short: none causes weight gain and improvement in appetite for the majority of weight-losing cancer patients with advanced disease. Hence, the promising data on ATP from Agteresch et al invite a robust, double-blind, placebo-controlled trial. Such a trial should help answer the question of whether ATP actually helps cancer patients regain their appetite and "get bigger and stronger."

REFERENCES

1. Agteresch HJ, Rietveld T, Kerkhofs LGM, et al: Beneficial effects of adenosine triphosphate on nutritional status in advanced lung cancer patients: A randomized clinical trial. J Clin Oncol 20: 371–378, 2002[Abstract/Free Full Text]

2. Agteresch HJ, Dagnalie PC, van der Gaast A, et al: Randomized clinical trial of adenosine 5`-triphosphate in patients with advanced non-small cell lung cancer. J Natl Cancer Inst 92: 321–328, 2000[Abstract/Free Full Text]

3. Jatoi A, Loprinzi CL: Current management of cancer-associated anorexia and weight loss. Oncology 15: 497–502, 2001[Medline]

4. Loprinzi CL, Ellison NM, Schaid DJ, et al: Controlled trial of megestrol acetate for the treatment of cancer anorexia and cachexia. J Natl Cancer Inst 82: 1127–1132, 1990[Abstract/Free Full Text]

5. Loprinzi CL, Schaid DJ, Dose AM, et al: Body composition changes in patients who gain weight while receiving megestrol acetate. J Clin Oncol 11: 152–154, 1993[Abstract]

6. Rapaport E, Fontaine J: Generation of extracellular ATP in blood and its mediated inhibition of host weight loss in tumor-bearing mice. Biochem Pharmacol 38: 4261–4266, 1989[CrossRef][Medline]

7. Asensi M, Lopez-Rodas A, Sastre J, et al: Inhibition of gluconeogenesis by extracellular ATP in isolated rat hepatocytes. Am J Physiol 261: R1522–R1526, 1991[Abstract/Free Full Text]

8. Haskell CM, Mendoza E, Pisters KMW, 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. Invest New Drugs 16: 81–85, 1998[CrossRef][Medline]

9. Jatoi A, Daly BDT, Hughes VA, et al: Do patients with nonmetastatic non-small cell lung cancer demonstrate altered resting energy expenditure? Ann Thorac Surg 72: 348–51, 2001[Abstract/Free Full Text]

10. Staal van den Brekel AJ, Schols AM, ten Velde GP, et al: Analysis of the energy balance in lung cancer patients. Cancer Res 54: 6430–6433, 1994[Abstract/Free Full Text]

11. Walsh D, Donnelly S, Rybicki L: The symptoms of advanced cancer: Relationship to age, gender, and performance status in 1000 patients. Support Care Cancer 8: 175–179, 2000[CrossRef][Medline]

12. Finkelstein DM, Cassileth BR, Bonomi PD, et al: A pilot study of the Functional Living Index-Cancer (FLIC) Scale for the assessment of quality of life for metastatic lung cancer patients: An Eastern Cooperative Oncology Group study. Am J Clin Oncol 11: 630–633, 1988[Medline]

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This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Jatoi, A. Articles by Loprinzi, C. L. Search for Related Content PubMed PubMed Citation Articles by Jatoi, A. Articles by Loprinzi, C. L. Social Bookmarking                            What's this?