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Optimizing End Points and Outcomes in Cancer-Associated Wasting

Edinburgh Cancer Centre, Edinburgh, Scotland

To the Editor:

We congratulate Jatoi et al¹ in completing a large, well-powered, phase III pharmaconutritional study in cancer-associated wasting (also referred to as cancer cachexia). This study highlights several points that deserve further discussion.

Although incompletely understood, cancer-associated wasting is common and debilitating. To date, efforts to mitigate it have met with limited success. Cancer-associated wasting is likely to be a multifactoral process. To date, this has not been reflected in the design and reporting of clinical studies. To better understand cancer-associated wasting and the effects of intervention, a consensus research definition incorporating contemporary knowledge is needed. This should attempt to characterize patients by, for example, the severity of wasting, the presence or absence of systemic inflammation, and predominant symptoms or symptom clusters. These parameters may reflect underlying differences in pathophysiology and influence the response to intervention. Such consensus in trial design should make it easier to compare and analyze wasting studies.

This study, like others, places the outcome emphasis on absolute weight gain. This may not be appropriate. First, the actual patient benefit from weight gain alone is unclear.² Second, a primary end point of 10%+ weight gain is likely to favor megestrol acetate (MA). Marked sarcopaenia is a major component of cancer-associated wasting. The predominant effect of eicosapentaenoic acid (EPA) on body composition seems to be modulation of the loss of muscle mass. This degree of weight gain as a result of muscle accretion is currently physiologically unrealistic for most patients with advanced cancer. With MA, weight gain is predominantly due to tissue other than muscle, which may be more readily achievable. Whereas the functional benefit of gaining adipose tissue is currently uncertain, a significant increase in physical activity level has been demonstrated in patients with advanced pancreatic cancer taking an EPA-containing oral nutritional supplement³ (although the mechanism by which this increase occurs is unclear).

A greater understanding of what constitutes meaningful patient-focused end points is needed in cancer-associated–wasting research. Increased appreciation of how current outcomes relate to one another may help in this. For example, the observation that weight gain or appetite stimulation doesn't necessarily improve quality of life is incompletely explained. Although pragmatic, relying on a global quality of life tool may limit the ability to answer questions like this one.

Jatoi et al reported on an apparent lack of benefit from a combination of an appetite stimulant and specialized supplement; this finding warrants further assessment. Additional information, such as the daily amount of supplement consumed, given a possible threshold effect of EPA supplementation, and plasma levels of fatty acid might have helped to assess compliance and interpret results.

The conclusion suggests that the EPA-containing supplement does not improve on MA in the management of cancer-associated wasting. Although we agree that MA may be helpful for selected patients, this study, for reasons that include the lack of demonstrable benefit from greater weight gain alone and the potential for increased toxicity from MA, suggests that there is little to recommend MA over the EPA-containing supplement for the majority of patients. There are also other reasons why MA may not be beneficial to patients with cancer-associated wasting, or help them maintain their ability to complete daily activities. These reasons include the possible antianabolic effect of MA.⁴

Research has generally tried to reverse established wasting in patients with advanced cancer who are not receiving antitumor therapy. This may not be the optimal paradigm. Physiologic changes associated with wasting (eg, hypermetabolism) can manifest early in the disease process,⁵ before patients are clinically recognized as "wasted," according to current criteria. Earlier intervention targeting cancer-associated wasting may be a better model to maintain well-being, functional independence, and disease-centered parameters.

Authors' Disclosures of Potential Conflicts of Interest

The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Honoraria: M. Dahele, Abbott. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section of Information for Contributors found in the front of every issue.

Acknowledgment

The authors whish to acknowledge Dr Gabriel N. Hortobagyi for reviewing this letter.

REFERENCES

1. Jatoi A, Rowland K, Loprinzi CL, et al: An eicosapentaenoic acid supplement versus megestrol acetate versus both for patients with cancer-associated wasting: A North Central Cancer Treatment Group and National Cancer Institute of Canada collaborative effort. J Clin Oncol 22:2469-2476, 2004[Abstract/Free Full Text]

2. Westman G, Bergman B, Albertsson M, et al: Megestrol acetate in advanced, progressive, hormone-insensitive cancer: Effects on the quality of life—A placebo-controlled, randomised, multicentre trial. Eur J Cancer 35:586-595, 1999

3. Moses AW, Slater C, Preston T, et al: Reduced total energy expenditure and physical activity in cachectic patients with pancreatic cancer can be modulated by an energy and protein dense oral supplement enriched with n-3 fatty acids. Br J Cancer 90:996-1002, 2004[CrossRef][Medline]

4. Lambert CP, Sullivan DH, Freeling SA, et al: Effects of testosterone replacement and/or resistance exercise on the composition of megestrol acetate stimulated weight gain in elderly men: A randomized controlled trial. J Clin Endocrinol Metab 87:2100-2106, 2002[Abstract/Free Full Text]

5. Jatoi A, Daly BD, Hughes VA, et al: Do patients with nonmetastatic non-small cell lung cancer demonstrate altered resting energy expenditure? Ann Thorac Surg 72:348-351, 2001[Abstract/Free Full Text]

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Related Reply

• In Reply:
  Aminah Jatoi, Charles Loprinzi, Kendrith Rowland, and Shaker Dakhil
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• In Reply:
  Aminah Jatoi, Charles Loprinzi, Kendrith Rowland, and Shaker Dakhil
  JCO 2005 23: 2872-2873 [Full Text]

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