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Journal of Clinical Oncology, Vol 22, No 19 (October 1), 2004: pp. 4028 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.99.333
Is Methylphenidate an Irreplaceable Therapy for the Fatigued Cancer Patient?Centro de Capacitación, INDESALUD, Campeche, Mexico I commend the Bruera et al evaluation of methylphenidate to mitigate fatigue in patients with cancer.1 However, several of their findings deserve comment. They propose that after correcting the medical alterations that can cause fatigue in the patient with cancer (anemia, depression, adrenal insufficiency, and so on), most factors that contribute to cancer-related fatigue have no specific treatments, and medications capable of improving fatigue might be useful, but none are currently available. I disagree with these concepts. Fatigue may be caused by factors within the muscle cells (like the peripheral fatigue of a stressed cancer patient) or the diminished activation from the CNS (central fatigue derived from proinflammatory cytokines acting in the brain for example), or, alternatively, by abnormal perception within a normal muscular condition (simulating the phenomena that occur in chronic fatigue syndrome).2 Complicating the scenario, most patients showed mixed causes for their fatigue. In central fatigue (motor or perceptual), the serum levels of free tryptophan, the rate-limiting 5-hydroxytryptamine precursor (5-HT or serotonin), are significantly higher at exhaustion and during recovery. These data provide evidence of a possible biochemical mechanism for central fatigue that involves a precursor of 5-HT.3 Moreover, in controlled trials, citalopram, a selective serotonin reuptake inhibitor (SSRI), has improved fatigue symptoms in depressed as well as nondepressed patients.4 Other neurotransmitters may also be involved in the causation of central fatigue. The antiglutamatergic action of amantadine (and its analogs) has been reported as beneficial for the fatigue of patients with multiple sclerosis.5 On the other hand, Bruera et al insist that the potential negative effects of methylphenidate on appetite, anxiety, and insomnia did not worsen, but in fact significantly improved. This conclusion is at odds with 50 years of experience with methylphenidate and is in line with a strong placebo effect, as authors themselves note. Additionally, this study also raises methodological problems. The Functional Assessment for Chronic Illness Therapy (FACIT) scale (cited in reference 14 of their article) is a general quality-of-life (QoL) scale for the patient with cancer, while the Edmonton Symptom Assessment Score (ESAS) scale assesses the intensity of symptoms in patients receiving palliative care. Although in both scales fatigue is important, overall score reflects QoL and stress changes, respectively. Consequently, in order to quantify fatigue, the authors use a 10-point fatigue scale that has not been validated (and is not shown). From it, they state that a decrease of two points is a clinical success. Under these conditions, conclusions about positive achievements in fatigue cannot be sustained. Moreover, readers cannot evaluate possible biases without a brief summary of the fatigue scale, showing at least the means and standard deviations (SDs). Taking into consideration that the normal distribution extends beyond two SDs on either side of the mean, if the mean value of a variable is smaller than twice the SD, the data are likely to be skewed.6 Therefore, valid qualifications are derived from the FACIT and ESAS scales only, which are not specific enough to evaluate fatigue. In conclusion, I am troubled with authors' suggestion, which may lead to the replacement of the most appropriate advice (exercise or other drugs) for fatigued patients, with the quick prescription of methylphenidate. Second, because of the low toxicity shown with the use of citalopram, I think that while further research on the topic progresses, it is beneficial for the fatigued cancer patient to receive these drugs before using a potentially dangerous medication like methylphenidate. Lastly, the likely central message from this work is that the QoL in cancer patients (fatigued or not) can be increased if more attention is delivered by the medical staff, being in daily contact with their patients. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. REFERENCES
1. Bruera E, Barnes EA, Willey J, et al: Patient-controlled methylphenidate for the management of fatigue in patients with advanced cancer: A preliminary report. J Clin Oncol 21:4439-4443, 2003 2. Westerblad H, Allen DG: Recent advances in the understanding of skeletal muscle fatigue. Curr Opin Rheumatol 14:648-652, 2002[CrossRef][Medline] 3. McGuire J, Ross GL, Price H, et al: Biochemical markers for post-operative fatigue after major surgery. Brain Res Bull 60:125-130, 2003[CrossRef][Medline] 4. Hartz AJ, Bentler SE, Brake KA, et al: The effectiveness of citalopram for idiopathic chronic fatigue. J Clin Psychiatry 64:927-935, 2003[Medline] 5. Branas P, Jordan R, Fry-Smith A, et al: Treatments for fatigue in multiple sclerosis: A rapid and systemic review. Health Technol Assess 4:1-61, 2000[Medline]
6. Altman DG, Bland JM: Detecting skewness from summary information. BMJ 313:1200, 1996
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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