Methylphenidate in the Management of Cancer-Related Fatigue

1. Patrick C. Stone⇑

+ Author Affiliations

1. St George's University of London, United Kingdom

1. Corresponding author: Patrick C. Stone, St George's University of London, 6th Floor Hunter Wing, Cranmer Terrace, London, United Kingdom, SW17 ORE; e-mail: pstone@sgul.ac.uk.

Cancer-related fatigue (CRF) is increasingly recognized as a significant problem for patients at all stages of the cancer journey¹ from diagnosis through treatment,^2–4 in disease-free survival,⁵ and in end-stage disease.⁶ Cross-sectional studies have reported that CRF causes patients more distress than pain or nausea and vomiting.^7,8 For many years, fatigue was not taken seriously by the research community, and few randomized controlled trials were undertaken to determine the most effective ways to manage this symptom. However the evidence base, although still relatively small, is now rapidly growing. A Medline search for randomized controlled trials using the key words “fatigue” and “neoplasms” produced only seven articles between 1993 and 2001, but the same search criteria returned 71 articles published between 2002 and 2012. Systematic reviews have summarized the evidence for the effectiveness of pharmacologic,^9,10 exercise-based,¹¹ and psychosocial¹² interventions.

Of the different pharmacologic interventions that have been evaluated to date, the most promising agent appears to be methylphenidate. A systematic review and meta-analysis¹³ of randomized controlled trials of psychostimulants for CRF identified five studies (four of which related to methylphenidate). Although only one of the studies¹⁴ showed a significant benefit for methylphenidate, the meta-analysis found that the overall standardized mean difference for psychostimulants was −0.28 (95% CI, −0.48 to −0.09; P = .005). The review concluded that further evaluation of methylphenidate was needed. The study by Bruera et al¹⁵ that accompanies this editorial is therefore to be welcomed as another piece of evidence in the hunt for a successful treatment for CRF.

Bruera et al¹⁵ have undertaken a double-blind, randomized controlled trial in which participants received either methylphenidate 5 mg every 2 hours up to 20 mg/d or a matching placebo (plus either a nursing telephone intervention or a nontherapeutic control call). All participants had CRF (fatigue score ≥ 4 of 10) and advanced cancer. At the completion of the 2-week study period, there was no difference in fatigue scores between participants who had received methylphenidate and those who had received placebo. In addition to assessing the effectiveness of a pharmacologic agent, Bruera et al have made a serious attempt to untangle the specific and the nonspecific effects of a “talking” therapy. A previous study by Bruera's team¹⁶ had suggested that simply having regular contact with a trained nurse had symptomatic benefits for trial patients. The current study found that a call from a trained nurse was no better at managing fatigue than a control (nontherapeutic) telephone call from a nonprofessional staff member. This underlines the importance of controlling for attention in assessing the effectiveness of psychosocial interventions.

Bruera and colleagues' finding that methylphenidate was ineffective in the management of CRF is supported by another recently published study¹⁷ which similarly failed to find a significant benefit over placebo. Despite the earlier promising findings from systematic reviews, should we now conclude that methylphenidate has no role to play in the management of CRF and that further investigation is no longer warranted? The evidence against methylphenidate is certainly beginning to accumulate, but it is probably a little premature to conclude that this agent is completely without merit. A number of questions about its possible effectiveness still remain.

First, it should be noted that the study by Bruera et al¹⁵ evaluated the use of an “as needed” dosing schedule for methylphenidate (5 mg every 2 hours up to 20 mg/d). Although participants were at liberty to take up to four capsules per day, in fact they only took a median of 18 capsules over the whole 2-week intervention period (an average daily consumption of approximately 6.4 mg/d). This is a relatively low dose of methylphenidate and possibly explains the lack of both positive effects and adverse events reported by patients in the intervention group. In contrast, the study by Lower et al,¹⁴ which reported a positive benefit, used a mean highest daily dose of 27.7 mg of the d-isomer of methylphenidate. In order to receive an equivalent dose of methylphenidate, the participants in the Bruera et al study would have needed to have consumed approximately 5.5 ×5 mg capsules of methylphenidate per day rather than the approximately 1.5 capsules per day that they actually consumed. However it should be noted that the lack of effectiveness reported by Bruera et al is further supported by the findings of Moraska et al.¹⁷ In a randomized controlled trial in fatigued patients with cancer, they evaluated the effectiveness of a high-dose racemic preparation of slow-release methylphenidate (delivering 27 mg/d of the d-isomer). They failed to find any differences in overall fatigue between the two treatment groups. The primary outcome in the Lower study was the difference in fatigue score between the two groups after 8 weeks of treatment, whereas efficacy was assessed at 2 and 4 weeks, respectively, in the Bruera and Moraska studies. It is possible therefore that the failure of both Bruera and Moraska to find any benefits for methylphenidate may have been due to either underdosing, short duration of treatment, or a mixture of both.

A second reason for caution before declaring methylphenidate to be completely ineffective in CRF is the potential heterogeneity of study populations. There is no international consensus as to what constitutes CRF. This means that different investigators may be studying the effectiveness of trial drugs in widely differing populations. CRF sometimes simply refers to the fatigue associated with having a cancer diagnosis,¹⁸ and more commonly it refers to treatment-related fatigue caused by chemotherapy,¹⁹ radiotherapy,²⁰ or combination therapy.⁵ Sometimes it refers to post-treatment fatigue in disease-free survivors,² and at other times it refers to off-treatment fatigue in patients with advanced disease.⁶ In the study by Lower et al,¹⁴ all participants met the proposed criteria for CRF syndrome.²¹ Other studies have identified suitable subjects for inclusion in clinical trials by their score on a simple 11-point (0-10) numerical rating scale of fatigue severity.^17,22 A score of ≥ 4 (of 10) is recommended by the National Comprehensive Cancer Network as a screening tool for identifying patients with at least moderate fatigue severity. The main conclusion of Moraska et al¹⁷ was that methylphenidate was ineffective; however, patients with advanced disease or more severe fatigue did significantly better than patients overall. Similarly, a large study (n = 867) of patients receiving chemotherapy²³ reported that although a non–amphetamine-based psychostimulant (modafanil) was not effective in unselected patients, it was effective at relieving fatigue in those patients with the most severe symptoms (≥ 7 of 10 on a numerical rating scale).

It is also likely that effective treatments for CRF will vary depending on the underlying mechanism by which the symptom is generated. A greater understanding of the underlying pathophysiology of CRF may lead to the identification of subtypes that are more responsive to specific modes of treatment. For instance, in the context of pain pharmacotherapy, it is known that neuropathic, bony, and visceral pains respond to different classes of analgesics, and it would make little sense to study the effectiveness of a new investigational agent without clearly defining the type of pain that was being assessed. In the same way, it may be that some interventions for CRF will work only in certain subtypes of CRF. For instance, the effectiveness of exercise may vary depending on whether patients are treated during or after treatment.²⁴

Further improvements in the management of CRF fatigue will need to go hand in hand with a greater understanding of the underlying mechanisms of this symptom and preferably with an international consensus about the best way to identify homogenous populations for inclusion in research studies.²⁵ The increasing number of randomized controlled trials in this area is an encouraging sign for the development of evidence-based palliative care. 

 © 2013 by American Society of Clinical Oncology