Methylphenidate in the Management of Cancer-Related Fatigue
© 2013 by American Society of Clinical Oncology
+ Author Affiliations
- 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.
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest.
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