Anemia may be a major
factor in the development of fatigue. Combined data from three
randomized, placebo-controlled trials of epoetin alfa, the recombinant
form of human erythropoietin, revealed an association between
increased hematocrit and an improvement in overall quality of
life (Abels
et al., 1992). Patients with an increase in hematocrit
of >6% had significant improvement in energy level and daily
activities. Three large, prospective, nonrandomized, multi-center,
community trials (combined N > 6000) similarly observed that
epoetin alfa-treated patients who experienced a rise in hemoglobin
reported significant improvements in energy level, activity
level, functional status, and overall quality of life (Demetri
et al., 1998; Glaspy
et al., 1997; Gabrilove,
2000). These outcomes were independent of antitumor
response. None of these studies had fatigue as a primary endpoint,
and controlled studies that specifically evaluated the effect
of change in hemoglobin on fatigue are clearly justified by
these data.
Other interventions
to reverse common etiologies of fatigue are also candidates
for future trials. Additional examples include a trial of oxygen
therapy for fatigue associated with primary lung disease, a
trial of hormone replacement therapy for fatigue associated
with hypogonadism, and a trial of short-acting hypnotics for
fatigue associated with sleep disorder.
The algorithm for
cancer-related fatigue indicates that symptomatic therapies
may be pharmacologic or non-pharmacologic. Very few of these
interventions have been evaluated in controlled clinical trials.
Psychostimulants, such as methylphenidate, pemoline, and dextroamphetamine,
have been studied for use as a treatment of opioid-related somnolence
and cognitive impairment (Bruera
et al., 1989), and some data suggest the utility
of these drugs as antidepressants (Breitbart
and Mermelstein, 1992). They are often administered
to fatigued patients based solely on clinical observation. Modafinil
is a newer psychostimulant that is also being used for this
purpose. Studies are needed to confirm the efficacy of these
drugs for fatigue, to clarify relative safety and efficacy of
the different drugs, and assess a variety of other clinically-relevant
issues, including dose-response and duration of effect.