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ONLINE EXCLUSIVE
Interferon-Induced Fatigue in Patients
With Melanoma: A Pilot Study of
Exercise and Methylphenidate
Anna L. Schwartz, PhD, FNP John A. Thompson, MD, and Nehal Masood, MD
,
Key Points . . .
Purpose/Objectives: To examine the effect of exercise
and methylphenidate on fatigue, functional ability, and
cognitive function in patients with melanoma.
Exercise and methylphenidate, either alone or in combination,
Design: Pilot study with comparison to historic controls.
may reduce interferon-a-induced fatigue.
Setting: University-based cancer center.
Sample: 12 patients with melanoma entered and com-
Exercise and methylphenidate may lessen the negative impact
pleted the study. The mean age was 44 years.
of interferon-a on cognitive function.
Method: Eligible patients were recruited before their first
Although further study is needed, exercise and methylpheni-
dose of interferon-a (IFN-a). Patients were instructed to take
date may be an effective intervention for management of inter-
20 mg sustained-release methylphenidate every morning
and follow an aerobic exercise program four days a week
feron-a-induced fatigue and, thus, may improve tolerance of
for 1530 minutes. Measures included a 12-minute walk, the
an effective treatment.
Schwartz Cancer Fatigue Scale, Trail Maker Forms A and B,
Medical Outcomes Study 36 Short Form, body weight, and
daily logs. Fatigue scores were compared to usual care his-
therapeutic regimens. Interferon-a (IFN-a) is one of the drugs
torical controls with melanoma receiving only IFN-a.
associated with this dose-limiting side effect (Capuron, Ra-
Main Research Variables: Fatigue, functional ability, and
vaud, & Dantzer, 2000). Although the efficacy of high-dose
cognitive function.
Findings: 66% adhered to exercise and methylphenidate;
IFN-a (i.e., 1020 million IU/m2) in the treatment of mela-
all adhered to exercise. Fatigue was lower for the exercise
noma has been demonstrated, the impact of treatment-related
and methylphenidate group than historic controls. Func-
fatigue is significant and contributes to reductions in the pre-
tional ability increased 6% for all patients and 9% for the ex-
scribed dose during both the induction and maintenance
ercise and methylphenidate group. Cognitive function was
phases of therapy (Kirkwood et al., 1996). Even when sub-
stable for the exercise and methylphenidate group. The
jects change from the IV induction phase to the subcutaneous
exercise-only group showed marked cognitive slowing.
maintenance phase of IFN-a, the effects of fatigue continue to
Conclusions: The combination of aerobic exercise and
influence patient adherence to IFN-a for the duration of treat-
methylphenidate may have a positive effect on fatigue,
ment. Although cognitive deficits were not an outcome measure
cognitive function, and functional ability. A larger sample
size and randomized trial is needed to more rigorously
evaluate the results of exercise and methylphenidate
alone or in combination.
Anna L. Schwartz, PhD, FNP, is an associate professor in the De-
Implications for Nursing: Although further study is
partment of Primary Care in the School of Nursing at Oregon Health
needed, a combination of exercise and methylphenidate
and Science University in Portland; and John A. Thompson, MD, is
may be a practical intervention for patients receiving IFN-
an associate professor, and Nehal Masood, MD, is an acting instruc-
a for melanoma.
tor, both in the Department of Medicine in the School of Medicine
at the University of Washington in Seattle. Funding for this study
was provided by an unrestricted grant from Integrated Therapeutics
ancer treatment-related fatigue is a significant problem
Group/Schering Pharmaceuticals, Inc. Thompson is a member of
C
for the majority of patients with cancer, affecting both
Schering Pharmaceuticals Speakers Bureau. (Submitted September
2001. Accepted for publication February 25, 2002.) (Description of
physical and cognitive function (Atkinson et al., 2000;
specific products and opinions related to those products do not in-
Curt et al., 2000). When examining the incidence of fatigue
dicate or imply endorsement by the Oncology Nursing Forum or the
across different types and stages of cancer and treatment, the
Oncology Nursing Society.)
incidence varies from 40%100% of patients (Atkinson et al.).
Fatigue is a recognized, treatment-limiting side effect of some
Digital Object Identifier: 10.1188/02.ONF.E85-E90
SCHWARTZ VOL 29, NO 7, 2002
E85
Methods
in the Kirkwood et al. study, patients treated with IFN-a have
performed poorly on neurobehavioral function tests (Meyers,
Patients
1999; Pavol et al., 1995), had a syndrome of mood distur-
bance with cognitive slowing, and experienced impaired func-
Twelve patients with histologically documented melanoma
tion (Valentine, Meyers, Kling, Richelson, & Hauser, 1998).
were entered into the study after consenting to participate. Eli-
To improve patient tolerance for high- and moderate-dose (>
gibility criteria included patients who were beginning IFN-a
3 million IU/m2) IFN-a, interventions are needed that will
treatment with a dose of at least five million IU/m2, ambulatory,
minimize side effects, improve quality of life, and potentially
more than 18 years of age, and able to read and write in English.
improve long-term outcomes.
Patients with uncontrolled hypertension; anxiety disorders; ac-
Few interventions for fatigue have been tested formally, al-
tive central nervous system metastasis; hypersensitivity to me-
though exercise has received some attention. Aerobic exercise
thylphenidate; a history of glaucoma, motor tics, or seizure dis-
has a powerful effect on reducing fatigue and improving qual-
orders; or a family history or diagnosis of Tourette's syndrome
ity of life in women with breast cancer receiving adjuvant che-
were excluded from the study. The exclusion criteria were set
motherapy and in patients following bone marrow transplant.
to minimize the risk of side effects from methylphenidate. All
Exercise studies in patients with cancer suggest that aerobic
patients signed a written consent approved by the local institu-
exercise prevents loss in functional capacity and reduces nau-
tional review board and were enrolled before their first dose of
sea, cognitive problems, fatigue, and other quality-of-life issues
IFN-a. Sixteen usual care historic controls receiving IFN-a
(Dimeo, Fletcher, Lange, Mertelsmann, & Keul, 1997; Dimeo,
treatment for melanoma enrolled in an instrumentation study
Stieglitz, Novelli-Fischer, Fetscher, & Keul, 1999; Dimeo,
were used to compare fatigue patterns between usual care pa-
Tilmann, et al., 1997; Mock et al., 1994, 1997; Schwartz, 1998,
tients and those in this study who adhered to exercise and me-
1999, 2000). The psychostimulant methylphenidate is an alter-
thylphenidate or only to exercise.
native pharmacologic intervention for fatigue. Methylphenidate
Intervention
is proposed to reduce fatigue and improve concentration in pa-
tients with cancer (National Cancer Institute [NCI], 2000).
Patients were instructed to take 20 mg sustained-release
Methylphenidate is a drug used to control hyperactivity and
methylphenidate by mouth each morning upon rising. Morn-
attention deficit disorder in children and has been suggested
ing dosing was selected so that the drug would be effective
to have a beneficial effect in controlling fatigue, increasing
during the day and not interfere with sleep at night. Patients
energy, and managing depression in patients with cancer
were given a booklet describing an aerobic exercise program
(NCI, 2000). Methylphenidate's mechanism of action is not
to follow four days a week for 1530 minutes. The duration
understood completely but is believed to increase brain stem
and intensity of exercise gradually increased over the four
and cortical arousal to produce its stimulant effect (Novartis
months of the study. The exercise intensity was limited by
Pharmaceuticals, 2001). Methylphenidate is promulgated
symptoms. Patients were instructed to choose an aerobic ac-
widely as an effective intervention to reduce fatigue and im-
tivity they enjoyed (e.g., walking, running, cycling), slow
prove concentration and cognitive function, although no stud-
down their pace if they experienced increases in fatigue, pain,
ies document its efficacy in the adjuvant IFN-a therapy set-
or other side effects, and stop if the discomfort persisted.
ting (NCI). Psychostimulants have been useful for patients
Instruments
with advanced cancer who express depression, diminished
All patients were assessed for fatigue, functional ability, cog-
concentration, decreased energy, and weakness (Olin &
nitive function, and ability to adhere to the exercise interven-
Masand, 1996; Wilwerding et al., 1995). Methylphenidate has
tion. Measures were completed before the first dose of IFN-a.
demonstrated efficacy in decreasing drowsiness and improv-
ing nighttime sleep in patients with cancer receiving strong
narcotics (Bruera, Miller, Macmillan, & Kuehn, 1992; Por-
Table 1. Sample Characteristics
tenoy, 1989; Wilwerding et al.) or with brain tumors (Meyers,
Weitzner, Valentine, & Levin, 1998). Methylphenidate also
Pilot Subjects
Historic Controls
has been shown to improve neurobehavioral functioning in
N = 12
N = 16
patients with tumor-related organic brain dysfunction (Weit-
%
n
%
Characteristic
n
zner, Meyers, & Valentine, 1995). Dose-limiting side effects
include elevated heart rate and blood pressure and feelings of
Race
nervousness and overstimulation (Novartis Pharmaceuticals).
Caucasian
11
92
16
100
The use of methylphenidate in combination with exercise may
08
Asian
01
prove to have beneficial effects in minimizing the fatigue and
Education
cognitive problems associated with IFN-a.
02
17
08
050
High school graduate
The primary objective of this pilot study was to examine tol-
Some college/techni-
02
17
05
031
erance for treatment, fatigue, functional ability, and cognitive
cal school
08
66
03
019
College graduate
function in patients with melanoma receiving at least five mil-
Employment status
lion IU/m2 of IFN-a three times per week over the first four
08
67
13
081
Full-time
months of treatment. The secondary aims were to determine the
Part-time
01
08
03
019
percentage of patients who adhered to IFN-a treatment, meth-
Retired
03
25
ylphenidate, and the exercise regimen. Researchers in the cur-
Stage of disease
rent study hypothesized that patients who adhered to the exer-
II
02
16
02
012
cise and pharmacologic intervention would have lower levels of
III
10
84
14
088
fatigue and improved functional ability and cognitive function.
ONF VOL 29, NO 7, 2002
E86
Table 2. Changes in Functional Ability Measured in a
data from more than 20,000 patients. The SF-36 was found to
12-Minute Walk
be a reliable (a = 0.70.9) and valid measure of physical and
mental health functioning and has published norms for the
Methylphenidate
general U.S. population (McHorney, Ware, & Raczek, 1993).
and Exercise
Exercise Only
The SF-36 has been used widely to measure quality of life in
patients with cancer during and following treatment (Albert-
--
--
Interval
SD
SD
X
X
sen, Aaronson, Muller, Keller, & Ware, 1997). Physical and
mental function are considered a reflection of a patient's qual-
Baseline
1,143
450
1,046
338
ity of life; quality of life generally is described as multidimen-
One month
1,175
450
1,094
386
Four months
1,257
467
1,104
161
sional. The physical and mental dimensions of quality of life
are aspects that patients commonly say are related to reduced
Note. Distance was measured in meters.
quality of life. This measure was obtained at baseline and
months one and four.
Functional ability was measured using a 12-minute walk.
Body weight was measured to the nearest 0.1 kg and ob-
Patients were asked to walk or run as far and as fast as they could
tained at monthly intervals. Researchers followed up by tele-
for 12 minutes. The 12-minute walk is a reliable and valid mea-
phone at regular intervals (i.e., one week, two weeks, four
sure that is used commonly to study functional exercise ability
weeks, and monthly thereafter) to improve compliance with
in patients with cancer (Cooper, 1968; Larson et al., 1996; Mock
exercise, address barriers to exercise, determine methylpheni-
et al., 1994, 1997; Schwartz, 1999, 2000). The 12-minute walk
date side effects, and assess compliance with the regimen.
is strongly correlated (r = 0.90) with oxygen consumption tested
Data Analyses
in the laboratory (Bernstein et al., 1994). The 12-minute walk
test was conducted at baseline and months one and four.
Descriptive analyses were used to describe the sample and
Daily activity and medication logs were maintained by all
each measure. Patients were defined as adhering to the exer-
subjects for the duration of the study and mailed to the study
cise intervention if they reported exercising at least four days
site at monthly intervals. Information from the logs was used
per week in their exercise logs. Patients were assumed to have
to determine exercise adherence. The logs included informa-
taken methylphenidate if they reported doing so in their logs
tion on duration, intensity, frequency, and effort of exercise
and returned to the clinic for refills. Correlations were exam-
and inquired about missed doses of methylphenidate.
ined between percent change in the 12-minute walk from
The Schwartz Cancer Fatigue Scale, a brief, six-item scale,
baseline to post-test and fatigue and cognitive function. Fa-
is used to measure fatigue on physical and perceptual subscales.
tigue levels of patients in this trial were compared to 16 usual
Scores for the scale then are summed and range from 636. The
care historic control patients with melanoma receiving IFN-
scale has demonstrated content and constructs validity and re-
a. This data was obtained in a multisite fatigue instrumenta-
liability. Cronbach's coefficient alpha for the total scale is 0.90
tion study (Schwartz, 1997).
and is 0.88 and 0.81 for the physical and perceptual subscales,
Results
respectively (Schwartz, 1998; Schwartz & Meek, 1999). Sub-
jects completed the fatigue scale at monthly intervals.
Patient Characteristics
Cognitive function was measured using Trail Maker Forms
A and B. Trail Maker is a good measure of general brain func-
The clinical characteristics of the 12 patients who partici-
tion because it requires recognition of numbers and letters, the
pated in this pilot study and the historic controls are presented
ability to scan an 8.5" x 11" page to identify the next number
in Table 1. Mean age was 44 years (range = 2064). Eighty-
or letter, flexible integration of number and alphabetical series,
four percent of patients had stage III disease. All were newly
and the ability to complete the test under time pressure. Form
diagnosed and had undergone surgery but had not received
A is simpler and requires connecting numbers that are scattered
prior adjuvant therapy for melanoma. Only two patients exer-
over the page. Form B is more challenging and requires the
cised regularly at study entry.
individual to connect numbers and letters in alphanumeric or-
der. The visual scanning tests the right brain hemisphere, nu-
meric and language symbols test the left brain hemisphere, and
36
adequacy of brain function is tested by the speed and efficiency
31
of completion (Reitan, 1955, 1958). Test-retest reliability has
been established in numerous studies (Reitan & Wolfson,
26
Methylpheni-
1992), and recent reports (Form A: r = 0.75; Form B: r = 0.85)
date and exercise
21
Exercise only
support the earlier results (Giovagnoli et al., 1996). Scores are
determined by time; therefore, the faster an individual com-
16
Historic subjects
pletes the tests, the higher his or her cognitive function is. Nor-
11
mal scores on Form A range from 2739 seconds, and Form B
scores range from 6685 seconds. This measure was obtained
6
at baseline and months one and four.
Base-
1
2
3
4
The Medical Outcomes Study 36 Short Form (SF-36)
line
physical functioning and mental health subscales were used as
Months After the Start of Interferon
general measures of function. Scores for each of the subscales
Figure 1. Pattern of Fatigue
range from 0100, with higher scores representing higher lev-
els of functioning. Validity of the SF-36 was determined using
SCFS--Schwartz Cancer Fatigue Scale
SCHWARTZ VOL 29, NO 7, 2002
E87
was in the expected direction (i.e., the more patients exercised,
100
the lower their levels of fatigue would be).
090
080
Cognitive Function
070
Cognitive function scores were normal for all subjects on
060
Methylphenidate
050
and exercise
Trail Maker Form A. Subjects who took methylphenidate
Exercise only
040
maintained a stable level of function (baseline = 30.5 seconds,
030
four months = 31.3 seconds), whereas the exercise-only group
020
declined in cognitive function from a mean at baseline of 23
010
seconds to 28 seconds at four months. Increasing time to
000
Base-
1
2
3
4
completion of the Trail Maker Forms indicates declining cog-
line
nitive function.
The majority of subjects' scores were in the normal range
Months After the Start of Interferon
(i.e., 6685 seconds) on Trail Maker Form B. At baseline, the
Figure 2. Physical Functioning Subscale Scores on the
methylphenidate group's mean score was 67.1 seconds and
Medical Outcomes Study 36 Short Form
69.8 seconds at four months. However, a decline in cognitive
SF-36--Medical Outcomes Study 36 Short Form
function --   identified among the exercise-only group
was
--
(baseline X = 72.6 seconds, four months X = 82.6 seconds).
The 82.6-second score at the four-month interval is considered
Treatment
borderline impaired. Two of the exercise-only subjects' scores
All patients (N = 12) exercised for four months, and eight
suggested mild to moderate cognitive impairment. These pa-
patients also took methylphenidate. Three patients (25%) vol-
tients' scores exceeded 86 seconds on Trail Maker Form B. An
untarily discontinued methylphenidate within 48 hours of be-
inverse correlation was identified between percent change in the
ginning the drug. One patient complained of indigestion, an-
12-minute walk and scores on Trail Maker Forms A (r = 0.64,
other complained of mild nervousness, and one chose to stop
p = 0.04) and B (r = 0.67, p = 0.05), which suggests a possible
taking the methylphenidate because she was taking too many
relationship between higher levels of exercise and improved
medications. A fourth patient returned for a follow-up appoint-
cognitive function (i.e., lower scores on Trail Maker). Taking
ment after one week with marked anxiety and was withdrawn
methylphenidate was correlated with improved performance on
from the methylphenidate. Although 33% of the sample
Trail Maker Form B at four months (r = 0.85, p < 0.001).
stopped taking methylphenidate within the first week of the
Physical and Mental Function
study, only one of the four patients appeared to experience side
All subjects taking methylphenidate reported that they con-
effects from the medication. The remaining eight subjects took
the methylphenidate throughout the study. The four patients
tinued to work and maintain their usual activities over the study
period. This contrasts the exercise-only group that unanimously
who stopped taking the methylphenidate but continued to ex-
reported disruptions in their activity and work patterns.
ercise remained in the study as an exercise-only group.
Exercise adherence was remarkable in this sample. All pa-
Scores on the physical functioning subscale of the SF-36
--
ranged from a high at baseline (methylphenidate group X =
tients (N = 12) reported exercising at least four days a week
--
87.5, exercise-only group X = 76.6)-- a low at the end of four
to
for at least 15 minutes in their exercise logs, and all demon-
month-- (methylphenidate group X = 76.7, exercise-only
strated improvements in their functional ability.
s
group X = 43.7). The scores for those who took methylpheni-
Functional Ability
date declined by 12.4%, whereas the scores for the exercise-
Functional ability increased an average of 6% for all sub-
only participants declined by 43%. The level of physical func-
jects (see Table 2). Greater improvements in functional abil-
tioning for the exercise-only group was lower at baseline and
ity were observed in the patients who also took methylpheni-
--
date (X = 9%). Because the sample was small, no statistical
differences were observed in functional ability between those
100
who took and those who did not take methylphenidate.
090
080
Fatigue
070
Fatigue scores on the Schwartz Cancer Fatigue Scale demon-
060
Methylphenidate
strated modest increases over the course of four months. When
050
and exercise
040
fatigue scores of usual care historic controls were compared to
Exercise only
030
results from this sample, exercise alone may have reduced fa-
020
tigue and the combination of exercise and methylphenidate may
010
have had a striking effect on the pattern of fatigue over time (see
000
Figure 1). The effect of exercise and perhaps methylphenidate
1
2
3
4
Base-
reduced fatigue scores and changed the daily pattern of fatigue
line
to be more regular and less chaotic (Schwartz, 2000) for all
Months After the Start of Interferon
patients in this pilot study compared to the historic control pa-
Figure 3. Mental Health Subscale Scores on the
tients. Although percent change on the 12-minute walk from
Medical Outcomes Study 36 Short Form
baseline to post-test was not significantly correlated with fatigue
scores of patients (r = 0.30, p = 0.56), the inverse correlation
SF-36--Medical Outcomes Study 36 Short Form
ONF VOL 29, NO 7, 2002
E88
trial is needed to determine the effects of exercise and meth-
Table 3. Differences in Body Weight in Kilograms
ylphenidate alone and in combination.
Between the Methylphenidate and Exercise Groupa
Methylphenidate is recommended for reducing fatigue and
and the Exercise-Only Groupb
improving concentration and attention. Similar to findings of
Methylphenidate
patients with organic brain dysfunction (Weitzner et al., 1995),
and Exercise
Exercise Only
methylphenidate in the current study's sample appeared to help
patients maintain relatively stable cognitive function. Changes
--
--
SD
SD
p
Interval
t
X
X
in attention and cognitive function have not been reported pre-
viously in patients with melanoma receiving IFN-a, so it is not
Baseline
87.2
17.5
85.0
17.8
0.86
0.185
possible to speculate to what extent exercise or methylphenidate
One month
85.5
16.5
78.5
19.5
0.56
0.600
may have affected physical or mental functioning.
79.1
15.2
76.8
17.7
0.70
Four month
0.396
Cognitive dysfunction is recognized as a serious side effect
a
N=8
of therapy that affects memory and ability to work (van Dam
b
N=4
et al., 1998). Negative effects of IFN-a therapy have been
noted in patients with leukemia who perform below expecta-
tions on neurobehavioral tests (Pavol et al., 1995). With the
continued to demonstrate declines in physical functioning
exception of a few studies about attentional fatigue (Cimprich,
over time. In contrast, those taking methylphenidate demon-
1992, 1998, 1999) and small studies of neurobehavioral defi-
strated some improved functional ability at months two
cits (Meyers & Weitzner, 1995; Pavol et al.), little research
through four (see Figure 2). Mental health scores also differed
--
has been conducted to examine changes in attention and cog-
for the two groups at  --
baseline (methylphenidate group X = 74,
nitive function. However, exercise and methylphenidate may
exercise-only group X = 69). However, both groups showed a
alleviate some of the psychomotor retardation associated with
gradual decline in mental health over time with four-month
IFN-a therapy in patients with melanoma. Measuring levels
mean scores of 70 for the methylphenidate group (6% decline)
of depression may have added insight into the relationship
and 58 for the exercise-only group (16% decline) (see Figure 3).
among cognitive dysfunction, fatigue, and depression.
Body Weight
Although the results of this pilot study are intriguing, signifi-
cant limitations exist that only can be addressed with a random-
Both groups lost weight over the four months: Those who
ized trial to rigorously evaluate the efficacy of exercise and
took methylphenidate, on average, lost 8.1 kg, and the exercise-
methylphenidate, alone and in combination, on side effect fre-
only group, on average, lost 8.2 kg (see Table 3). The weight
quency and intensity and tolerance for treatment. The limita-
loss observed was consistent with the degree of weight loss com-
tions of this study include its small sample size, lack of random-
monly noted in patients receiving comparable doses of IFN-a.
ization, and lack of depression measure. Future studies should
consider a methylphenidate regimen with provisions for dose
Discussion
escalation and reduction and a lower starting dose of meth-
ylphenidate (e.g., 10 mg daily) to reduce the drug's side effect
This pilot study was designed in an attempt to improve tol-
profile. In addition, interesting clinical evidence supports the
erance to IFN-a treatment. Because of the small sample size
examination of selective serotonin reuptake inhibitors (SSRIs)
and nonrandomized design, the results need to be interpreted
in the management of fatigue and depression associated with
with caution. Although fatigue is recognized as a severe and
IFN-a therapy. SSRIs, such as Effexor (venlafaxine, Wyeth-
dose-limiting side effect of IFN-a therapy, the combination of
exercise and methylphenidate appears to have a positive effect
Ayerst, Philadelphia, PA), may reduce fatigue by acting on both
norepinephrine and serotonin reuptake and enhancing seroto-
on functional ability, fatigue, and cognition. Exercise has a
nin neurotransmission (Stahl, 1998). The information gained
strong effect on reducing fatigue in patients with breast cancer
and patients receiving peripheral stem cell transplants (Dimeo,
from future neurobehavioral and quality-of-life studies may im-
Fletcher, et al., 1997; Dimeo, Tilmann, et al., 1997; Mock,
prove the functioning of patients during treatment and, ulti-
mately, affect survivorship.
1994, 1997; Schwartz, 1998, 1999, 2000). In this small sample,
exercise appeared to reduce fatigue and have a positive effect
The authors gratefully thank Lillian Nail, PhD, RN, FAAN, for her
on cognitive function. For the few patients who did not take
thoughtful review and critique and Integrated Therapeutics Group/
methylphenidate, exercise may have contributed to lower lev-
Schering Pharmaceuticals, Inc., for unrestricted educational support
els of fatigue than were reported in historic controls. Meth-
of this work.
ylphenidate may have a positive effect on exercise adherence,
which may influence other variables, such as functional ability,
Author Contact: Anna L. Schwartz, PhD, FNP, can be reached at
fatigue, cognitive function, and perhaps even overall tolerance
s c h w a r t a @ o h s u . e d u , with copy to editor at rose_mary@
for treatment. However, a larger sample size and randomized
earthlink.net.
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