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The Management of Fatigue in Cancer Patients

The Management of Fatigue in Cancer Patients

ABSTRACT: Severe, debilitating fatigue is common in cancer patients. For many, it is the symptom that interferes most with normal routines. Virtually every modality used to treat cancer may cause fatigue, as can complications of the disease such as sleep disturbances, infections, malnutrition, hypothyroidism, and anemia. There is a significant overlap between depression and fatigue in many patients. Given the high prevalence of cancer-related fatigue, frequent assessment of patients is essential. The evaluation should include an attempt to identify reversible causes of fatigue, and screening for depression. However, many cancer patients suffer from fatigue even in the absence of any identifiable, reversible cause. For these patients, consideration can be given to suitable exercise programs, educational support and counseling, and energy conservation strategies. A trial of a stimulant medication is also reasonable. Given the heterogeneity of patients, individualized approaches are needed. For anemic patients undergoing chemotherapy, erythropoietic agents can increase hemoglobin levels. The impact of these drugs on fatigue and quality of life is uncertain. Recent reports of increased mortality and thrombotic events in cancer patients treated with epoetin require further investigation.

Fatigue is a complex, subjective
experience that defies facile definition.
Roget's Thesaurus offers
30 synonyms for fatigue used as
a verb, and 18 as a noun. Despite
ambiguities in terminology, a large
proportion of cancer patients, when
asked, report unambiguously that they
are fatigued. Furthermore, cancerrelated
fatigue differs from the common
variety in that it is unrelieved by
rest and interferes with routine activity.
In some contexts, fatigue appears
to be the most prevalent cancer symptom,
as well as the most troublesome
to patients.[1]

The material presented below represents
a summary and selective update
of a recent evidence report on
cancer-related fatigue prepared for the
Agency for Healthcare Research and
Quality (AHRQ) at the request of the
National Institutes of Health (NIH).[2]
The purpose of the evidence report
was to provide a comprehensive overview
of published studies on the occurrence,
assessment, and treatment
of cancer-related fatigue for a Stateof-
the-Science Conference on cancer
symptoms convened by the NIH in
2002.

Etiology of
Cancer-Related Fatigue

The pathophysiology of the debilitating
fatigue experienced by cancer
patients is poorly understood. In some
instances, fatigue is temporally related
to treatments such as chemotherapy,
hormonal therapy, or radiotherapy,
resolving spontaneously after their
completion. Other causative or contributing
etiologic factors can sometimes
be identified (eg, infections,
malnutrition, depression, endocrine
disorders, anemia). The extent to
which cancer-related fatigue can be
attributed to cancer treatment or to
identifiable complications is unknown.
It seems certain, however, that
many cancer patients suffer from
pathologic levels of fatigue for which
no obvious cause is evident. This is
also undoubtedly the case in some
subsets of cancer survivors.

It has been hypothesized that otherwise
unexplained cancer-related fatigue is mediated by inflammatory
cytokines, gonadal dysfunction, or disruption
in sleep patterns.[3] There is
limited evidence to support the hypothesis
that any of these factors is a
predominant cause of fatigue. The etiology
of cancer-related fatigue is probably
multifactorial, and the term
fatigue actually encompasses a wide
array of related syndromes. Research
on the etiology of cancer-related fatigue
is hampered by a paucity of animal
models and human studies
assessing putative biologic correlates
of fatigue.

Cancer-related fatigue is frequently
associated with other cancer symptoms,
particularly pain and psychological
distress. It is unclear whether
these clusters of symptoms have a
common, underlying etiology, or
whether they exacerbate one another.

Occurrence of Cancer-Related
Fatigue

Estimates of the percentage of cancer
patients affected by fatigue are
highly variable, ranging from 4% to
91% depending on the population
studied and the methods of assessment
employed.[4-30] The majority
of studies in which the occurrence
rate of cancer-related fatigue was a
defined end point have focused on
relatively small cohorts of patients at
referral centers. These studies may
underestimate the true burden of cancer-
related fatigue, since the patients
most affected by it may have been
unable to participate.

Case-control studies[15,16,19,23,
25] suggest that levels of fatigue in
cancer patients almost always exceed
that of people without cancer. No longitudinal
studies have tracked the
course of cancer-related fatigue over
successive phases of illness, treatment,
and remission. Despite these limitations,
a clearer picture is emerging of the prevalence and impact of cancerrelated
fatigue in various diseases and
treatment settings. The occurrence of
fatigue has been evaluated during
treatments, near the end of life, and in
cancer survivors. To date, no studies
have examined fatigue as a presenting
symptom of cancer. Data on the
occurrence of fatigue in children and
the elderly with cancer are quite limited.[
28,31]

Chemotherapy, radiation therapy,
combined-modality treatment, and biologic
and hormonal therapies have
all been found to exacerbate fatigue.[
4,5,7-10,12,14,15,17,18,24,30]
The lowest rate of fatigue was reported
in women with early-stage breast
cancer prior to chemotherapy (4%).
After four cycles of treatment, 28%
were fatigued.[15] Similarly, fatigue
rates rose from 8% at baseline to 25%
after the completion of radiotherapy
in men with localized prostate cancer.[
18]

A decline in fatigue with treatment
was reported in only one context. In a
cohort of 127 patients with small-cell
lung cancer, the proportion with moderate
to severe fatigue declined slightly
during chemotherapy, from 43% to
30%-37%.[5] All other disease symptoms
were relieved, however, presumably
due to the responsiveness of
small-cell carcinoma to chemotherapy.
As a result, fatigue was the most
prevalent symptom over the course of
treatment. This study was one of a
very few that attributed fatigue to disease
or treatment factors-43% of the
burden of fatigue was ascribed to disease
symptoms, and 37% to the effects
of treatment.

In patients on palliative care services,
fatigue is highly prevalent, with
48% to 75% suffering from severe or
clinically important fatigue, even in
the absence of chemotherapy or radiotherapy.[
6,19,29] Fatigue is also
reported by 17% to 56% of cancer
survivors, months or years after the
completion of treatment.[11,13,16,20-
23,27] Only one study found a rate of
fatigue in survivors that was no higher
than that in a noncancer control
group.[13] The largest study, involving
1,957 breast cancer survivors,
found that 35% of subjects had fatigue
in the disability or limitation range, using an instrument for which
norms in noncancer subjects are well
established.[20] Even at a mean of 12
years after treatment, 26% of 459
Hodgkin's disease survivors were
found to be fatigued.[16] Little is
known about the cause of this persistent
phenomenon.

Assessment of Cancer-Related
Fatigue

Heterogeneous methods have been
used to assess cancer-related fatigue,
including visual-analog scales, Likert
scales, nonvalidated questionnaires,
and, especially in the more contemporary
studies, sophisticated instruments
that captured multiple aspects
of fatigue.[2] While most of the instruments
currently employed for research
purposes are psychometrically
valid and reliable, the clinical significance
of what they measure remains
somewhat obscure. The definitions of
fatigue and the grading of its severity
are quite variable, and therefore comparison
of the reported rates of cancer-
related fatigue in different studies
is problematic. Diagnostic criteria for
cancer-related fatigue have been proposed
but have not yet been widely
adopted.[27]

The approach to clinical assessment
of cancer-related fatigue is empiric.
The National Comprehensive
Cancer Network (NCCN) guidelines
for assessment and management of
cancer-related fatigue[32] recommend
the use of simple verbal (mild, moderate,
severe) or numeric (0-10)
scales. If moderate or severe fatigue
(corresponding to a score > 3/10) is
reported, then the time course, associated
symptoms, and impact on functioning
should be elicited.

The evaluation should focus on the
identification of reversible factors
known to be associated with cancerrelated
fatigue, eg, pain, emotional
distress, hypothyroidism, sleep disturbance,
and anemia. If none of these
is present, or if fatigue persists despite
reversal of potential causes, an
in-depth evaluation is indicated, including
a review of systems, review
of medications, nutritional and metabolic
evaluation, and assessment of
activity level. As with pain and other symptoms, frequent reassessment is
essential to evaluate the impact of therapeutic
interventions. These recommendations
represent the consensus
of a panel of experts but have not
been evaluated prospectively.

Treatment of Cancer-Related
Fatigue
Nonpharmacologic Approaches
Several randomized controlled trials,
recently reviewed by Mock,[33]
indicate that exercise is beneficial in
the treatment or prevention of fatigue
in cancer patients and cancer survivors.
Although the numbers of subjects
in these studies were
small,[52-135] the impact of exercise
was pronounced, with reduction in
fatigue typically in the 40% to 50%
range. Improvements in overall quality
of life were noted in three out of
four studies. Numerous nonrandomized
studies also suggest that exercise
has beneficial effects on cancer-related
fatigue.

Certain caveats regarding these
data should be noted. The participants
in these studies were probably highly
selected and motivated, resulting in
good adherence to the exercise programs.
The majority of exercise trials
focused on patients with early-stage
cancer, particularly breast cancer, although
benefits were also observed in
patients with prostate cancer and other
malignancies. Exercise programs
must be individualized; some types
may present risks for patients with
severe cytopenias, bone metastases,
compromised pulmonary function, or
cardiovascular disease. No sham-controlled
studies have been performed
(in fact, it is difficult to imagine how
they could be designed). One cannot
exclude the possibility that some of
the reported benefits of exercise represent
a placebo effect. However, it
can be argued that the distinction between
a placebo effect and a "real"
improvement in a subjective symptom
such as fatigue is meaningless
when the intervention has negligible
risks and cost.

Sleep disturbances may be a prime
cause of fatigue in some patients.[34]
Mood disorders, pain, cough, and other
symptoms may disrupt sleep. Even
when the duration of sleep is adequate
or increased, sleep patterns may
be aberrant, leading to disturbances
in circadian rhythms. Some evidence
suggests that energy conservation
strategies may improve sleep patterns
and daytime functioning in patients
with cancer-related fatigue.[35] The
impact of sedatives in cancer patients
suffering from disordered sleep has
not been studied.

Debilitating fatigue may contribute
to the high incidence of depression
in cancer patients. Conversely,
in some patients the vegetative symptoms
of depression may exacerbate
fatigue. The vicious cycle of depressive
symptoms and fatigue has not
been explored in detail, but, not surprisingly,
strong correlations between
mood states and fatigue have been reported
in numerous studies.[20,22,36-
42] In some cases, psychological
distress appears to be the single most
powerful predictor of fatigue.

There is evidence that behavioral
or psychological interventions may
ameliorate fatigue.[33] Support
groups, individual counseling and education,
and psychotherapy have been
reported to reduce cancer-related fatigue.[
2] However, studies of these
interventions have generally been
small and of limited applicability. Given
the multiple etiologies of cancerrelated
fatigue, and the cultural and
psychological diversity of those who
suffer from it, no single approach is
likely to be helpful in all patients.

Pharmacologic Approaches

  • Traditional Stimulants-Since
    the pathophysiology of cancer-related
    fatigue remains obscure in many
    cases, pharmacotherapy is either empiric,
    or geared toward reversing possible
    contributing factors. Stimulant
    medications such as methylphenidate
    and dextroamphetamine are probably
    the most widely prescribed medicines
    for cancer-related fatigue when no reversible
    cause is evident. Methylphenidate
    has been shown to
    ameliorate fatigue in people with
    AIDS.[43] In cancer patients, small
    crossover studies suggest a benefit,
    and larger randomized controlled trials
    are ongoing.

    The adverse effects of these medicines
    are a concern, however. Anorexia
    and irritability are common, and
    hypertension, tachycardia, and arrhythmias
    may occur. There is some evidence
    that these medications lower the
    seizure threshold. Methylphenidate inhibits
    the metabolism of warfarin and
    some anticonvulsants. Pemoline has
    central nervous system (CNS) effects
    similar to the other stimulants but lacks
    sympathomimetic effects. Its interactions
    with other medications have not
    been well studied.

  • Modafinil-Modafinil (Provigil)
    is a wakefulness-promoting agent that
    has been approved for use in narcolepsy.
    Its mechanism of action is unknown,
    but it is not a sympathomimetic
    agent and does not appear to
    act on dopaminergic pathways in the
    brain. The drug lacks the cardiovascular
    and hemodynamic effects of the
    conventional psychostimulants. It has
    been studied in fatigue associated with
    sleep deprivation and in multiple sclerosis.
    Randomized controlled trials of
    modafinil for cancer-related fatigue
    are ongoing.
  • Paroxetine-Based in part on the
    observation that cancer-related fatigue
    and depression frequently coexist, a
    common etiology involving synaptic
    5-hydroxytryptamine levels has been
    hypothesized. This hypothesis was the
    basis for a randomized controlled trial
    of the selective serotonin-reuptake
    inhibitor (SSRI) antidepressant paroxetine
    in patients with cancer-related
    fatigue.[44] Subjects reporting
    fatigue after two cycles of chemotherapy
    were randomly assigned to
    20 mg of paroxetine daily (n = 277),
    or placebo (n = 272). Of note, 32% of
    patients in both arms had significant
    depressive symptoms at baseline, and
    half reported fatigue scores ≥ 5 on a
    10-point scale. As in numerous other
    studies, depression and fatigue correlated
    strongly. After four cycles of
    chemotherapy, those receiving paroxetine
    had significantly lower mean
    levels of depression, but paroxetine
    had no impact-either positive or negative-
    on fatigue. Even in the subgroup
    of patients who were depressed,
    there was no improvement in fatigue
    with paroxetine.

    This study was one of a very few
    adequately powered, rigorously designed
    drug trials for cancer-related
    fatigue. The findings strongly support
    screening and treating cancer patients
    for depression, but the impact
    of this treatment on fatigue was disappointing.
    It is possible that the acute
    fatigue induced by chemotherapy is
    so overwhelming that it is not amenable
    to such an approach. Antidepressants
    might have a greater effect on
    fatigue in cancer survivors, in whom
    fatigue and depression are prevalent
    and frequently coexist.

  • Miscellaneous Drugs-Other
    agents currently being investigated for
    treatment of cancer-related fatigue include
    L-carnitine and infliximab
    (Remicade).
  • Erythropoiesis-Stimulating
    Agents-
    There is little doubt that recombinant
    human erythropoietin
    (rHuEPO, epoetin alfa [Epogen, Procrit]
    and epoetin beta) and the related
    compound darbepoetin (Aranesp)
    stimulate erythropoiesis and reduce
    the likelihood of red blood cell transfusion
    in cancer patients undergoing
    chemotherapy.[45] The impact of
    these treatments on quality of life and
    symptoms (including cancer-related
    fatigue) is less well established. A trend
    toward increased survival with recombinant
    erythropoietin has been reported
    in some studies; however, several
    recent reports have raised concerns
    about increased thrombotic events, accelerated
    tumor growth, and decrements
    in survival in cancer patients treated
    with such agents.[46-49]

The Data on
Erythropoietic Agents

In a meta-analysis of 12 randomized
controlled trials involving 1,390
patients undergoing cancer treatment,
the combined odds ratio for transfusion
with rHuEPO, compared with placebo
or no treatment, was 0.38 (95%
confidence interval [CI] = 0.28-0.51).
The number of patients who would need
to be treated with rHuEPO to prevent
one patient from being transfused was
4.4 (95% CI = 3.6-6.1). The higherquality
studies indicated a less robust,
although still statistically significant
effect, with one patient avoiding transfusion
for every five to six patients
treated with rHuEPO. The transfusionsparing
effect of rHuEPO seems to be
similar in patients with hemoglobin levels
less than or greater than 10 g/dL.[45]

Despite the findings that some patients
treated with recombinant erythropoietin
can avoid transfusion, it
remains unclear whether this treatment
is associated with improvements
in symptoms or quality of life. The
American Society of Clinical Oncology
(ASCO) and the American Society
of Hematology (ASH) have issued
evidence-based guidelines for the use
of rHuEPO in patients with cancer.[
50] The guidelines are based on
a comprehensive, systematic evidence
report on this topic published by
AHRQ.[51] Both the ASH/ASCO
guidelines, and the AHRQ evidence
report on which they are based, failed
to find convincing evidence for symptomatic
improvements in patients
treated with rHuEPO.

Several large, community-based
clinical trials of epoetin, involving
over 7,000 subjects in total, have reported
quality-of-life benefits correlating
with increases in hemoglobin
levels in patients undergoing chemotherapy.[
52-54] However, these studies
were nonrandomized, open-label,
single-arm studies, and thus subject
to a placebo effect. There was substantial
dropout of patients due to
death, intercurrent illness, progressive
disease, discontinuation of treatment
and other causes. Tumor response was
a confounding factor in these studies,
affecting both quality of life and, potentially,
hemoglobin levels. Although
in some cases investigators took into
account the impact of tumor response,
the interpretation of these studies is
hampered by the assumptions that
were made in their analyses to account
for nonrandom, missing
data.[51]

Randomized Controlled Trials
The effects of any treatment on
symptoms or quality of life are optimally
assessed in randomized, controlled
studies. At least nine such
studies of recombinant erythropoietin
have been published[51]; several others
remain unpublished. All but one
of the published randomized controlled
trials were small and reported
very limited data on quality of life,
fatigue, or other symptoms. Their applicability
is generally quite low.

Only one adequately powered,
double-blind, randomized, placebocontrolled
trial of the effects of
rHuEPO on fatigue and quality of life
in patients undergoing chemotherapy
has been published.[55] Patients were
randomly assigned to receive placebo
(n = 124) or rHuEPO (n = 251) subcutaneously
three times per week. Patients
were required to have a hemoglobin
level ≤ 10.5 g/dL, or 10.6 to 12
g/dL with a decline of ≥ 1.5 g/dL per
cycle of chemotherapy. The primary
end point in the trial was the proportion
of patients transfused after 4
weeks. Quality of life was assessed
using the Functional Assessment of
Cancer-Anemia (FACT-An) instrument
(which contains a fatigue subscale),
the Medical Outcomes Short
Form-36 (SF-36), and a Linear Analog
Scale Assessment.

Hematologic response to rHuEPO was consistent with the results of prior
studies: The proportion of patients
requiring transfusion after day 28 was
reduced by 14.8% (P = .0057). The
mean increase in hemoglobin from
baseline to final measurement was 2.2
g/dL in the rHuEPO arm, and 0.5
g/dL in the placebo arm, despite greater
use of transfusion in those receiving
placebo. It should be noted,
however, that the change in hemoglobin
was not reported on an intentionto-
treat basis.

The investigators found a statistically
significant difference in the mean
change on the fatigue subscale of the
FACT-An, favoring rHuEPO over placebo.
Significant advantages for
rHuEPO were also observed in scores
on the FACT-G, Linear Analog Scores
for Energy, Ability to do Daily Activities,
and Overall QOL scales. Nonsignificant
trends in quality-of-life
improvement favoring rHuEPO were
observed on the SF-36. This study is
frequently cited as providing the most
robust evidence for an impact of recombinant
erythropoietin on fatigue
and quality of life. However, its conclusions
are open to question for a
number of reasons.

A higher proportion of patients in
the placebo arm had received transfusions
within 3 months prior to starting
the study (36% vs 28%),
suggesting that they may have had
impaired hematopoiesis, despite similar
mean baseline hemoglobin levels
in the two groups. Baseline data on
important prognostic factors for quality
of life, such as performance status
and weight loss, were not reported.
Hence, one cannot assume that the
two arms were well balanced for these
factors. Indeed, no baseline data was
reported on any of the quality-of-life
measures used in the study; the results
were reported only as changes
from baseline.

Transfusions were permitted at the
discretion of the physician but were
to be avoided unless the hemoglobin
was < 8 g/dL. Thus, patients were
allowed to become significantly anemic.
More reasonable transfusion support
may have resulted in improved
quality of life and less fatigue in the
placebo group, and consequently attenuated
the observed differences between placebo and treatment.

In addition, the analysis of symptoms
and quality of life was not based
on an intention to treat. Twenty-six
patients were excluded from this analysis
because of missing data. FACTAn
and SF-36 data were missing for
an additional 54 patients because validated
versions of these instruments
were not available in the languages
they spoke. The minimum differences
in quality-of-life measures considered
clinically significant were not
defined prospectively. Finally, there
was a trend toward prolonged survival
in the rHuEPO arm (17 vs 11
months, P = .13), which the investigators
speculated might be attributable
to higher hemoglobin levels.
However, it is also possible that the
prolongation in survival was due to
imbalances favoring the rHuEPO arm
in important, but unreported, prognostic
factors for both survival and
quality of life, such as burden of disease,
number of prior treatments, response
to chemotherapy, performance
status, and weight loss.

  • Question of Increased Mortality-
    Concerns about the use of erythropoietic
    agents in cancer patients
    have been heightened by recent reports
    of two randomized, doubleblind,
    placebo-controlled trials in
    which subjects receiving recombinant
    erythropoietin had statistically significant
    decrements in survival.

    Henke et al[46] randomized 351
    anemic head and neck cancer patients
    undergoing radiation therapy to epoetin
    or placebo. Those treated with
    rHuEPO had a much higher hematologic
    response rate (82% vs 15%).
    However, in an intention-to-treat analysis
    taking into account other known
    prognostic factors, locoregional progression-
    free survival was poorer with
    rHuEPO (relative risk [RR] = 1.62;
    95% CI = 1.22-2.14; P = .0008). Overall
    survival was also worse (RR =
    1.39; 95% CI = 1.5-1.84; P = .02).
    There were no obvious study design
    issues that could have accounted for
    these findings.

    In a second randomized, doubleblind
    study,[47] 939 nonanemic patients
    with metastatic breast cancer
    were assigned to recombinant erythropoietin
    or placebo in order to prevent
    anemia. The trial was designed
    to assess the effects of 12 months of
    rHuEPO treatment on survival. It was
    terminated early, at the recommendation
    of an independent data monitoring
    committee, due to a higher
    mortality rate in the rHuEPO arm.
    The 12-month survival rate was 76%
    in the placebo arm and 70% in the
    erythropoietin arm (P = .0117), mainly
    as a result of increased mortality in
    the first 4 months (41 deaths in the
    rHuEPO group and 16 in the placebo
    group). Most of the deaths were due
    to disease progression or thrombotic
    events. The investigators could not
    exclude the possibility that the survival
    difference was due to imbalances
    between the treatment groups,
    rather than to the treatment itself, although
    a multivariate analysis incorporating
    available prognostic factors
    reached results similar to the univariate
    analysis.

    The basis for increased mortality
    in patients treated with recombinant
    erythropoietin in these studies is unclear.
    The studies have been analyzed
    by their industry sponsors and by the
    US Food and Drug Administration
    (FDA) to determine if factors other
    than rHuEPO treatment could have
    contributed to the observed outcomes.
    At present, no firm conclusions can
    be drawn.

    The outcomes of these clinical
    studies have also refocused attention
    on the complex and pleiotropic biologic
    effects of erythropoietin. The
    erythropoietin receptor is widely expressed-
    in the central nervous system,
    the gastrointestinal tract, on
    vascular endothelium, and elsewhere.[
    56] Expression of the erythropoietin
    receptor has also been found
    in many tumor types, including 80%
    of the head and neck tumors from the
    study by Henke.[46,56]

    Although the clinical significance
    of these findings is unknown, erythropoietin
    has been found to accelerate
    the proliferation of some cancer
    cells in vitro, to render them resistant
    to chemotherapy, and to promote angiogenesis.[
    56] In vivo animal studies
    also support the hypothesis that
    erythropoietin is a growth factor for
    some types of tumors.[57]

  • Thrombosis Risk-As with the
    breast cancer study cited above,[47]
    an increase in the risk of venous
    thrombosis with rHuEPO was suggested
    by a retrospective, case-control
    study of women with cervical or
    vaginal cancer.[48] The rate of symptomatic
    thrombosis in those receiving
    rHuEPO was 22.6% (17 events in 75
    patients), compared with 2.8% (2/72)
    in those not receiving the drug , even
    though the groups were similar in
    terms of other known risks for thrombosis.
    In multivariate analysis, the
    odds ratio for thrombosis with rHuEPO
    was 15.3 (95% CI = 3.1-76.7).
    Recently, a randomized trial of recombinant
    erythropoietin to reduce
    fatigue in patients with metastatic
    breast cancer and mild anemia was
    terminated after 4 out of 14 patients
    treated with the agent developed
    thrombotic events.[49] None of the
    13 patients in the control arm had a
    thrombotic event.

    Among 15 other randomized controlled
    trials of rHuEPO included in
    the AHRQ evidence report,[51] only
    6 reported rates of thrombotic events.
    The total number of subjects in these
    studies was 580; 4.7% of those treated
    with rHuEPO and 2.5% of controls
    had deep-vein thromboses or thromboembolism
    (P = .41). Thus, the number
    of cancer patients in whom the
    risk of thrombosis has been assessed
    may not be large enough to exclude a
    small but significant increased risk
    associated with rHuEPO, especially
    in cancer patients otherwise predisposed
    to thrombotic events.

    Due to the concerns raised by these
    studies, several other ongoing clinical
    trials of epoetin were terminated
    early. A common factor in the studies
    in which increased adverse events or
    excess mortality were reported was
    the targeting of hemoglobin to higher
    levels than recommended in the prescribing
    information for these drugs.
    Rapid increases in hemoglobin levels may also be associated with excess
    cardiovascular and thrombotic complications.

  • Data Reconsidered-The possibility
    that recombinant erythropoietin
    has an adverse effect on survival under
    some circumstances, and the data
    on thrombotic risks, were reviewed
    on May 4, 2004, by an Oncologic
    Drugs Advisory Committee of the
    FDA's Center for Drug Evaluation
    and Research. Extensive unpublished
    data and analyses were presented in
    an FDA briefing document, and by
    industry representatives. Interested
    readers are referred to the briefing
    document and transcript of the meeting,
    available on the Internet
    (www.fda.gov/ohrms/dockets/ac/04/
    briefing/4037B2_04_Aranesp-
    Procrit.doc, and www.fda.gov/ohrms/
    d o c k e t s / a c / 0 4 / t r a n s c r i p t s /
    4037T2.htm).

    Aside from these concerns, rHu-
    EPO appears to be generally well tolerated,
    with a low incidence of serious
    adverse events. Pure red cell
    aplasia due to anti-erythropoietin antibodies
    has been reported in more
    than 200 patients, most of whom were
    treated with epoetin alfa.[58] Although
    rare, this syndrome should be
    considered when a patient treated with
    erythropoietin develops worsening
    anemia.

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