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Psychological Outcomes Associated With Anemia-Related Fatigue in Cancer Patients

Psychological Outcomes Associated With Anemia-Related Fatigue in Cancer Patients

ABSTRACT: This article examines the relationships between chemotherapy-induced anemia, fatigue, and psychological distress among anemic cancer patients with solid tumors. Patients participating in two randomized clinical trials evaluating the efficacy of darbepoetin alfa (Aranesp) completed a questionnaire at baseline, at the beginning of each chemotherapy cycle, and at the end of the 12-week treatment period. The questionnaire included four psychological distress outcomes: Brief Symptom Inventory (BSI) Depression and Anxiety, Functional Assessment of Cancer Therapy (FACT)-Emotional Well-Being, numeric rating scale of Overall Health, and the FACT-Fatigue subscale. Patients with a hemoglobin response of at least a 2 g/dL increase were more likely to experience meaningful improvements (at least 3 points) in FACT-Fatigue scores than nonresponders (55.0% vs 39.8%; P = .0004). Patients with meaningful improvements in FACT-Fatigue scores reported significantly greater improvements in each of the psychological outcomes relative to those without improved fatigue (P < .0001). For BSI Depression and Anxiety, the differences in mean change scores between patients with and without improved fatigue were 8.2 and 7.7, respectively. Improving the hemoglobin levels of patients undergoing chemotherapy and suffering from anemia-related fatigue has the potential to produce significant positive effects on patients’ fatigue, depressive symptoms, anxiety, feelings of helplessness, and overall health. [ONCOLOGY 16(Suppl 10):117-124, 2002]

Recent studies report that
prevalence of adjustment disorders[1] (ie, the development of clinically significant emotional or behavioral
symptoms) in patients with cancer ranges from 15% to 25%.[2,3] It is theorized
that adjustment disorders arise in response to the diagnosis of cancer and the
stress of coping with cancer treatment. These disorders are often serious enough
to warrant therapeutic intervention, but do not meet all of the criteria for a
major mental disorder.[1-3] Further, several studies have reported prevalence
rates of clinical depression in oncology patients to be between 7% and 10%.[2-5]

Psychological Distress
in Cancer Patients


An early study of the prevalence of psychiatric disorders in
cancer patients conducted by Derogatis et al[5] at three cancer centers in the
early 1980s found that 32% of nonterminal patients (n = 215) undergoing active
treatment had adjustment disorders, and that adjustment disorders comprised more
than two-thirds of all Diagnostic and Statistical Manual of Mental Disorders
diagnoses identified in the sample. In more recent studies,
Morasso et al reported that 23.5% of breast cancer patients completing
chemotherapy were found to have adjustment disorders.[3] Similarly, Skarstein et
al found that 24.3% of hospitalized and ambulatory cancer patients with a
variety of tumor types scored as borderline cases on the Hospital Anxiety and
Depression Scale (HADS)-Anxiety scale, while for depression, borderline
disorders represented 15.5% of patients.[2] Using the Brief Symptom Inventory
(BSI), Zabora et al determined the prevalence of distress to range from 29.6% in
patients with gynecologic cancer to 43.4% in those with lung cancer.[6] Thus,
one can conclude from this review of the literature that the prevalence of
psychological disorders in the oncology population is approximately 15% to 32%.


Identification and treatment of patients with the symptoms of
depression/anxiety or clinical depression is important, not only because
patients’ functioning and well-being are compromised, but because these
symptoms may also affect the ability to comply with and tolerate treatment, and
thus could affect survival.[7] Clinicians face several challenges in
identifying, assessing, and treating the presence of psychological distress in
cancer patients: selecting a screening tool from the many available; having the
space and time necessary for valid and reliable assessment, and having trained
staff available for the assessment and treatment of anxiety and depression.

First, one must choose from a wide variety of instruments
that have been shown to be approximately equivalent in their reliability and
validity. Issues that vary widely across the instruments that the clinician must
grapple with include the length of the instrument, the scoring, and
interpretation of the scores. Diagnosis of psychological distress, moreover, is
complicated in patients with cancer because the diagnostic criteria for specific
psychological conditions include somatic symptoms that may also be associated
with cancer or its treatment. For example, the symptoms of decreased appetite,
insomnia, and fatigue (or loss of energy) can be either the direct result of the
toxic effects of chemotherapy or indicators of psychological distress. Thus, it
is difficult for well-trained and highly experienced clinicians to diagnose
anxiety and depression in patients with cancer. Finally, many oncology clinics
are not appropriately staffed to diagnose and treat psychological distress.

In this article, we examine the relationships between
anemia-related fatigue and patients’ emotional well-being and psychological
distress—specifically, depression and anxiety. Many cancer patients suffer
anemia as consequences of the disease process and particularly of chemotherapy,
with fatigue being the most common symptom of anemia.[8] Previous blinded,
randomized controlled trials have shown that levels of fatigue experienced by
patients undergoing treatment for cancer can be significantly reduced by
increasing hemoglobin levels through the use of either epoetin alfa (Epogen,
Procrit) or darbepoetin alfa (Aranesp).[9,10] However, little attention has been directed
to the effects of fatigue on patients and the benefits of reducing fatigue.

Clinical Data

This study incorporated individual patient data from two
multicenter, randomized, clinical trials evaluating the efficacy of darbepoetin
alfa among anemic cancer patients receiving multicycle chemotherapy. The
dose-finding phase II study of darbepoetin alfa was an active-controlled,
open-label trial for anemia treatment among patients with solid tumors receiving
chemotherapy conducted in the United States. The doses and schedules of
darbepoetin alfa that were studied in this trial were 0.5, 1.0, 1.5, 2.25, 4.5,
6.0, and 8.0 µg/kg/wk and 3.0, 5.0, 7.0, and 9.0 µg/kg every 2 weeks.

The pivotal phase III study was a double-blind,
placebo-controlled study of darbepoetin alfa (2.25 µg/kg) for treatment of
anemia among lung cancer patients (either small-cell lung cancer or non-small-cell
lung cancer) receiving platinum-containing chemotherapy, conducted in Canada,
Australia, and Europe. The two clinical trials were carried out between April
1999 and January 2001.

Patients from these studies were included in these analyses
if they completed at least 4 weeks of treatment, reported BSI depression and
anxiety scale scores at baseline, and reported BSI depression or anxiety scores
at least one time after 4 weeks of treatment. Baseline and last-observed BSI
scores were used to assess change over time, where the last observed value
occurred any time after week 4 and before the end of the 12-week treatment
period. In the two trials, darbepoetin alfa, epoetin alfa, or placebo were
administered for a maximum of 12 weeks. Written, signed informed consent was
obtained from each subject.

Eligibility criteria for the two trials were almost the same,
with the exception of the phase III lung cancer trial that was limited to lung
cancer patients receiving platinum chemotherapy. Inclusion and exclusion
criteria included anemia, as indicated by a hemoglobin concentration ≤
11.0 g/dL; no evidence of iron, folate, or vitamin B12
deficiency; adequate renal and liver function; and Eastern Cooperative Oncology
Group (ECOG) performance status of 0 to 2. Patients were required to be
receiving cyclic chemotherapy, with no recombinant human erythropoietin therapy
within 8 weeks of randomization and no more than two red blood cell transfusions
within 2 weeks of randomization.

Patient-reported health-related quality-of-life outcomes were
included as secondary end points to assess patient-perceived functioning and
well-being. Patients completed the quality-of-life questionnaire at the
beginning of each chemotherapy cycle and at the end of the treatment period.

Outcome Measures

Four measures of psychological distress were used in this

(1) the depression scale
from the BSI
(2) the anxiety scale from
the BSI
(3) the emotional
well-being scale from the Functional Assessment of Cancer Treatment-General
(4) the 11-point numeric
rating scale of Overall Health status.

Fatigue was measured using the Fatigue subscale of the
FACT-Anemia instrument. These measures are summarized in Table

Subjects completed the questionnaires at baseline,
approximately every 3 to 4 weeks during treatment, and at the end-of-treatment
period. Since one of these studies was multinational, linguistically validated
versions of the BSI and FACT surveys were used for the required languages.

Brief Symptom
Inventory Anxiety and Depression Scales
BSI was developed as a shorter version of the Symptom Checklist-90 (SCL-90) to
measure the psychological symptom patterns of both patients and nonpatients.[11]
It has
been used extensively to assess the psychological distress of cancer patients
[12-14], and Zabora found it to yield a specificity of .87 and a sensitivity of
.89 in this population.[15] The BSI scales each include six symptoms;
respondents report how much the symptom or problem distressed or bothered them
during the past 2 weeks on a 5-point scale: not at all (0), a little bit (1),
moderately (2), quite a bit (3), or extremely (4). In this study, we computed
norm-based scores by applying gender-specific general population means and
standard deviations for an adult, nonpatient sample. These normed scores have a
mean of 50 and standard deviation of 10 in the general population.

Criteria for defining low, moderate, and high levels of
distress have been defined in previous cancer studies for normed BSI scores.[16]
Specifically, low, moderate, and high distress have been defined as
0.5 standard deviations above the mean,
0.5 to 1.49 standard deviations above the mean, and
1.5 standard deviations above the mean,
respectively. As such, low, moderate, and high levels of distress are associated
with normed BSI scores of ≤
55, 55 to 64.9, and ³
65. A "case" of psychological distress for the BSI Depression and
Anxiety scales was defined as a normed score ³ 65 on both scales.[16] This case definition
is a conservative one, given that Derogatis uses a normed score of 63 on two
scales to define a case.[11]

Assessment of Cancer Therapy Scales
FACT-Emotional scale score ranges from 0 to 24. Responses to each question can
vary from "not at all true" (0) to "very much true" (4). A
higher score indicates better emotional well-being. The FACT-Emotional scale was
found to have reliability and validity in a population of 545 oncology patients
with several different tumor types and chemotherapy regimens.[17] The
FACT-Fatigue subscale (Table 1) has 13 questions evaluating the impact of anemia
on cancer patients receiving chemotherapy. Responses to each question can range
from 0 to 4, with a total fatigue subscale score ranging from 0 to 52.[18] A
higher score indicates less fatigue. The FACT-Fatigue subscale was found to have
good reliability and validity.[19] "Clinically meaningful improvement"
in fatigue was defined as an increase of 3 points in the FACT-Fatigue subscale
score; a "case" of fatigue was defined as a FACT-Fatigue
subscale score £  36.5.[20]
This cut-off is one standard deviation above the mean of an anemic cancer
patient population.[21]

Clinical efficacy outcomes included the proportion of
patients achieving a hemoglobin response (³ 2 g/dL increase from baseline) and the change
in the subject’s last hemoglobin in the treatment phase compared with

Statistical Analysis

To analyze these two clinical trials, we used a meta-analytic
approach that pooled individual patient data.[22-25] Darbepoetin alfa at several
doses and schedules, epoetin alfa at several doses and schedules, and placebo
were combined. This meta-analysis was done to improve the power of the analysis.
To describe the study sample, we computed means, standard deviations, and ranges
of continuous variables and frequency distributions of categorical variables. We
conducted bivariate analyses evaluating the association of changes in normed BSI
scores with changes in FACT-Fatigue subscale scores and with the other
covariates. For changes in FACT-Fatigue scores and continuous covariates, we
computed Pearson correlation coefficients. For the fatigue case variable and
categorical covariates, we compared mean changes in normed BSI scores across
levels of the covariates using analysis of variance (ANOVA) models. Statistical
significance was evaluated at the .05 level.


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