Psychological Outcomes Associated With Anemia-Related Fatigue in Cancer Patients

Recent studies report that the 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

Prevalence

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 (DSM-III) 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%.

Symptom-Specific Assessments

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(Drug information on epoetin alfa) (Epogen, Procrit) or darbepoetin alfa(Drug information on 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(Drug information on 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 study:

(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 (FACT)-G
(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 1.

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—The 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 ³ 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]

Functional Assessment of Cancer Therapy Scales—The 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 baseline.

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.