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The Effects of Anemia and Anemia Treatment on the Quality of Life of People With Cancer

The Effects of Anemia and Anemia Treatment on the Quality of Life of People With Cancer

ABSTRACT: Anemia, common in people with cancer, can be due to the disease itself or to the associated therapy. Fatigue, the most prevalent of all symptoms experienced by cancer patients, is the primary symptom of anemia. Caused by many factors, fatigue, regardless of etiology, has an adverse impact on health-related quality of life. Anemia is among the more treatable of those causes. Prior to the development of recombinant human erythropoietin, red blood cell transfusion was the standard treatment for cancer-related anemia. Erythropoietic agents are an effective alternative to blood transfusion: they improve hematocrit, reduce transfusion dependency, and eliminate transfusion-related risks. Although studies are mixed, most clinical trials have also suggested that erythropoietic agents have a positive impact upon cancer patients’ quality of life. However, the cost of drug supply is quite high in the oncology setting, where much higher doses are required relative to the nephrology setting. Thus, although few challenge the treatment’s effectiveness, cost-effectiveness remains an open question. The data collected over the years to address these questions have helped define and clarify the relationship between anemia and health-related quality of life in people with cancer. That relationship is summarized in this article. [ONCOLOGY 16(Suppl 10):125-132, 2002]

Anemia, typically
characterized
by hemoglobin levels below
12 g/dL, is a common occurrence in oncology practice, particularly in patients
receiving myelosuppressive chemotherapy.[1] Mild to moderate anemia, with
hemoglobin levels between 8 and 12 g/dL, results in symptoms of fatigue, lethargy, dizziness, headache, and
difficulty breathing and rapid or irregular heartbeat after exercise. More
severe anemia, when hemoglobin levels are below 8 g/dL, results in markedly
reduced exercise capacity, difficulty breathing at rest, rapid or irregular
heartbeat at rest, and an increased risk of angina pectoris, myocardial
infarction, or transient ischemic events.[1-3] Anemia can adversely affect the
schedule and tolerability of cancer therapy, which may in turn influence the
efficacy of the treatment.

Anemia, Fatigue, and
Quality of Life

Anemia has been shown to have an adverse impact on
health-related quality of life (QOL).[2-7] Fatigue is the principal symptom of
anemia, but other associated symptoms (eg, headache, depression, cognitive
impairment) adversely affect patients’ quality of life as well.[3,6]
Health-related quality of life is reduced through compromised functional ability
(reduced exercise tolerance, ability to work, social interaction, pursuit of
leisure activities) and decline in subjective sense of well-being.[8] Even mild
anemia (10-12 g/dL) can substantially impair quality of life.[2,3,5,7,9-12] In
one study of patients with hemoglobin levels below 12 g/dL, 25% were not able to
work at all, compared with 8% of patients with hemoglobin levels above 12
g/dL.[2,3] In addition, cancer-related anemia may compromise patients’
tolerance of treatments, resulting in the need to reduce duration or
intensity.[13,14] Anemia has also been associated with reduced local tumor
control and decreased survival.[1,6,9]

Fatigue is highly prevalent in cancer patients, and is
associated with impairments in physical, functional, and emotional well-being
and quality of life.[2-8,15] A number of studies have demonstrated significant
associations between anemia, fatigue, and quality of life in cancer
patients.[5,7,9,10,16]

Figure 1 presents a model depicting the potential impact of
anemia on quality of life. According to the model, anemia directly causes
fatigue, which in turn mediates a cascade of other potential problems. Fatigue
can be defined as decreased capacity for work and reduced energy reserve,[17]
leading to less activity, lower productivity, cognitive difficulties, and a
decline in the ability to function normally in daily activities. These factors
then often combine to compromise one’s social relationships and social role,
due to a lack of interest and energy. If fatigue becomes chronic, self-esteem
may suffer as people are unable to fully participate in the regular activities
and relationships that provide a sense of accomplishment and
fulfillment.[5,17,18] Ultimately, some patients with chronic, unremitting
fatigue may be at risk for withdrawal from daily life and major depression.

Fatigue, like anemia, is complex and has a host of
interactive etiologic factors, including anemia, mood disturbance, anorexia/cachexia,
infection, pain, sleep disturbance, tumor burden, and prolonged
stress.[13,18-20] In addition to negatively affecting quality of life, fatigue
also poses physical, psychological, and economic problems for patients[14,21]
and their caregivers.[18]

In summary, the symptoms of anemia in cancer patients have
rather far-reaching consequences for cancer patients and their families. If
anemia can be corrected with therapy, it is likely to have significant value to
the patient’s quality of life. Assuming cost-effectiveness can be
demonstrated, it will likely have value to society as well.

Treating Anemia in
Cancer Patients

Prior to the development of recombinant human erythropoietin,
red blood cell transfusion was the standard treatment for cancer-related anemia.
This treatment had historically not been utilized until hemoglobin levels
dropped well below 10 g/dL—often below 8 g/dL. Given what has been learned
about the QOL correlates of mild to moderate anemia, this practice has
compromised health status in large numbers of patients. The introduction of
erythropoietic agents has added an earlier treatment option, at considerable
cost, thus introducing the question of the cost-effectiveness of managing anemia
in cancer patients.

Evaluations of the efficacy of erythropoietic agents have
relied on one or more of three criteria: change in hemoglobin, reduced
transfusion requirements, or subjective benefits that fall under a general
heading of patient-reported outcomes. These criteria are summarized in Table
1
.
Absolute or relative change in hemoglobin or hematocrit is the most direct
indicator of drug effect, with a two-point increase from baseline hemoglobin
most typically considered to be indicative of significant improvement. Anemia
correction, or bringing the patient above 12 g/dL, has been another proposed
approach to expressing the benefit of therapy to hemoglobin level.

A second indicator is the number of units of transfused
blood, or the proportion of patients who require a transfusion during the period
of study. Erythropoietin trials have consistently shown that these end points
are achieved, with response rates in the vicinity of 50% to 60% and relative
risk of transfusion reduced by 30% to 50%.[9,11,12,16,22-31a] Among the
patient-reported outcomes, fatigue and quality of life are the two that are
utilized most frequently in erythropoietin studies.

QOL Instruments Used in Efficacy Studies

Quality of life is now a widely accepted patient-reported
health outcome measure for clinical trials among patients with chronic
illnesses, particularly cancer. Most of the early trials of recombinant
erythropoietin used a set of three linear analog self-assessment (LASA)
scales.[24,32] The LASA scale is a 100-mm line on which the respondent is
instructed to make a mark indicating the degree of endorsement. The content of
the three scales included perceived energy level, ability to perform daily
activities, and overall quality of life. Scores range from 0, indicating
"as low as could be," to 100, indicating "as high as could
be."

The Functional Assessment of Cancer Therapy-General
(FACT-G)[33] is a cancer-specific QOL instrument that measures physical,
emotional, social/family, and functional well-being. The FACT-G can be
supplemented with condition-specific subscales, including a
20-item anemia subscale that includes a 13-item fatigue component.[2,3] The
general instrument plus the condition-specific subscale is then referred to as
the Functional Assessment of Chronic Illness Therapy (FACIT)-Anemia or FACIT-Fatigue,
respectively.[2,3](See Appendix for all scales.) There is now a new subscale for
the FACT measurement system that assesses the cognitive complaints experienced
by cancer patients undergoing chemotherapy (www.facit.org). Some cognitive
complaints during chemotherapy may be influenced by anemia. This question is now
being studied.

In most trials initiated after 1996, the Functional
Assessment of Cancer Therapy-Anemia (FACT-An) or the Fatigue Subscale has been
included with or replaced the LASA scales. In the FACT-An, fatigue and other
symptoms of anemia (eg, dizziness, joint aches, etc) are measured using an
anemia-specific symptom scale that assesses self-report of the cognitive,
physical, and emotional manifestations of anemia. In one pivotal study, the
generic SF-36 instrument (see Appendix) was also used in combination with the
LASA and FACT-An.[9] In that trial of erythropoietic therapy vs placebo, the
FACT-An and LASA scales (but not the SF-36) scores improved significantly in the
erythropoietin-treated patients compared to the placebo-treated patients.[9]

Some studies have used the European Organization for Research
and Treatment of Cancer (EORTC) core QOL questionnaire (see Appendix), including
its three-item fatigue subscale, to assess efficacy of erythropoietin.[34,35a]
Studies that have employed the EORTC core questionnaire have not supported
evidence for a benefit of erythropoietic therapy on an intent-to treat basis. It
is not clear whether this is due to the true absence of a difference in these
studies at doses employed, relative imprecision in the measurement of fatigue,
or relatively low sample sizes.

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