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(Drug information on 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.
A 70-year-old man with a history of localized prostate cancer treated with whole-pelvis radiation therapy with a boost to the prostate, in conjunction with androgen deprivation therapy 7 years prior, presented with lower back pain. A bone scan revealed an area of activity in the sacrum. What is the most likely diagnosis?
