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Optimizing the Treatment of Anemia in Cancer Patients

Optimizing the Treatment of Anemia in Cancer Patients

ABSTRACT: Cancer-related anemia, in addition to having detrimental effects on quality of life and adding the risk and inconvenience of blood transfusions, may also be associated with decreased survival or time to progression. Yet despite increasing awareness of the value of treating cancer-related anemia, over 60% of US cancer patients receiving chemotherapy who have hemoglobin values below 10 g/dL are not treated for this condition. Current treatment options include red blood cell transfusions, iron supplementation for iron deficiency, or erythropoietic agents, including recombinant human erythropoietin (rHuEPO) and darbepoetin alfa (Aranesp). The articles in this supplement describe the basic scientific research and clinical development of darbepoetin alfa—another safe, effective, and approved treatment for chemotherapy-induced anemia. [ONCOLOGY 16(Suppl 11):9-12, 2002]

Anemia, a frequent complication of cancer, is also induced
or exacerbated by chemotherapy. Generally defined as a hemoglobin concentration
of < 12 g/dL, anemia is estimated to affect about 50% of cancer
patients.[1] The incidence of anemia can, however, vary substantially depending
on tumor type, extent of disease, and whether the patient is receiving
myelosuppressive therapy.[2]

Anemia is associated with many symptoms, including exhaustion, weakness,
impaired concentration, dyspnea, respiratory distress, lethargy, and fatigue.
Fatigue is the symptom generally identified as the most significant contributory
factor to poor quality of life in patients with cancer.[3-7] In addition, some
studies suggest that anemia may reduce the efficacy of anticancer therapy.[8-12]
An association between anemia and poorer therapeutic outcome and survival
following radiotherapy and/or chemotherapy has been documented in patients with
some malignancies.[8,9,11,13]

Etiology

The etiology of anemia in the oncology setting is multifactorial. The release
of cytokines in response to the inflammatory or neoplastic process reduces the
erythrocyte lifespan and impairs erythroid colony formation, erythropoietin
production, and iron reutilization. Anemia may also be induced by acute and
chronic blood loss, particularly among patients with gastrointestinal, head and
neck, genitourinary, and uterine cancers.[2,14] Other factors, such as
replacement of active bone marrow in advanced metastatic carcinoma or
hematologic malignancies, may destroy progenitor cells, induce fibrotic or fatty
replacement, and contribute to anemia.

Both chemotherapy and radiotherapy can induce or further exacerbate anemia by
suppressing erythropoiesis.[2,14] In addition, chemotherapy can reduce
erythropoietin production by direct effects on the renal tubules, decrease the
sensitivity of the hematopoietic system to erythropoietin, and cause stem cell
damage, or destroy mature hematopoietic cells. Chemotherapy may also lead to
long-term myelodysplasia or microangiopathy. Radiotherapy may damage bone marrow
stem cells, and lead to transient or sustained anemia as these cells have a
limited capacity to repair such damage.[2]

Treatment

Until recently, anemia that was not severe or life-threatening was considered
of little consequence and was frequently untreated. However, increasing
recognition that the treatment of mild-to-moderate anemia can yield clinically
significant improvements in patient health-related quality of life has resulted
in advances in the palliative management of cancer. The statistically
significant correlation of hemoglobin increase and improved quality of life,
independent of the tumor response to therapy, clearly demonstrates the impact of
improving hemoglobin levels in anemic patients with cancer.[6,15,16]

Current treatment options for patients with anemia and malignant disease
include red blood cell transfusions, iron supplementation for iron deficiency,
or erythropoietic agents, including epoetin alfa (Epogen, Procrit) and
darbepoetin alfa (Aranesp).[2,17] Red blood cell transfusions provide an
immediate benefit in the case of life-threatening or severe symptomatic anemia,
but are associated with inherent risks and inconvenience. Although associated
with a slower onset of efficacy, erythropoietic agents are safer than
transfusion, and are effective and widely used to treat chemotherapy-induced
anemia.

Recombinant human erythropoietin (rHuEPO) was initially studied in anemic
cancer patients receiving chemotherapy based on the observation that endogenous
erythropoietin concentrations are inadequate for the degree of anemia, and that
the administration of chemotherapy may blunt the erythropoietin response to
anemia. In one of the first published reports of rHuEPO treatment in anemic
cancer patients receiving chemotherapy, Henry and Abels[18] reported results
from a series of large, placebo-controlled trials in which rHuEPO was
administered at 150 U/kg three times per week for 12 weeks, with dose increases
permitted after 8 weeks. The results showed that rHuEPO therapy could
alleviate the need for blood transfusions in anemic cancer patients receiving
chemotherapy (combined platinum- and nonplatinum-based chemotherapy groups) in
the second and third month of therapy. In addition, a statistically significant
increase in hemoglobin concentration relative to placebo both in patients
receiving non-cisplatin-based chemotherapy as well as in patients receiving
cisplatin-based chemotherapy was observed, with 58% and 48% of patients,
respectively, achieving a 6-point hematocrit increase from baseline in the
absence of a transfusion.

Numerous controlled and uncontrolled studies, including several large US
community-based studies, have confirmed these findings. In a study of over 2,000
anemic patients with nonmyeloid malignancies receiving chemotherapy treated with

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