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. The incidence of anemia can, however, vary substantially depending
on tumor type, extent of disease, and whether the patient is receiving
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
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.
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
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 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
1. Groopman JE, Itri LM: Chemotherapy-induced anemia in adults: Incidence and
treatment. J Natl Cancer Inst 91:1616-1634, 1999.
2. Mercadante S, Gebbia V, Marrazzo A, et al: Anaemia in cancer:
Pathophysiology and treatment. Cancer Treat Rev 26:303-311, 2000.
3. Curt CA: Impact of fatigue on quality of life in oncology patients. Semin
Hematol 37(4 suppl 6):14-17, 2000.
4. Vogelzang NJ, Mani S, Schilsky RL, et al: Phase II and pharmacodynamic
studies of pyrazine diazohydroxide (NSC 361456) in patients with advanced renal
and colorectal cancer. Clin Cancer Res 4(4):929-934, 1998.
5. Cella D: Factors influencing quality of life in cancer patients: Anemia
and fatigue. Semin Oncol 25(3 suppl 7):43-46, 1998.
6. Gabrilove JL, Cleeland C, Livingston RB, et al: Clinical evaluation of
once-weekly dosing of epoetin alfa in chemotherapy patients: Improvements in
hemoglobin and quality of life are similar to three-times-weekly dosing. J Clin
Oncol 19:2875-2882, 2001.
7. Littlewood TJ, Bajetta E, Nortier J, et al: Effects of epoetin alfa on
hematologic parameters and quality of life in cancer patients receiving
nonplatinum chemotherapy: Results of a randomized, double-blind,
placebo-controlled trial. J Clin Oncol 19:2865-2874, 2001.
8. Glaser CM, Millesi W, Kornek GV, et al: Impact of hemoglobin level and use
of recombinant erythropoietin on efficacy of preoperative chemoradiation therapy
for squamous cell carcinoma of the oral cavity and oropharynx. Int J Radiat
Oncol Biol Phys 50:705-715, 2001.
9. Caro JJ, Salas M, Ward A, et al: Anemia as an independent prognostic
factor for survival in patients with cancer: A systemic, quantitative review.
Cancer 91:2214-2221, 2001.
10. Grogan M, Thomas GM, Melamed I, et al: The importance of hemoglobin
levels during radiotherapy for carcinoma of the cervix. Cancer 86:1528-1536,
11. Lee WR, Berkey B, Marcial V, et al: Anemia is associated with decreased
survival and increased locoregional failure in patients with locally advanced
head and neck carcinoma: A secondary analysis of RTOG 85-27. Int J Radiat Oncol
Biol Phys 42:1069-1075, 1998.
12. Dubray B, Mosseri V, Brunin F, et al: Anemia is associated with lower
local-regional control and survival after radiation therapy for head and neck
cancer: A prospective study. Radiology 201:553-558, 1996.
13. Fein DA, Lee WR, Hanlon AL, et al: Pretreatment hemoglobin level
influences local control and survival of T1-T2 squamous cell carcinomas of the
glottic larynx. J Clin Oncol 13:2077-2083, 1995.
14. Erslev AJ: Erythropoietin and anemia of cancer. Eur J Haematol
15. Glaspy J, Bukowski R, Steinberg D, et al: Impact of therapy with epoetin
alfa on clinical outcomes in patients with nonmyeloid malignancies during cancer
chemotherapy in community oncology practice. J Clin Oncol 15:1218-1234, 1997.
16. Demetri GD, Kris M, Wade J, et al: Quality-of-life benefit in
chemotherapy patients treated with epoetin alfa is independent of disease
response or tumor type: Results from a prospective community oncology study. J
Clin Oncol 16:3412-3425, 1998.
17. Ludwig H: Epoetin in cancer-related anaemia. Nephrol Dial Transplant
18. Henry DH, Abels RI: Recombinant human erythropoietin in the treatment of
cancer and chemotherapy-induced anemia: Results of double-blind and open-label
follow-up studies. Semin Oncol 21:21-28, 1994.
19. Kotasek D, Albertsson M, Mackey J, et al: Randomized, double-blind,
placebo-controlled, dose-finding study of darbepoetin alfa administered once
every 3 (Q3W) or 4 (Q4W) weeks in patients with solid tumors. Proc Am Soc
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20. Smith RE, Tchekmedyian S, Richards D, et al: Darbepoetin alfa effectively
alleviates anemia in patients with chronic anemia of cancer: Efficacy and
pharmacokinetic results of a dose-escalation study. Proc Am Soc Clin Oncol
21. Vansteenkiste J, Pirker R, Massuti B, et al: Double-blind,
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