For oncologists, the
importance of recognizing the presence of anemia is clear, given that anemia is
the most common hematologic abnormality in patients with cancer.1
Depending on the tumor type, between 32% and 49% of patients are anemic at the
time of cancer diagnosis,2 and approximately 50% of all patients
will develop anemia at some point.1
Anemia in patients with
cancer reflects multiple possible etiologic factors. The type of cancer
present, the patients underlying medical issues, and the treatment itself
all may act independently or interact to result in anemia.3 In
patients with cancer, anemia may result from a combination of noncancer-related
and cancer-related etiologies. Noncancer-related etiologies include underlying
comorbidities (eg, bleeding, hemolysis, nutritional deficiencies,
hemoglobinopathies) or infection.1,2 The malignancy itself can
contribute to or exacerbate a preexisting anemia, and anemia can also develop
as a side effect of cancer treatments (chemotherapy-induced
Due to the numerous
potential etiologies of anemia in patients with cancer, the evaluation may be
complex.2 Thus, understanding the pathophysiology behind cancer and
chemotherapy-induced anemia is an important step in gaining a more thorough
understanding of cancer-related anemia.
Anemia in patients with cancer
Oncologists will most
often see anemia resulting from chemotherapy or anemia primarily due to the
malignancy itself. Nutritional anemias, particularly those resulting from iron
deficiency, as well as deficiencies in folate or vitamin B12, are
more common in noncancer populations but may also be present in patients with
cancer.1,3,4 The goal of the anemia evaluation is to characterize
the anemia and identify any underlying comorbidity that can be potentially
corrected; therefore it is important to understand how the various anemias can
Anemia of cancer
Anemia of cancer may
also be evident at initial diagnosis. Activation of the immune system appears
to be the driving force for a global diminution of erythropoiesis, analogous to
chronic inflammatory conditions observed in anemia of chronic
disease.3,5 It is postulated that the immune system may be mobilized
to stimulate production of inflammatory cytokines that can impede
erythropoiesis. Consequently, there is insufficient differentiation and
proliferation of erythroid precursors, leading to anemia.3
Inflammatory cytokines can also impair iron metabolism which can result in
reduced serum iron levels and iron retention within the reticuloendothelial
system.3 Tumors can also produce cytokines, which induce iron
sequestration, thereby decreasing RBC production. Shortened RBC survival may
also result from overexpression of inflammatory cytokines.3
Furthermore, chronic blood loss at tumor sites can exacerbate anemia from
cancer.2,5 Anemia can result from bone marrow invasion by leukemia
or solid tumors. Myelophthisis, resulting from bone marrow replacement of solid
tumors or hematologic malignancies, may manifest as anemia or pancytopenia.
Breast cancer, prostate cancer, small cell lung cancer, and lymphoma are among
the most common tumors associated with bone marrow
While anemia in
patients with cancer is often produced by the cancer itself, the addition of
chemotherapy significantly increases the proportion of patients with
anemia.6 The myelosuppressive effects of cytotoxic chemotherapy
agents on erythropoiesis are generally cumulative in nature and up to 50% of
patients with cancer may develop chemotherapy-induced anemia over the course of
chemotherapy.1,7 A steady increase in the rate of anemia occurs with
additional cycles of chemotherapy as evidenced by data from the European Cancer
Anaemia Survey (ECAS). This study showed that the rate of anemia (hemoglobin
[Hb] <12 g/dL) increased from 19.5% in cycle 1 to 46.7% by cycle 5. The
percentage of patients with more severe anemia (grades 2 and 3) also increased
with greater numbers of chemotherapy cycles.7 Patients can also
become anemic within the first 2 cycles of chemotherapy as evidenced by data
from a separate analysis of ECAS data in patients who were not anemic (Hb
>12 g/dL) prior to initiating chemotherapy. In this analysis, 62% of
patients experienced a Hb decline by 1.5 g/dL within a median time of 6.1 to
7.2 weeks and 51% experienced a Hb decline by 2 g/dL within a median time of
7.3 to 8.9 weeks.8
Depending on the
chemotherapeutic agent or regimen, anemia may be mild in degree (grade 1 or 2)
in about 10%85% of patients. Moderate or severe anemia will develop in
about 2%55% of patients and require intervention (Table).2,9
An individual patients ability to tolerate anemia will vary depending on
the presence of preexisting conditions and comorbidities; the decisions for
correction of anemia should be based on an assessment of individual patient
characteristics, severity of anemia, symptoms, comorbidities and clinical
judgment of the physician.2
Chemotherapy may cause
anemia in multiple ways. First, some chemotherapeutic agents will affect the
production of new RBCs. For example, chemotherapy can damage normal bone marrow
precursor hematopoietic cells. When these cells are damaged, the ability of the
bone marrow to produce new RBCs is impaired. Some drugs, such as
platinum-containing agents, are nephrotoxic, and can also affect the
development of new RBCs by interfering with erythropoietin production by the
Based on in vitro
studies, the production of an RBC from its stem cell precursor takes
approximately 26 days.10-13 In culture, stem cells differentiate
into burstforming unit-erythrocyte (BFU-E) cells, which are stimulated by
erythropoietin to mature into colonyforming unit-erythrocyte (CFU-E)
cells. These cells mature through the proerythroblast stage into erythroblasts
and then reticulocytes. Reticulocytes are released into the bloodstream and
take approximately 24 hours to terminally differentiate into mature RBCs.
Reticulocytes are generally slightly larger than the mature
progenitor cells divide rapidly regardless of their developmental stage.Thus,
chemotherapy, which interferes with cell division, can clearly impede RBC
production. Finally, certain chemotherapeutic treatments, such as alkylating
agents or nitrosureas, can damage dividing and resting cells, causing harm to
more cells, including hematopoietic stem cells, than those chemotherapeutic
agents that are cell-cycle specific.14
Anemia due to nutritional deficiency
Patients with cancer
may develop anemia secondary to poor nutrition in general or due to reduced
function in the gastrointestinal (GI) tracts to absorb nutrients.1-3
Folate deficiency may develop in anorexic patients with cancer, while vitamin
B12 deficiency can arise in patients who have undergone gastric or
small bowel resection or bypass or have atrophy of stomach parietal cells,
which produce intrinsic factor necessary for vitamin B12
absorption.1,15 Iron deficiency anemia due to blood loss or the
inability to absorb iron in the GI tract often occurs in patients with
malignancies of the GI tract, including colorectal cancers.1,3
Nutrient deficiencies in folate, vitamin B12 or iron may lead to
anemia because all of these nutrients are essential to red blood cell (RBC)
production and development.10,15
Prevalence by cancer type
The type of cancer that
a patient has can also contribute to the risk of developing anemia. On a
broader level, patients with hematologic malignancies are more likely to have
anemia at the time of diagnosis, with about half of patients presenting with
anemia. In contrast, about one third of patients with solid tumors will be
anemic at diagnosis.16
A retrospective study
conducted by Wu and colleagues in 2009 shed some additional light on the
variations in prevalence of anemia by cancer type. In the observational cohort
study of 47,159 adult patients with cancer, anemia was defined as an Hb less
than 11 g/dL at any time during chemotherapy. Information was obtained from
electronic medical records from community- and hospital-based clinical oncology
practices between 2000 and 2007. At baseline 20.9% of the 42,923 patients
evaluated were anemic.17
The results indicated
that about 56.3% of patients with ovarian cancer were anemic during
chemotherapy. The next highest prevalence for anemia was 53.3% among patients
with breast cancer, and 50.9% among patients with non-small cell lung cancer
(NSCLC).17 Many factors may alter the prevalence of anemia among
these patients. For example, patients with NSCLC may be more commonly diagnosed
with anemia because of their reduced lung function, which results in a limited
ability to tolerate anemia and more prominent symptoms of anemia (such as
dyspnea).18 This reduced tolerability and increased severity of
symptoms may bring anemia to the attention of the health care team. To date,
the distinct mechanisms underlying the development of anemia in patients with
different cancer types is unknown.
Prevalence by treatment type
The type of
chemotherapy and the length and intensity of the treatment can affect the
prevalence of anemia.
Platinum-based regimens, including cisplatin or
carboplatin, are well recognized for causing anemia in patients with
cancer.9 These agents are often used to treat cancers of the lung,
ovary and GI tract. They reduce erythropoietin production via direct negative
effects on bone marrow and the kidneys.2,6 In general, all
myelosuppressive agents are likely to result in anemia to some
In their study, Wu and
colleagues also reported the percentage of patients who develop anemia
according to chemotherapy regimen. A chemotherapy regimen was defined as more
than 1 administration of a drug, with no more than 45 days between consecutive
The results indicated
that patients receiving gemcitabine-based (59% of patients), platinum-based
(50.7%), and anthracycline-based (50.8%) regimens were the most likely to
develop anemia. Platinum-based regimens comprised the most common regimens
among patients receiving chemotherapy in this study. In fact, platinum-based
regimens were used in 27.8% of all patients treated, including 76.8% of
patients with head and neck cancers and 66.6% of patients with non-small cell
lunch cancer. For patients with lung, ovarian, head and neck, and colorectal
cancers, platinum-based regimens were most common; however, anthracycline-based
regimens were more common for patients with breast and hematologic
The intensity of
chemotherapy may also contribute to the severity of anemia.9 In the
Wu study, of the 60.5% of patients who experienced cycle delays, anemia
occurred during 51.9% of the delayed chemotherapy cycles. The largest
proportion of delayed cycles occurred in patients receiving platinum-based
regimens (45.3%), followed by anthracycline-based (13.9%), gemcitabine-based
(8.6%), and taxane-based regimens (7.6%).17 Additionally, as we move
into an era of targeted therapies, including biologics and small molecule
inhibitors, there may be a greater risk for the development of
anemia.2,9 For example, imatinib therapy for GI stromal tumors
resulted in almost 90% of patients developing anemia, with 10% experiencing
grade 3 or 4 anemia.19 Patients with metastatic renal cell
carcinoma, receiving the newer agent sunitinib as monotherapy, experienced an
increased rate of clinically significant anemia compared with patients
receiving temsirolimus (26% vs. 9%).20,21
Anemia in patients with cancer is multifactorial in its etiology. It is highly prevalent, whether a
result of nutritional deficiency, a consequence of the effects of the tumor
itself on RBC production, or as a side effect of chemotherapy.
Chemotherapy-induced anemia is frequent, as a result of myelosuppressive
cytotoxicity of the chemotherapeutic regimens.2 The incidence and
severity of chemotherapy-induced anemia and its symptoms depend on a variety of
factors, including the tumor type and chemotherapy regimen (including the
schedule and intensity of therapy).17 The health care team must
always be vigilant regarding the possibility of anemia and be alert for signs
and symptoms associated with this common disease associated with cancer and
- Marks PW, Rosenthal,
DS. Hematologic manifestations of systemic disease: infection, chronic
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- The NCCN Clinical Practice Guidelines in Oncology.
Cancer- and Chemotherapy-Induced Anemia. Version 2.2012. National Comprehensive
Cancer Network website.
August 5, 2011.
- Birgegård G, Aapro MS, Bokemeyer C, et al.
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- Brittenham GM. Disorders of iron metabolism: iron
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Hematology: Basic Principles and Practice. 4th ed. Philadelphia, PA: Churchill
- Spivak JL. The anaemia of cancer: death by a thousand
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- Bridges KR, Pearson HA. Cancer and anemia. In: Bridges
KR, Pearson HA, eds. Anemias and Other Red Cell Disorders. New York, NY:
McGraw-Hill Medical Publishing Division; 2008:58-80.
- Ludwig H, Van Belle S, Barrett-Lee P, et al. The
European Cancer Anaemia Survey (ECAS): a large, multinational, prospective
survey defining the prevalence, incidence, and treatment of anaemia in cancer
patient. Eur J Cancer. 2004;40:2293-2306.
- Barrett-Lee PJ, Ludwig H, Birgegård G, et al;
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- Groopman JE, Itri LM. Chemotherapy-induced anemia in
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- Guyton AC, Hall JE. Red blood cells, anemia, and
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- Papayannopoulou T, DAndrea AD, Abkowitz JL,
Migliaccio AR. Biology of erythropoiesis, erythroid differentiation, and
maturation. In: Hoffman R, Benz EJ Jr, Shattil SJ, et al, eds. Hematology:
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- Bunn HF. Pathophysiology of the anemias. In:
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- Camp-Sorrell D. Chemotherapy toxicities and
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- Ludwig H, Birgegard G, Barrett-Lee PJ, Krzakowski M.
Prevalence and management of anemia in patients (pts) with hematologic
malignancies (HMs) and solid tumors (STs): results from the European Cancer
Anaemia Survey (ECAS). Blood. 2002;100:234a. Abstract 884.
- Wu Y, Aravind S, Ranganathan G, Martin A, Nalysnyk
L. Anemia and thrombocytopenia in patients undergoing chemotherapy for solid
tumors: a descriptive study of a large outpatient oncology practice database,
2000-2007. Clin Ther. 2009;31:2416-2432.
- Kosmidis P, Krzakowski M; the ECAS Investigators.
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- Duffaud F, Lecesne A, Ray-Coquard I, et al.
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- Motzer RJ, Rini BI, Bukowski RM, et al. Sunitinib in
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- Atkins MB, Hidalgo M, Stadler WM, et al. Randomized
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