Practitioners’ Practical Model for Managing Cancer-Related Anemia

Anemia is the most common hematologic abnormality seen in patients with cancer. Anemia is associated with debilitating symptoms and poorer health-related quality of life and may result in less than optimal disease/treatment outcomes. The high prevalence of anemia and the potential clinical and prognostic impact make it important to have a systematic approach to the diagnosis and treatment of cancer-related anemia. A rigorous diagnostic evaluation should be undertaken to identify the cause of anemia and guide appropriate treatment. Treatment of anemia with erythropoiesis stimulating proteins offers an alternative treatment to red blood cell transfusions and has been shown to improve quality of life for patients being treated for cancer. In addition, recent studies suggest improved cancer treatment outcomes. Data indicate that treatment with darbepoetin alfa, a novel erythropoiesis stimulating protein, improves hemoglobin levels and quality of life in anemic patients with cancer who are not receiving chemotherapy or radiotherapy. Symptoms of anemia, when searched for properly, are identified often at hemoglobin levels less than 12 g/dL. As the understanding of the importance of anemia grows, and more convenient methods of therapy become available, patients will benefit with a more proactive approach to early treatment or prevention of this complication of cancer and its treatment. [ONCOLOGY 16(Suppl 10):55-63, 2002]

While granulocytopenia and thrombocytopenia frequently receive greater attention in cancer management as a consequence of their potential life-threatening risks, anemia is the most common hematologic abnormality seen with malignancies. Anemia occurs in more than 50% of patients with cancer[1,2] and is itself associated with debilitating symptoms, lower health-related quality of life (QOL) and potentially poorer disease/treatment outcomes.[3-9]

Wide variability exists in the incidence and severity of anemia in different malignant conditions. A review of the incidence of severe anemia requiring red blood cell (RBC) transfusion found the highest incidence (50%-60%) in patients with lung cancer, lymphoma, gynecologic (ovarian), and genitourinary tumors.[10] In a study of a single oncology practice, 31% of patients (103 of 331) required transfusion on at least one occasion during a 1-year period of cancer treatment.[11]

Owing to the high prevalence of clinically significant anemia and its potential impact on quality of life and patient outcomes, it is important to have a systematic approach to cancer-related anemia with regard to diagnosis, evaluation, and treatment. Such an approach could prove beneficial not only for medical oncologists, but also for other caregivers involved in managing patients with malignant conditions.

Defining Anemia in Cancer

Anemia is normally defined as a reduction in hemoglobin or hematocrit below well-defined gender-based levels. Several systems are used for defining and grading the severity of anemia (see Table 1).[10]

For the care of an individual patient, however, it is more relevant to have a functional definition of anemia, namely that there are insufficient RBCs to provide adequate tissue oxygenation.[12] The hemoglobin level at which this state is reached depends on the clinical circumstances of the individual patient. For example, a patient with lung cancer and coexistent chronic obstructive lung disease might be "anemic," with all the associated symptoms, despite hemoglobin levels falling within the accepted normal ranges.

Patients with anemia may experience a variety of symptoms, again depending on their underlying condition and general clinical state. Symptoms may result directly from the oxygen deprivation of tissues, or as a result of the body’s efforts to compensate for this, such as increased cardiac output, increased respiratory rate, and preferential shunting of blood to oxygen-sensitive organs. Common symptoms include fatigue, irritability, insomnia, depression, impaired cognitive function, tachycardia and palpitations, dyspnea, pallor, fluid retention, irregular bowel movements, and reduced sexual desire.[3]

Varying symptoms may manifest with different degrees of anemia. For example, impaired cognitive function, gastrointestinal disturbance, and reduced sexual function may start to appear at higher hemoglobin levels than do the cardiovascular symptoms, which become apparent only when a patient is severely anemic. The severity of symptoms experienced by the individual patient also varies; for example, elderly patients with comorbid conditions may experience more severe symptoms than younger patients.[3]

The Regulation of Red Blood Cell Production

To optimally approach anemia in any clinical situation, an understanding of the erythropoietin system that regulates RBC production by the bone marrow is important. This is especially true for the patient with cancer-related anemia, which can be complex in its etiology. A remarkable process for regulating red blood cell production has evolved in humans. The process is a classic hormonal system with a feedback loop, the stimulus for increased RBC production being tissue hypoxia, with down-regulation of RBC production being controlled by increasing red cell mass, and therefore increased oxygen delivery to tissues (as reviewed by Spivak).[13]

Erythropoietin is a glycoprotein, composed of a 165-amino-acid polypeptide chain with three sialic-acid-containing carbohydrate side chains N-linked to asparagine, and one side-chain O-linked to serine. Although classified as a hematopoietic growth factor, erythropoietin acts as a hormone.[14] Erythropoietin is primarily produced by dedicated peritubular cells in the renal cortex, although the liver is also capable of producing a small "maintenance" amount of erythropoietin. Recently, erythropoietin receptors and production have even been recognized in neural tissues[15]; however, their role and function remain to be fully clarified.

Since the human spleen does not act as a storage organ, it cannot (as can spleens in canine and other species) release additional RBCs into the circulation in response to situations requiring a rapid increase in oxygen delivery. Sufficient erythropoietin is produced by the dedicated peritubular cells of the kidneys to maintain hemoglobin at levels of approximately 14 to 18 g/dL for an adult male, and 12 to 16 g/dL for an adult female.[16] Tissue hypoxia triggers increased erythropoietin production when hemoglobin falls below 12 g/dL.[17] Thus, the normal basal production of erythropoietin by the kidney is more than sufficient to keep hemoglobin levels well above this "trigger" point, allowing the body to compensate in acute or emergency situations when additional oxygen-carrying capacity is suddenly needed.

There is a wide variation in plasma erythropoietin levels between individuals, so an unequivocal increase in plasma erythropoietin in response to tissue hypoxia is not generally measurable until hemoglobin levels are < 10.5 g/dL.[18] This increased erythropoietin production is achieved by up-regulation of the gene expressing erythropoietin, thus recruiting additional renal cells for production, and also through stimulation of hepatic cells already producing the factor at lower levels.

Once produced, erythropoietin acts on the erythroid progenitor cells in the bone marrow (as reviewed by Spivak).[12] The earliest progenitor form that can be identified is the erythroid burst-forming unit (BFU-E). These units evolve into erythroid colony-forming units (CFU-E), and erythropoietin acts primarily on these cells by stimulating cell division and maturation and reducing apoptosis.[19]

Due to the potential for exponential increases in erythropoietin production and its exponential effect on bone marrow, the RBC production process must be tightly regulated to avoid large variations in red cell mass in a given individual over time.[20,21] Precise regulation does indeed seem to occur, as both hemoglobin and erythropoietin levels remain remarkably constant in a given individual, with fluctuations of erythropoietin primarily due to diurnal variation.[22]

Between individuals, however, there may be wide variations in erythropoietin and hemoglobin levels, and therefore, the normal ranges for these parameters are large. The precise control of RBC production appears to be accomplished by rapid down-regulation of the erythropoietin gene, and by the fact that receptors for erythropoietin are seen only in late BFU-E and CFU-E.[23,24] In these cells, clonal expansion is much more limited than in early BFU-E, which are regulated in part by cytokines such as interleukin (IL)-3, granulocyte-macrophage colony-stimulating factor (GM-CSF, Leukine), and insulin-like growth factor 1 (IGF-1).[25,26] In patients with cancer, this efficient and conservative system for regulating RBC production can be substantially disturbed.

The Pathophysiology of Anemia

In considering anemia in patients with cancer, it is important to realize that, with the exception of a few, relatively rare, inherited conditions involving RBC defects, anemia is always secondary to some other underlying abnormality. Indeed, anemia seen in the setting of cancer can be totally unrelated to the presence of cancer. Anemia in patients with cancer can be due either to a shortened red blood cell lifespan or to an inability of the erythropoietin-producing cells/bone marrow to respond appropriately to tissue hypoxia (see Table 2).

There are many possible causes for a shortened RBC lifespan. The most common cause is mucosal blood loss, which may or may not be tumor-associated, or hemorrhage into soft tissues, which is frequently a complication of anticoagulant therapy or a result of impaired coagulation associated with cancer. Hemolysis, of both an immune and nonimmune nature, must be considered, as well as microangiopathic processes, and, more rarely, hematophagocytosis.

The conditions potentially involved in impaired erythropoietin-producing cells/bone marrow responsiveness are more varied. In cancer, as in other conditions, including chronic infections, inflammatory conditions, and congestive heart failure, a common set of factors results in anemia, referred to as the anemia of chronic disease. Triggered by the immune and inflammatory cytokines common to these conditions, especially tumor necrosis factor (TNF), IL-1, and the interferons,[27] reduced erythropoietin production for a given degree of anemia results. That is, a relative erythropoietin deficiency occurs in which less erythropoietin is produced for an individual with anemia of chronic disease at a given hemoglobin level than would be the case in other types of anemia, such as anemia resulting from iron deficiency.

The cytokines involved in anemia of chronic disease may also blunt the response of erythroid progenitors (BFU-E, CFU-E) in the bone marrow to erythropoietin, and thereby decrease RBC production.[27] Other cytokine-mediated effects contributing to anemia include shortened RBC survival and abnormal mobilization of reticuloendothelial iron stores (see Figure 1).[27]

Aside from the effects of anemia of chronic disease, erythropoietin production may be limited by the renal toxicity of chemotherapy or, rarely, radiation renal injury, as well as other coexisting causes of renal insufficiency. Severe catabolism associated with cancer may impair protein production, so that anemia results, or there may be deficiencies of iron, vitamin B12, folate, or possibly vitamin B6, which render the bone marrow unable to produce adequate numbers of red blood cells. The metabolic effects may be compounded by physical factors; the bone marrow may be displaced by tumor metastases or fibrosis or, rarely, damaged by bone marrow necrosis. Chemotherapy or radiation therapy may additionally cause depletion of pluripotential stem cells or cause dysmyelopoiesis.

Diagnosing the Cause of Anemia in Patients With Cancer

While anemia in cancer patients will most commonly prove to be due to the presence and effect of cytokines, as previously outlined, plus the direct toxic effects of chemotherapy and radiation therapy, diagnostic steps (as reviewed by Spivak)[12] are important and should not be omitted. Proceeding directly to treatment of anemia based on assumption of cause may result in a failure to correctly diagnose etiologies that require more specific treatments.

When considering the likely cause of anemia in a patient with cancer, it is important to know the extent and type of prior chemotherapy and radiation therapy the patient has received. The type of cancer is important, since, as previously discussed, certain cancers have a comparatively greater propensity to cause anemia. Knowledge of a patient’s prior hemoglobin levels and the time course of the decrease in hemoglobin, as well as any associated clinical events, is also important in helping to focus the differential diagnosis.

Of particular importance on physical examination are the degree of muscle wasting and other signs of protein catabolism, an evaluation of spleen size, and the presence of jaundice. Venous engorgement might suggest the presence of a paraprotein, and excessive bruising or prolonged bleeding from puncture sites might implicate a coagulopathy or disseminated intravascular coagulation. Rectal examination and stool guaiac testing is indicated if gastrointestinal bleeding is suspected.

Before embarking on nonspecific treatment for anemia, the physician or laboratory technologist should review a blood smear, with the aim of better defining the etiology of the anemia. For example, the blood smear might contain spherocytes suggesting hemolysis, fragmented cells implicating a microangiopathic process, rouleaux pointing toward the presence of a paraprotein, or clumping of red blood cells suggesting an agglutinin. Nucleated red blood cells might implicate bone marrow replacement by tumor metastases with a myelophthisic process, myelofibrosis, or an acute hemorrhagic or hemolytic process.

Laboratory studies must, at a minimum, include a reticulocyte count. An extremely low count might indicate RBC aplasia, or a greatly increased count might indicate hemolysis. Creatinine and indirect bilirubin levels should also be measured. In appropriate situations, measurement of iron, transferrin, serum transferrin receptor, and ferritin levels are indicated, although interpretation is confounded by the effect of the underlying cancer on each of these parameters. Guaiac stool testing, vitamin B12, folate, serum protein electrophoresis, and testing for autoantibodies are sometimes indicated, based on the clinical situation, as is the examination of a bone marrow specimen.

Measurements of erythropoietin levels are only infrequently beneficial in the differential diagnosis of anemia of cancer and are rarely useful in this situation. They may, however, be of use in other settings; for example in myelodysplasia, where measurement of erythropoietin levels can help predict whether a patient is likely to respond to treatment with erythropoietic therapy.

Treatment of Anemia

The assessment and treatment of anemia are summarized in Figure 2. Even with thorough investigation, it is possible that no one specific etiology for a patient’s anemia will be found, for which a targeted therapy could be initiated. The cause is then suspected to be chronic anemia of cancer, which may or may not be aggravated by other cancer or non-cancer-related factors, in particular concurrent chemotherapy. There are then several possible approaches that a clinician could pursue:

• A "watch and wait" strategy, with therapeutic intervention only if the anemia worsens to a severity level at which red blood cell transfusion is necessary
• A more proactive approach using erythropoietic therapy, or
• A combination of the two.[28]

Treatment Using a ‘Watch and Wait’ or Transfusion Approach

The "watch and wait" approach has its historical basis prior to the clinical availability of recombinant human erythropoietin in the 1990s.[29,30] Transfusion with two or more units of packed RBCs was usually initiated when hemoglobin fell below 8 g/dL. Each unit would normally yield a 1 g/dL incremental increase in measured hemoglobin levels.[28] However, it has been noted frequently that transfusion usually produces only small benefits in performance status. This, in addition to potential transfusion-related complications (Table 3), led clinicians to view the use of transfusions in anemic cancer patients somewhat negatively. They acknowledge that transfusions are sometimes necessary, but the prevalent view is that they generally offer little benefit to patients other than protection from the cardiovascular effects of extremely low hemoglobin levels.

The explanation for this perceived lack of benefit for patients has perhaps best been demonstrated in a study by Cleeland and colleagues.[31] In analyzing the data from two large, community practice-based trials of epoetin alfa (Epogen, Procrit)[32,33] Cleeland et al showed that there was little improvement in quality of life when hemoglobin levels were increased to 10 g/dL, the hemoglobin target often aimed for with transfusion. The greatest incremental benefit in quality of life was seen when hemoglobin increased from 11 to 12 g/dL, precisely the level below which tissue hypoxia in the normal subject up-regulates endogenous erythropoietin release.[17] This effect has been confirmed in a more recent review of the data from more than 7,000 patients; most of the observed improvement in quality of life occurred with hemoglobin levels between 10 and 12 g/dL.[34]

In today’s treatment setting, the availability of erythropoietic therapy has made it less desirable to take the "watch and wait" approach, which invariably leads to patients experiencing excessive fatigue and poor quality of life. Also, transfusion guidelines now encourage a reduced use of allogeneic transfusion, and avoidance of automatic transfusion when hemoglobin falls below 10 g/dL. The current recommendation is to transfuse only for anemia that fails to respond to other treatment.[35,36]

Erythropoiesis-Stimulating Therapy

Large community-based clinical studies of recombinant human erythropoietin[32,33,37] have raised awareness of the benefits of higher hemoglobin levels in patients undergoing chemotherapy. A previous study[38] showed a statistically significant benefit, in terms of reduction in transfusion requirements, in patients concurrently receiving erythropoietic therapy and chemotherapy, but has failed to show this statistically significant benefit in anemic patients not undergoing chemotherapy.

It was not until the late 1990s that erythropoietic therapy began to be used more frequently to treat anemia in patients with cancer. Primarily driving this shift in clinical practice was the clinical recognition that it was possible to administer erythropoietic therapy once-weekly at a dose of 40,000 units, instead of the Food and Drug Administration (FDA)-licensed regimen of approximately 30,000 units per week in three divided doses. This finding was later corroborated in a large, open-label study.[37] The dose could also be increased to 60,000 units once-weekly in those patients who did not respond adequately to the lower dose. Currently two erythropoietic agents are approved for use in the United States in cancer chemotherapy anemia patients: epoetin alfa (Procrit) and darbepoetin alfa (Aranesp); their doses and schedules of administration are outlined in Table 4 (see opposite page). Darbepoetin alfa has a longer half-life, requiring less frequent dosing.

With the development of objective means of assessing quality of life in cancer and anemia, such as the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire, with the subscales FACT-Fatigue (FACT-F) and FACT-Anemia (FACT-An), it has become easier to evaluate the impact of anemia treatment on the lives of patients with cancer.[4,39] Use of these assessment scales has led to better recognition of the QOL benefits of erythropoietic therapy. A recent review reported, however, that 52% to 70% of cancer patients, with a range of tumor types, did not receive erythropoietic therapy despite being anemic.[40]

Underuse of Erythropoietic Therapy

Two main factors contribute to the underuse of erythropoietic therapy:

• First, approximately 40% to 50% of patients treated with erythropoietic therapy are "nonresponders" to such therapy. It should be noted, however, that these patients may well have benefited from treatment, but just not have reached the standard definition of hemoglobin response (³ 2 g/dL from baseline), or the newer criterion of hematopoietic response- achievement of a hemoglobin rise of ³ 2 g/dL response or achievement of a hemoglobin level of ³ 12 g/dL).
• Second, due to the failure of early studies[38] to show significant transfusion reduction in the nonchemotherapy cohort of patients, there is no FDA-licensed indication for the use of erythropoietic therapy in the large number of anemic patients with cancer not undergoing cytotoxic treatment. Subsequent data have suggested that there may be a transfusion reduction in this patient population, but further confirmation is still required.[41] Importantly, there is a paradigm shift in practice, with the aim of therapy for anemia increasingly being to preserve and improve patient function and quality of life, rather than just intervene to avoid transfusion.

The problem is compounded by the fact that, for many patients, erythropoietic therapy is initiated only after hemoglobin levels are already too low for patients to substantially benefit from treatment. Starting therapy at, for example, a hemoglobin level of 9 g/dL, means that even an increase of 2.5 g/dL will not result in optimal functional hemoglobin levels.

This is further complicated by the fact that many patients with cancer, especially those with smoking-related cancers and those with comorbid conditions causing compromised lung function, are physiologically anemic even when their hemoglobin levels fall in the accepted "normal" ranges. In this setting, tissue hypoxia causes up-regulation of erythropoietin production, resulting in the development of secondary polycythemia at their baseline status. Thus, a lung cancer patient with a hemoglobin level of 13 g/dL may already have a 25% or greater reduction in basal hemoglobin level. Therefore, even when current best practice guidelines are employed, with initiation of erythropoietic therapy at hemoglobin levels of 10.5 to 11.0 g/dL, this relatively large group of patients is probably inadequately treated. Thus, optimal therapy now encompasses earlier initiation of erythropoietic therapy in patients with anemia receiving chemotherapy.

Impact of Anemia on Treatment Outcomes

Another important issue concerns the impact of anemia on therapeutic outcomes. Two studies have generated interesting results-one with epoetin alfa[5] and one with the novel erythropoiesis-stimulating protein darbepoetin alfa (Aranesp),[42] which has been shown to have a longer serum half-life than epoetin alfa in the chronic kidney disease setting.[43]. Both studies retrospectively suggested a potential survival advantage when using an erythropoietic agent in anemic subjects receiving chemotherapy.

The literature on radiotherapy also contains many studies showing that hemoglobin levels may be a predictor of outcome.[7,44-47] One study in patients receiving combination chemoradiotherapy has suggested that erythropoietic therapy produces outcome benefits as a result of hemoglobin levels.[48]

The observed effects of anemia on therapeutic outcomes, if proven in prospective studies in the next few years, may well result in a change in practice to include treating cancer patients receiving chemotherapy or radiotherapy with erythropoietic proteins to prevent the occurrence of anemia. This could result, potentially, in improved responses to chemotherapy and radiotherapy, and may also lead to improved survival outcomes.

Even these developments, unfortunately, would not affect the treatment of anemia in patients with cancer not receiving chemotherapy. As has previously been noted, a registrational study[38] failed to show a statistically significant reduction in the need for transfusions in this group of patients. These are, for the most part, patients with breast or prostate cancer on hormonal therapy, patients with lymphoma not receiving chemotherapy, and patients with extensive prior chemotherapy or irradiation for solid malignancies.

While no outcome enhancement of their therapy is likely to result from erythropoietic treatment, preliminary studies with epoetin alfa[49] and darbepoetin alfa[50,51] have been undertaken. In the epoetin alfa study, 49% of patients were reported to achieve a hemoglobin response. In the study utilizing once-weekly darbepoetin alfa, 92% of patients in the highest dose cohort (4.5 m/kg) achieved a hemoglobin response, with 100% of those patients showing a hematopoietic response. This latter study has also shown that even when dosing as infrequently as once every 4 weeks with darbepoetin alfa, 60% to 70% of patients at three different doses still appeared to achieve a hematopoietic response. Further, quality of life has been shown to improve with darbepoetin alfa treatment,[52] and in those patients not subjected to the detrimental effects of chemotherapy, there is probably even greater potential for improved quality of life and functional capacity. Phase III studies to confirm this result are planned.

Conclusions

Anemia is the most frequent and perhaps least appreciated hematologic abnormality seen in cancer. Patients with anemia may experience a variety of debilitating symptoms, which lead to poorer quality of life, and anemia is potentially associated with poorer disease and treatment outcomes. To optimally approach anemia in a clinical setting, it is necessary to understand the erythropoietin system that regulates RBC production. A rigorous diagnostic evaluation should be undertaken in cancer patients with a diagnosis of anemia, to identify the underlying cause and enable initiation of the appropriate treatment.

Management of anemia in patients with cancer using an erythropoiesis- stimulating protein and, if necessary, RBC transfusion has been shown to have a proven QOL benefit. The literature also suggests that improved treatment outcomes may be associated with erythropoietic therapy, although this effect remains to be confirmed. Data also suggest that treatment with the novel erythropoiesis-stimulating protein darbepoetin alfa may improve hemoglobin levels and quality of life in anemic patients with cancer who are not receiving chemotherapy or radiotherapy. Future prospective studies may show that using erythropoietic agents in a preventive manner in cancer patients receiving chemotherapy or radiotherapy may also have a beneficial effect on treatment outcomes. This would continue to shift the paradigm of anemia therapy from a transfusion-based approach to one of maintaining optimal hemoglobin levels by erythropoietic therapy.

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