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The Oncologist, Vol. 3, No. 4, 275-278, August 1998
© 1998 AlphaMed Press

Commentary

Supplemental Iron: A Key to Optimizing the Response of Cancer-Related Anemia to rHuEPO?

David H. Henry

Allegheny University of the Health Sciences, Graduate Hospital, Philadelphia, Pennsylvania, USA

Correspondence: David H. Henry, M.D., Allegheny University of the Health Sciences-Graduate Hospital, 1840 South Street, 2nd Floor, Philadelphia, Pennsylvania 19146, USA. Telephone: 215-893-7520; Fax: 215-893-7461; e-mail: dhhenry{at}juno.com


   Abstract
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 Abstract
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About 50% of cancer patients develop anemia; this incidence rises dramatically in patients with more advanced cancer or in those receiving chemotherapy or radiation therapy. Since the late 1980s, recombinant human erythropoietin (rHuEPO) has provided a safe and effective option for treating cancer-related anemia and fatigue. However, only about 50% of patients treated with rHuEPO adequately respond to therapy.

In the chronic renal failure (CRF) population, true iron deficiency is the most common cause of an inadequate response to rHuEPO. Functional iron deficiency occurs when iron cannot be provided rapidly enough to meet the demands of rHuEPO-induced erythropoiesis, despite the presence of adequate bone marrow iron stores. It is hypothesized that functional iron deficiency can also occur in cancer patients receiving rHuEPO and may account for the lack of response in a proportion of the oncology population.

Studies in CRF patients have shown that the administration of i.v. iron can correct functional iron deficiency more effectively than oral iron and may improve rHuEPO response. Therefore, it is important to monitor iron status and to address either true or functional iron deficiency prior to and during rHuEPO therapy to optimize the effect of rHuEPO in cancer patients. Studies are currently under way to determine the role of i.v. iron in treating cancer-related anemia.

Key Words. Recombinant human erythropoietin (rHuEPO) • Anemia • Intravenous iron • Iron deficiency • rHuEPO resistance • Serum ferritin • Transferrin saturation

Recombinant human erythropoietin (rHuEPO; Procrit®) is recognized as a safe and effective option in addition to or instead of transfusion for the treatment of anemia in cancer patients. Less recognized, however, is the role of iron supplementation to ensure an optimal response to rHuEPO in this patient population. In patients with chronic renal failure (CRF), iron deficiency is the most common cause of an inadequate response to rHuEPO therapy [1].

Anemia is common in patients with cancer, with a prevalence approaching 50%. This figure may rise to over 90% in patients with more advanced cancer or in those treated with chemotherapy or radiation therapy.

Anemia in cancer patients is often attributed to the anemia of chronic disease (ACD) [2], a form of anemia mediated by inflammatory cytokines [3, 4]. These cytokines have a direct inhibitory effect on erythropoiesis and may also inhibit the production of erythropoietin. [5, 6] ACD frequently develops in patients with any chronic inflammatory illness [7]. Other contributing causes of anemia in cancer patients include chemotherapy [8] and radiation therapy, nutritional factors [9], and bleeding associated with gastrointestinal [10] or genitourinary malignancies [11]. In contrast, anemia in CRF patients is largely caused by the insufficient production of erythropoietin by the diseased kidneys [12], as well as ongoing blood losses associated with the dialysis procedure [13].

In the past, transfusion was the only choice for the treatment of cancer-related anemia. Transfusion results in a rapid rise in hemoglobin and is safer today than ever before. Nevertheless, it still carries the risk of infection, allergic reactions, or adverse immunologic effects that may decrease the time to tumor relapse and reduce overall survival.

The introduction of rHuEPO in the early 1990s provided a new option for the treatment of cancer-related anemia. The increase in hematocrit in cancer patients treated with rHuEPO is accompanied by an improved quality of life and a decreased transfusion requirement [11]. A community-based study involving more than 2,000 cancer patients treated with rHuEPO found the increase in energy level, activity level, and overall quality of life in responding patients to be independent of the tumor response, indicating that these beneficial effects were not attributable solely to improvement of the underlying disease [14].

Interestingly, only 50% of cancer patients with anemia respond to rHuEPO therapy [8, 11, 15]. The persistence of anemia in some of the nonresponders may be caused by a phenomenon known as functional iron deficiency, which results from the rapid induction of erythropoiesis by rHuEPO. In contrast to absolute iron deficiency, which is characterized by inadequate iron stores (transferrin saturation [TSAT] <20%, and a serum ferritin <100 ng/ml [16]), functional iron deficiency is defined as the failure to provide iron rapidly enough to meet the demands of rHuEPO-induced erythropoiesis, despite the presence of adequate iron stores [17]. In addition to the CRF population [18, 19], functional iron deficiency occurs in other populations receiving rHuEPO therapy, including patients with ACD [20, 21], those undergoing autologous blood donation [22, 23], and normal subjects [24, 25].

The iron needed by developing red blood cells (RBCs) in the bone marrow is provided by the labile iron pool in the reticuloendothelial system (RES). This labile or usable pool of iron is in dynamic equilibrium with iron stores in the RES. Stimulation of RBC production by rHuEPO can exceed the rate of iron mobilization from iron stores to the labile iron pool, despite the presence of sufficient iron in storage form. Additionally, inflammatory cytokines associated with ACD may inhibit storage iron release, limiting the rate of RBC production even further. As a result, the labile pool can be rapidly depleted and the response to rHuEPO can be stalled [26].

Therefore, despite the presence of adequate storage iron, iron supplementation may still be necessary to achieve or maintain the effectiveness of rHuEPO. Oral iron formulations cannot always provide iron rapidly enough to support the accelerated erythropoiesis that occurs with rHuEPO. Furthermore, the high doses of oral iron that would be required in this setting can cause intolerable side effects [26], such as cramping and constipation [27]. Because of these undesirable effects and the need to administer oral iron three times daily [28], patients are unlikely to always comply with an oral iron regimen.

In contrast to oral iron, i.v. iron provides sufficient quantities of iron at the rate needed to sustain erythropoiesis during rHuEPO therapy. Clinical data from patients with CRF show that failed responsiveness to rHuEPO can be restored by administration of i.v. iron [18]. In this population, i.v. iron therapy has been shown to reduce the rHuEPO dose required for the correction of anemia, thereby increasing the cost-effectiveness of this drug [27].

In the United States, all i.v. iron is provided as iron dextran. Two i.v. iron dextran preparations are currently available: Infed® (Iron Dextran Injection, USP) and Dexferrum® (Iron Dextran Injection, USP). It is important to note, however, that these two products are not therapeutically equivalent [29].

The safety of i.v. iron is well documented in CRF patients. In an analysis of the safety of i.v. iron dextran (Infed®) in patients with end-stage renal disease, severe adverse reactions occurred in only 0.7% of 573 patients receiving this i.v. iron preparation [30]. In patients receiving chronic i.v. iron, there is a risk of developing iron overload, which may cause liver and heart damage. There are no published studies that clearly establish an upper limit of serum ferritin or TSAT which will avoid iron overload in patients receiving i.v. iron therapy. In some studies, increased body iron stores may cause a higher incidence of infection [31-34] and may also increase the risk of cancer [35-38]. However, there are no prospective controlled studies that actually link increased iron stores to a higher incidence of infection or cancer risk in humans. Of note, there is no evidence of increased cancer risk or development of tumors in dialysis patients who have received long-term i.v. iron therapy.

Assessment of iron stores is important for detecting functional iron deficiency and determining the need for iron supplementation during rHuEPO therapy. Serum ferritin, although useful for diagnosing absolute iron deficiency, may not be a reliable indicator of iron stores in cancer patients on rHuEPO. Serum ferritin increases with inflammation, and high levels may be seen in patients with ACD and cancer. The most accurate method for detecting functional iron deficiency in these patients is the measurement of the percentage of hypochromic RBCs or reticulocyte hemoglobin content [17]. Such measurements, however, require specialized instrumentation that is not widely available in the United States. Consequently, the best method for evaluating available iron stores in this country at the present time is the TSAT. A TSAT of 20% to 30% generally indicates sufficient iron stores to support erythropoiesis in rHuEPO-treated patients, whereas lower levels may reflect functional iron deficiency.

Correction of functional iron deficiency with i.v. iron, in addition to correction of absolute iron deficiency, might convert a proportion of rHuEPO nonresponders to responders and prevent plateauing of hematocrit after an initial response to rHuEPO. The change in hemoglobin together with either the erythropoietin level or the reticulocyte count increase at two to four weeks after initiation of rHuEPO therapy may be helpful in predicting the likelihood of a response to rHuEPO in patients with adequate iron stores [15].

Correction of anemia by administration of rHuEPO can improve the quality of life in patients with cancer and should not be neglected. An understanding of the concept of functional iron deficiency and the importance of maintaining adequate functional iron stores with iron therapy in patients treated with rHuEPO is essential for optimizing the response to this safe and effective approach to the management of cancer-related anemia. To the extent that a more readily available source of iron is necessary in functional iron deficiency, i.v. iron may play an important role in the treatment of anemia in cancer patients. Clinical trials are currently in progress to evaluate the safety and efficacy of i.v. iron, with or without rHuEPO, in cancer patients with anemia.


   References
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 References
 

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accepted for publication June 18, 1998.




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