Role of Iron in Optimizing Responses of Anemic Cancer Patients to Erythropoietin

Role of Iron in Optimizing Responses of Anemic Cancer Patients to Erythropoietin

Increasingly, oncologists are recognizing the importance of understanding the patient’s perception of anticancer treatment. Supportive care for cancer has improved to the point that patients no longer need fear overwhelming nausea, uncontrolled pain, or high risks of life-threatening infections from myelosuppression. However, minimizing the toxicity of therapy and the negative impact of cancer on the patient’s functional status is still not the same as maximizing the patient’s ability to live a full, normal life. A new paradigm of cancer management has focused on how to help patients live with cancer as a chronic disease. How can oncologists provide patients with the tools to help them achieve this goal?

One strategy has been to measure how well patients function in the activities of their daily lives, as assessed by the patients themselves.[1] Typically, cancer patients score low on such assessments.[2] Much research has focused on how to improve the functional status of cancer patients, especially those undergoing chemotherapy.

The poor functional status of cancer patients has important implications, particularly with respect to the quality of their lives. Also, the economic implications are clear because patients may not return to their jobs and may require more costly caretaker support. Therapies that can decrease the debilitation of cancer patients are likely to improve patient satisfaction and, if effective and used judiciously, are likely to lead to economically favorable results.

How Should rHuEPO Be Used in Oncology?

One of the more controversial areas in the supportive care of cancer patients revolves around the use of recombinant human erythropoietin (rHuEPO, known as epoetin alfa [Epogen, Procrit] in North America). Prospective, randomized, placebo-controlled clinical trials have demonstrated the efficacy of rHuEPO in stimulating erythropoiesis in cancer patients. This, in turn, leads to a decreased need for transfusions and—intriguingly—is associated with improved patient-reported quality-of-life indicators (such as energy level and the ability to carry on normal activities).

Subsequent to the randomized studies, large, nonrandomized, community-based studies in more than 4,000 patients have confirmed these initial observations.[3,4] In addition, these observations are comparable to the magnitude of effect seen with rHuEPO stimulation of erythropoiesis in dialysis patients.[5]

The physiology of anemia suggests that patients would likely not feel completely “normal” while their circulating hemoglobin is low, and that has proven to be true when investigated in these multiple settings. It is important to recognize that the degree to which anemia (as a single variable) affects a cancer patient’s quality of life remains unclear. However, there is a clear consistency in the studies of rHuEPO to date, which demonstrate a clear correlation among lower energy levels, decreased capacity to live a normal life, and poorer overall “quality of life” in patients with lower levels of hemoglobin.

Nonetheless, because transfusion has been viewed as an acceptable substitute for rHuEPO in the management of anemia, oncologists have varied widely in their acceptance of rHuEPO as a useful therapeutic agent for anemic cancer patients. Although some cost offsets may be recovered by decreased transfusion utilization,

rHuEPO almost certainly will add costs within a health care system. Fears of increasing overall costs of care have hindered the more routine acceptance of rHuEPO in clinical oncology. However, identifying groups of patients in whom quantifiable, important gains can be achieved by rHuEPO would take the discussion into the realm of “quality of care,” where additional costs may be justified if important clinical outcomes are improved.

An Important Question

One important question surrounding rHuEPO use is how to optimize its effectiveness in patients. Although between 40% and 60% of patients respond to this agent, not all patients have comparable responses. Clearly, iron represents a key component required for rHuEPO to stimulate the production of red blood cells. If patients are not properly assessed for functional iron deficiency, supplementation with rHuEPO is inappropriate, resulting in the use of an expensive agent in a setting where it is doomed to be ineffective. In our experience, the incidence of borderline iron stores is quite high, especially in younger women, and ignoring this fact limits the effectiveness of rHuEPO supplementation.

Glaspy and Cavill nicely summarize many of the issues surrounding rHuEPO use in oncology and identify the oft-neglected importance of iron supplementation in ensuring an optimal erythropoietic response. Oral iron preparations vary with respect to patient tolerability, with some causing a high incidence of gastrointestinal side effects. Although some of the newer oral iron preparations are far more tolerable than the older ones, all of these products can potentially cause problems.

The overview of intravenous iron administration presented in this article is useful, in that it accents the lack of definitive data on the optimal iron-loading strategy. Most clinicians are understandably concerned about the potential of intravenous iron to induce sporadic anaphylactoid reactions. Better understanding of this rare—but worrisome—adverse reaction would assist clinicians in making informed decisions about the potential risks and benefits of this method of iron repletion.

Which Patients Are Appropriate Candidates for rHuEPO?

We will all continue to struggle with the controversy of identifying patients who are appropriate candidates for rHuEPO therapy. Were it not for the costs, most cancer patients would probably be offered a trial of this agent. However, given the cost-consciousness of modern medicine, it is important to identify patients in whom rHuEPO offers maximal value: In other words, in which patients does it confer a clinically relevant benefit?

If the characteristics of these patients could be identified, more rational use of this agent would follow. As most studies show, if a medical therapy truly provides an important, measurable clinical benefit in a patient, use of that therapy is virtually always worthwhile. Measuring the value and optimizing the effectiveness of rHuEPO in the appropriate groups of patients seem like reasonable goals that can help us all to help our patients feel better while living with cancer.


1. Yellen SB, Cella DF, Webster K, et al: Measuring fatigue and other anemia-related symptoms with the Functional Assessment of Cancer Therapy (FACT) measurement system. J Pain Symptom Management 13:63-74, 1997.

2. Cella DF, Bonomi AE: Measuring quality of life: 1995 Update. Oncology 9(suppl 11):47-60, 1995.

3. 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.

4. 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.

5. Adamson JW, Eschbach JW: Erythropoietin for end-stage renal disease. N Engl J Med 339:625-627, 1998.

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