Management of Anemia in Cancer Patients

Aknar Calabrich; Artur Katz

Future Oncol. 2011;7(4):507-517.

Anemia in Cancer Patients

Anemia can compromise the delivery of sufficient amounts of oxygen to all cells, including tumor cells. This hypoxic condition can worsen the results of radiotherapy and chemotherapy, because low tissue oxygenation is associated with a reduced sensitivity of tumors to radiation and some forms of chemotherapy, contributing to the progression of cancer and reduction in survival.^[4,5] Furthermore, there is abundant evidence suggesting that hemoglobin levels of less than 12 g/dl result in worse QOL and functional status for cancer patients when compared with higher levels. Present treatment options for anemia include blood transfusions, iron supplementation when there is iron deficiency or erythropoiesis-stimulating agents (ESAs), such as recombinant human erythropoietin (EPO) and darbepoetin-α.^[6] Given the impact of anemia on the survival of cancer patients, the management of anemia has been explored in several clinical trials to date.^[7]

The epidemiology of anemia in cancer patients was evaluated in at least two large studies. The European Cancer Anemia Survey (ECAS), conducted between 2001 and 2002, was a large, prospective study of 15,367 patients with cancer at any stage and who were undergoing treatment of any type.^[8] Approximately 40% of patients had hemoglobin levels lower than 12 g/dl, and 75% of patients undergoing chemotherapy developed anemia within 6 months. Factors independently associated with the development of anemia were the baseline level of hemoglobin, the site of the primary tumor, the use of platinum-containing regimens, female gender, advanced age and low performance status. An interesting finding from the ECAS study was that only 40% of patients received treatment for anemia: 17.4% of patients were treated with EPO, 15% received blood transfusion and only 6.5% were treated with iron. The Anemia of Cancer Therapy (ACT) study was a retrospective, observational evaluation of 2192 cancer patients with hemoglobin levels of less than 11 g/dl, conducted between 2005 and 2007.^[9] This study evaluated the patterns of treatment for anemia and the effectiveness of such treatment. The ACT study found a greater percentage of patients treated for anemia (68.3%) than the ECAS study: ESAs were used in 62.2% of patients, blood transfusions were performed in 19.4% of patients and 32.8% received iron supplementation. In the ACT study, the use of ESAs was able to raise hemoglobin levels by an average of 1.34 g/dl. The differences between these two studies in the proportion of patients treated for anemia, as well as in the use of therapeutic modalities, suggest a growing recognition of the importance of management of anemia in cancer patients.

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Table 1. Grading of anemia according to the National Cancer Institute.
Grade	Hemoglobin level/definition
0	≥lower limit of normal
1	10 g/dl to lower limit of normal
2	8.0–9.9 g/dl
3	6.5–7.9 g/dl
4	<6.5 g/dl
5	Death

Data taken from [101].

Table 2. Recommendations for the use of erythropoiesis-stimulating agents in patients with nonhematological malignancies.
Organization	Anemia related to chemotherapy	Untreated patients	Patients treated with curative intent	Ref.
ASH/ASCO	ESAs indicated for Hb ≤10 g/dl. Hb target is lowest value to avoid BT. BT is an option If Hb is between 10 and 12 g/dl, consider ESAs according to clinical condition. BT is an option	ESAs are not recommended	There is no specific recommendation	[45]
NCCN	BT if immediate correction is necessary Consider treatment with ESAs by US FDA indications/dosing/dosing adjustments, under REMS	BT according to symptoms ESAs are not recommended	ESAs are not recommended	[103]
US FDA	Therapy should not be initiated at Hb levels ≥10 g/dl Use the lowest dose of ESAs able to raise the levels of Hb values to avoid BT	ESAs are not recommended	ESAs are not recommended	[104]
EORTC	ESAs should be initiated at an Hb level of 9–11 g/dl based on anemia-related symptoms ESAs may be considered in selected asymptomatic patients with a Hb level of 11–11.9 g/dl if this would prevent a further decline in Hb iv. iron use should be reserved for patients with absolute or functional iron deficiency	ESAs may be given in selected patients with a Hb level of 9–11 g/dl	There is no specific recommendation	[43]

ASCO: American Society of Clinical Oncology; ASH: American Society of Hematology; BT: Blood transfusion, EORTC: European Organisation for Research and Treatment of Cancer; ESA: Erythropoiesis-stimulating agent; Hb: Hemoglobin; iv.: Intravenous; NCCN: National Comprehensive Cancer Network; REMS: Risk evaluation and mitigation strategy.

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Executive Summary

Erythropoiesis-stimulating agents

Erythropoiesis-stimulating agents (ESAs) are capable of increasing hemoglobin levels in most anemic patients with cancer.
Using ESAs to treat anemia in cancer patients reduces transfusion requirements and improves quality of life, predominantly by reducing fatigue.
ESAs increase the risk of thromboembolic events.
During chemotherapy, ESA treatment should be initiated when hemoglobin values are lower than 10 g/dl.
There is no evidence of increased mortality when the target hemoglobin levels during treatment with ESAs were less than 12 g/dl in patients receiving anticancer treatment.
ESAs should not be used in patients with cancer who are not receiving chemotherapy.

Iron

Chemotherapy is associated with abnormal iron metabolism.
Another mechanism contributing to iron deficiency in cancer patients is the low bioavailability of orally administered iron.
The use of intravenous iron (and not oral iron) during treatment with ESAs may improve hemoglobin levels even in the absence of depleted iron stores (or absolute iron deficiency).
Recommendations for the optimal formulations, doses and treatment schemes of iron supplementation concurrently with ESA treatment in cancer-related anemia need to be established.

Blood transfusion

Blood transfusion is capable of immediately correcting the signs or symptoms resulting from anemia.
There is wide variation in the levels of hemoglobin that are used to justify blood transfusions among the various studies and among different types of cancers.
There are several acute hazards related to blood transfusion, and long-term side effects have not been properly studied.

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