For Physicians

Controversies in Treatment of Anemia for Cancer

Anemia is very common in cancer patients and it is under-recognized and under-treated. Anemia develops in up to 90% of patients, and as many as 60% receive no therapy for it, reducing their quality of life, and arguably increasing their potential for disease progression¹.

Diagnosis

The most common laboratory findings are similar to those described in the anemia of inflammation: a normochromic, normocytic anemia characterized by an underproduction of red cells. The low reticulocyte response is a sign of inadequate repair of anemia due to bone marrow suppression. Erythroid marrow activity appears either normal or hypoproliferative; the expected compensatory erythroid hyperplasia for anemia is lacking. Serum erythropoietin, serum iron, and transferrin saturation may be normal or low, serum ferritin usually is increased (often > 500 ng/mL), and the marrow shows increased iron stores. Late in the course of the anemia, red cells actually may become microcytic and hypochromic, creating confusion with iron deficiency.

Anemia is very common in cancer patients and it is under-recognized and under-treated. Anemia develops in up to 90% of patients, and as many as 60% receive no therapy for it, reducing their quality of life, and arguably increasing their potential for disease progression¹.

Diagnosis

The most common laboratory findings are similar to those described in the anemia of inflammation: a normochromic, normocytic anemia characterized by an underproduction of red cells. The low reticulocyte response is a sign of inadequate repair of anemia due to bone marrow suppression. Erythroid marrow activity appears either normal or hypoproliferative; the expected compensatory erythroid hyperplasia for anemia is lacking. Serum erythropoietin, serum iron, and transferrin saturation may be normal or low, serum ferritin usually is increased (often > 500 ng/mL), and the marrow shows increased iron stores. Late in the course of the anemia, red cells actually may become microcytic and hypochromic, creating confusion with iron deficiency.

Mechanism

Anemia develops through complex mechanisms. Active cancer impairs production of erythropoietin (EPO) and this suppresses the marrow erythroid response. Furthermore, the mobilization of iron from iron stores is blocked, curtailing the delivery of iron to the marrow. There may be a mild shortening of red cell life span, and often marrow erythroid reserve also is limited by the effects of chemotherapy.

Blunting of EPO synthesis is the result of over-production of pro-inflammatory cytokines that interfere with the usual upregulation of the EPO gene during anemia/hypoxia². The cytokine-mediated suppression of erythropoietin is reversed by exogenous EPO in some but not all cases.

Hepcidin appears to play the central role in blocking iron mobilization from tissue stores and the G-I tract, thereby impairing delivery to the marrow. This polypeptide hormone is produced by hepatocytes and monocytes, and under normal conditions is the main regulator of iron absorption and tissue distribution. Abnormally high levels of hepcidin are stimulated by the pro-inflammatory cytokines (such as IL-6) that occur in metastatic cancer. Hepcidin then inhibits the release of cellular iron, trapping it in jejunal enterocytes and hepatic, splenic, and other iron storage sites. Iron transfer to the marrow therefore is impaired causing iron-restricted erythropoiesis, otherwise designated as “functional or relative iron deficiency”². This defect in iron utilization explains the increased ferritin, low serum iron and percent transferrin saturation, and if severe, hypochromic, microcytic red cells.

Treatment with Erythropoietin (EPO)

It has been estimated that about 50% of cancer patients on chemotherapy will require red cell transfusions before the completion of treatment. Many clinical trials worldwide have confirmed that erythroid stimulating agents (ESA) can be very effective in raising the hemoglobin (Hgb) and lowering transfusion requirements. Millions of individuals have been treated with ESAs for the anemia of cancer and other types of anemia. The early ESA trials had a clinical endpoint of avoidance of transfusions by achieving a target hemoglobin of about 11 g/dL. Subsequently, open label and community-based trials also focused on improving quality of life (QOL) with the largest improvement occurring at Hgb 11-12 g/dL². However, a scientific randomized and blinded U.S trial did not find statistical improvement in QOL⁴, while a similar British trial, also with a target Hgb of 12-15 g/dL, to the contrary reported considerably better QOL, and in fact, a (non-statistical) trend towards improved survival³.

This set the stage for trials with survival or disease progression as clinical endpoints. To accomplish this, it was theorized that the target hemoglobin should be pushed as close to normal as possible, although this was off-label treatment. This policy proved to be very unfortunate, because when Hgb targets were 12-14 g/dL ESAs were found not to be as safe as portrayed. Four trials of cancer patients taking chemotherapy and ESAs reported decreased overall survivals, and of two radiotherapy trials, one reported decreased survival and the other decreased locoregional control. Decreased overall survival on ESA even was reported in two trials of anemic cancer patients not being treated with chemo-or radiotherapy⁵. Of five meta-analyses performed to clarify these disturbing results, three reported increased and two found no significant effect on mortality⁶. However, the association between ESAs and thromboembolic risks (arterial and venous) was more definite. Four meta-analyses established a significant risk for thrombotic events with ESA usage, and another study, a combined analysis of six trials, found a correlation between thromboembolism risk and Hgb >12 g/dL⁶. The increased thrombotic risk even extended to anemic active cancer patients not on chemotherapy when treated to a target Hgb of 12-13 gm/dL ⁷.

These safety concerns led to black box warnings on ESA product labels and warning letters from manufacturers to physicians indicating that ESA treatment should be administered only to patients with non-myeloid malignancies receiving palliative chemotherapy and/or radiotherapy, and should cease when this therapy has been completed. The trigger for ESA treatment was lowered to a Hgb of 12 g/dL. Also, ESAs were no longer indicated for patients undergoing chemotherapy with curative intent, such as those receiving adjuvant or curative chemotherapy. The recommendations were quite similar to guidelines adopted by ASH, ASCO, and Medicare/Medicaid ^5,6.

The rather restrictive guidelines were driven mainly by data accumulated when the target was to normalize the Hgb of cancer patients, many of whom were ill and had other comorbid conditions. It is unknown if shortened survivals and increased thromboembolism would have occurred had the target Hgb been kept in the 11-12 g/dL range as intended when ESAs were marketed initially.

Iron Therapy for the Anemia of Cancer

Unless cancer patients have been bleeding or are grossly malnourished, they usually have increased iron stores as described above. It is counterintuitive but nevertheless true, that iron-replete cancer patients with anemia often respond to intravenous iron and have poor responses to oral iron. This is especially true when ESAs are administered, since red cells are being produced at a more rapid rate and there is a greater need for iron delivery to the bone marrow. Although intravenous iron bypasses the hepcidin-induced block in iron release and also enhances the ability to saturate transferrin, the precise reason for its effectiveness is unknown.

Treatment for so-called “functional iron deficiency anemia” of cancer involves the administration of iron, and evidence from five published studies of patients on ESAs indicated that IV iron was much superior to oral or no iron. The endpoints of these trials were the percentage of patients able to reach a target Hgb and the duration of time it took to do so ⁹. In addition, one study also found a significant reduction in the rate of transfusions. Recently, the largest clinical trial of ESA and IV iron to date reported conflicting results showing no benefit with the addition of IV iron to ESAs, but this discrepancy could relate to the fact that many enrolled patients did not have the laboratory features of true functional iron deficiency⁸ (high ferritin with transferrin saturation <20%). Overall, the conclusion to these ESA studies has been that IV iron may not only enhance the hematological response, but also reduce the total dose of ESA needed as well as the number of transfusions^6,9. Currently, management guidelines recommend considering the addition of IV iron to ESA provided the cancer-related anemia fulfills the criteria for functional iron deficiency. In the end, this regimen could reduce costs significantly.

Not everyone agrees, since IV iron adds additional costs including physician visits, and even though current IV iron preparations are much safer than before, reactions still may occur. An alternative approach would be to reserve IV iron for patients with inadequate or no response to ESAs after five or six weeks of treatment.

References:

1. Vaupel P., Oncologist, 2008, 13 Supp 3:21
2. Adamson J., ASH Education Book, 2008, p.159
3. Littlewood T., J Clin Oncol, 2001, 19:2865
4. Witzig T., J Clin Oncol, 2005,23:2606
5. Fishbane, S., Am J Manag Care, 2010, 16:S67
6. NCCN Guidelines, Ca CT-Ind Anemia, Version 2.2011
7. Smith R., J Clin Oncol, 2008, 26:1040
8. Steensma D., Blood, 2009, 114:abs 630
9. Shander A., Transfusion, 2010, 50:719

This newsletter is meant as a review and not as a guideline for medical treatment.