Erythropoiesis-stimulating agents (ESAs) in breast cancer

July 1, 2010

Overview

Erythropoiesis-stimulating agents (ESAs) represent a class of biologic drugs that stimulate the production of red blood cells to increase oxygen load in blood.  The drugs are copies of the human hormone erythropoietin and are sold under the generic names epoetin-alfa (Epogen® and Procrit®) and darbepoietin (Aranesp®).

ESAs were originally developed to avoid the need for blood transfusions in patients with chronic renal failure who were experiencing anemia.  ESAs were later approved for cancer patients with anemia associated with chemotherapy.  The definition of anemia and the lower cutoff value of hemoglobin level that necessitate ESA treatment or blood transfusions are not well defined.  Concerns about the safety of ESAs including the possibility that they cause tumors to progress and questions about their efficacy in treating the symptoms of anemia have arisen from numerous studies conducted since the drugs were approved.

Research on ESAs

ESAs were approved in 1989 for the treatment of anemia in chronic renal failure, and approval was expanded in 1993 for chemotherapy-associated anemia in the cancer setting.  Approval for anemia related to chemotherapy was based on six small, randomized trials with a total of 131 patients receiving cancer chemotherapy.  The trials demonstrated ESAs' ability to reduce but not eliminate the need for transfusions; these trials were not designed to show differences in cancer-related outcomes.  FDA noted at the time of approval that ESAs had the potential to promote the growth of tumors (FDA, 2007).

Most of the studies performed to date on ESAs in cancer have targeted hemoglobin levels higher than those recommended (i.e., 10-12 g/dL) according to the currently approved prescribing information, and there is insufficient evidence to support the use of ESAs at the recommended hemoglobin levels. 

Beyond reducing the need for blood transfusions, researchers have examined whether ESAs have an impact on quality of life including assessment of fatigue.  A Cochrane systematic literature review of randomized clinical trials deemed the evidence for the ability of ESAs to improve quality of life including cancer-related fatigue only suggestive (Bohlius, 2007).  Specifically, the quality of the randomized clinical trials was considered marginal, and the effect was difficult to quantify (Bohlius, 2007).  No studies since then have provided convincing evidence of an increase in quality of life associated with ESAs.

Safety concerns with ESAs

Since ESAs were approved for cancer in 1993, a number of randomized clinical trials have attempted to assess the risk/benefit profile of ESAs in cancer including breast cancer.  Troubling safety signals have emerged from these studies leading to a steady increase in the level of warnings in the labeling of these agents. The studies showed that ESAs were associated with toxic effects, particularly thromboembolic events (e.g., blood clots and strokes).  ESAs were also shown to promote tumor progression and in some cases, shortened survival.

Studies of ESAs with cancer-relevant outcomes

The BEST study of advanced breast cancer (Leyland-Jones, 2005)

• Designed to test whether ESAs at a dose that would maintain hemoglobin levels at >12 g/dL, compared with standard transfusion, would improve cancer outcomes and overall survival;
• Showed evidence of poorer survival associated with ESAs;
• Terminated early a second randomized trial in breast cancer because of higher numbers of thrombotic events (e.g., clots and strokes) associated with ESAs.

The PREPARE study of breast cancer (FDA, 2008)

• In the neoadjuvant treatment setting (i.e., patients received chemotherapy treatment before the surgical removal of their tumors, and ESA treatment was given to prevent anemia);
• Primary outcomes were relapse-free survival and overall survival;
• Tumor progression could not be assessed after chemotherapy and ESA treatment because tumors were removed;
• An interim analysis after 3 years of follow up showed that survival and relapse-free survival were lower in the ESA-treated arm than the control arm, although the differences were not statistically significant

The ENHANCE study of head-and-neck cancer (Henke, 2003)

• Shorter overall survival, higher incidence of "vascular disorders," and more deaths due to "cardiac disorders" in ESA-treated chemotherapy patients compared to those not receiving ESAs;
• Designed to look at target hemoglobin levels >12 g/dL.

The DAHANCA study of head-and-neck cancer study (Bohlius, 2007)

• Showed evidence of tumor progression and shorter overall survival.

Three more trials terminated early because of thrombotic and cardiovascular events in the ESA arm (Bohliums, 2007).

• Small cell lung cancer – EPO-CAN-15
• Gastric and rectal cancer - PR00-03-006
• Cervical cancer – GOG 191

Cochrane review of ESAs in cancer looked at overall survival and tumor progression but their results for these outcomes were inconclusive; they did find that ESAs were strongly associated with reduced transfusions (Bohlius, 2007).

FDA actions

FDA oversight has resulted in two black-box warnings in the labeling for ESAs in 2007.  Each of them, incorporating new data, has raised the level of caution regarding the use of ESAs.  The warning in March 2007 reflected the cancer studies showing evidence of ESA's effects on overall survival and/or deaths attributed to disease progression in breast and head-and-neck cancer.  The second, in November 2007, included new warnings that renal failure patients were at greater risk for death and serious cardiovascular events when administered ESAs, and that ESAs shortened overall survival in patients with small-cell lung or lymphoid cancer.  The portions of the current black box warning relevant to cancer read as follows:

WARNINGS: INCREASED MORTALITY, SERIOUS CARDIOVASCULAR AND THROMBOEMBOLIC EVENTS, AND TUMOR PROGRESSIONM

• ESAs shortened overall survival and/or time-to-tumor progression in clinical studies in patients with advanced breast, head and neck, lymphoid, and non-small cell lung malignancies when dosed to target a hemoglobin of > 12 g/dL.
• The risks of shortened survival and tumor progression have not been excluded when ESAs are dosed to target a hemoglobin of < 12 g/dL.
• To minimize these risks, as well as the risk of serious cardio- and thrombovascular events, use the lowest dose needed to avoid red blood cell transfusions.
• Use only for treatment of anemia due to concomitant myelosuppressive chemotherapy.
• Discontinue following the completion of a chemotherapy course.

In February 2010, FDA announced that all prescribed and used ESA drugs will be required to be under a risk management program, known as a risk evaluation and mitigation strategy (REMS) (FDA, 2010).  The manufacturer (Amgen) of these drugs has been required to develop a risk management program because ESAs have been shown to increase the risk of tumor growth and shorten survival in cancer patients who have used these drugs.       

As part of the REMS, all patients will now receive a Medication Guide explaining the risks and benefits of ESA.  In addition to the Medication Guide, Amgen was required to develop the ESA APPRISE (Assisting Providers and Cancer Patients with Risk Information for the Safe use of ESAs) Oncology program for healthcare professionals who prescribe ESAs to cancer patients. Under the ESA APRISE program, Amgen will ensure that only those hospitals and medical professionals who have completed the training program will prescribe and give ESAs to cancer patients. 

The goals of the REMS for the ESAs include:

• Supporting informed decisions between patients and their healthcare professionals who are considering treatment with an ESA by educating them on the risks of ESAs;
• Mitigating the risk of decreased survival and/or poorer tumor outcomes in patients with cancer by implementing the part of the REMS called the ESA APPRISE Oncology Program.

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