ESAs can be given to chemotherapy patients to reduce the need for blood transfusions.  However, there can be problems with ESAs including causing some tumors to grow faster or some patients to die sooner.  They can also increase risk for blood clots, heart failure, heart attack or stroke.

ESAs, including Procrit®, Epogen®, and Aranesp®, are now covered by a REMS or Risk Evaluation and Mitigation Strategy which requires that patient receive a Medication Guide from their health care providers that tells them how to safely use an ESA drug.

In addition, health care providers who use ESAs with their patients must be be actively enrolled in  the APPRISE (Assisting Providers and Cancer Patients with Risk Information for the Safe Use of ESAs) Oncology program and receive training in their safe use. 

ESAs are forms of the human protein erythropoietin, which stimulates bone marrow to make red blood cells.   Chemotherapy can cause anemia, which is the loss of these cells.  If red cells counts fall too low, a blood transfusion may be necessary.

Because of the potential risks of ESA treatment, the FDA required Amgen, Inc., which manufacture Aranesp, Epogen, and Procrit, to develop a Medication Guide and REMS.

The Medication Guide tells patients:

• If you decide to take an ESA, your healthcare provider should prescribe the smallest dose to lower the chance of getting red blood cell transfusions.
• After you have finished your chemotherapy course, ESA treatment should be stopped.
• ESAs do not improve the symptoms of anemia (lower than normal number of red blood cells), quality of life, fatigue, or well-being for patients with cancer.
• You may get serious heart problems such as heart attack, stroke, heart failure, and may die sooner if you are treated with an ESA to a hemoglobin level above 12 g/dL.
• You may get blood clots at any time while taking an ESA . If you are receiving ESA and you are going to have surgery, talk to your healthcare provider about whether or not you need to take a blood thinner to lessen the chance of blood clots during or following surgery. Clots can form in blood vessels (veins), especially in your leg (deep venous thrombosis or DVT). Pieces of a blood clot may travel to the lungs and block the blood circulation in the lungs (pulmonary embolus).
• Before ESA treatment begins, patients must sign an acknowledgment form that says they have talked with their healthcare professional about the risks of ESAs.

The APPRISE Oncology program requires that health care professionals who treat cancer patients with ESAs:

• Complete a training module that covers the use of ESAs. Completion of the training module is required for enrollment in the ESA APPRISE Oncology program.
• Sign the patient/healthcare professional acknowledgement form prior to the patient receiving an ESA. The acknowledgement form attests that the healthcare professional and patient have discussed the risks of using an ESA.
• Re-enroll in the ESA APPRISE Oncology program every three years.

Only health care professionals who are part of APPRISE can prescribe ESAs for their cancer patients receiving chemotherapy.

Richard Pazdur, M.D., director of the Office of Oncology Products in the FDA’s Center for Drug Evaluation and Research said,

Evaluation of Erythropoiesis-Stimulating Agents has been an ongoing and intensive process since 2004, involving a series of public meetings, labeling changes, and a required Medication Guide. This new risk management program will help ensure that patients and their health care professionals have fully considered the benefits and risks of using ESAs.

Disclosure: C3 has accepted funding for projects and educational programs from Amgen in the form of unrestricted educational grants. C3 has ultimate authority over website content.

Among over 56,000 cancer patients 65 and older treated in community settings from 1991 through 2002, 27 percent received an erythropoiesis-stimulating agent (ESA).   Fifteen percent of those who got ESAs developed a blood clot (venous thromboembolism) compared to 10 percent of patients who didn’t have ESA treatment.

Although the goal of ESAs was to reduce the need for blood transfusions, the percentage of transfusions remained steady at 22 percent each year from 1991 through 2002.  Overall survival didn’t differ between the patients who received ESAs and those who didn’t.

Chemotherapy can cause anemia when the bone marrow doesn’t keep up with the need to replace normally lost red blood cells. Erythropoiesis-stimulating agents such as Procrit® and Epogen® (epoetin alfa) and Aranesp® (darbepoetin alfa) stimulate the bone marrow to produce new red blood cells.  Ideally, use of ESAs should reduce the need for blood transfusions during chemo.

However, when researchers reviewed data in the Surveillance, Epidemiology, and End Results (SEER)–Medicare database for patients who were diagnosed with colon, lung, or breast cancer or with lymphoma from January 1991, through December 2002 and who received chemotherapy, they found no difference in blood transfusion rates.

They did find more blood clots, both in deep leg veins and in the lungs, among those who were treated with ESAs.  The rate of venous thromboembolism was 14.3 percent in the ESA patients and 9.8 percent in patients who didn’t get ESAs.

After FDA approval of ESAs, their use increased rapidly.  In 1991, 4.8 percent of patients got an ESA, but by 1992 nearly half of all chemotherapy patients in the SEER-Medicare database (45.9 percent) received ESA treatment.

Writing in the Journal of the National Cancer Institute, Dawn L. Hershman, MD, and her colleagues concluded,

Use of erythropoiesis-stimulating agent increased rapidly after its approval in 1991, but the blood transfusion rate did not change. Use of erythropoiesis-stimulating agents was associated with an increased risk of venous thromboembolism but not of mortality.

The FDA-approved label for Aranesp, Epogen, and Procrit limit their use to patients with anemia who are receiving chemotherapy.  They are not appropriate for anemic cancer patients not on chemo or for cancer patients whose treatment goal is cure.  A Medication Guide has been developed to help patients discuss the use of ESAs with their doctors.

SOURCE: Hershman et al., Journal of the National Cancer Institute, Advance Access online November 10, 2009.

Disclosure: C3 has accepted funding for projects and educational programs from Amgen in the form of unrestricted educational grants. C3 has ultimate authority over website content.

The Guides are designed to help patients make informed decisions about the risks and benefits of using ESAs and to give them a starting point for discussions with their doctors.  The Medication Guide must be given to directly patients or their caregivers at the time an ESA is dispensed.

Erythropoiesis-stimulating agents trigger the bone marrow to produce more red blood cells when anemia is due to low red cell counts.   For cancer patients, ESAs are only used during chemotherapy to reduce the need for blood transfusions.  They are not appropriate for anemic cancer patients who not are having chemo, nor are they approved for chemotherapy patients whose treatment goal is cancer cure.

The FDA tells cancer patients who are considering ESA treatment that

• The tumor may grow faster and the patient may die sooner when ESA treatment is used.
• The healthcare provider should prescribe the lowest dose of the ESA that is needed to avoid red blood cell transfusions.
• ESAs work by stimulating the bone marrow to make more red blood cells. ESAs have not been shown to improve the symptoms of anemia, quality of life, fatigue, or well-being for patients with cancer.   For that reason, ESAs should be used only to reduce the chance that a patient with low red blood counts (anemia) will get a blood transfusion.
• Treatment with an ESA should be stopped when chemotherapy treatment is finished.

The Medication Guides warn about the dangers of blood clots while using ESAs and tell patients to call their healthcare provider or get medical help right away if they have any of these symptoms of blood clots:

Chest pain

Trouble breathing or shortness of breath

Pain in the legs, with or without swelling

A cool or pale arm or leg

Sudden confusion, or trouble speaking or understanding speech

Sudden numbness or weakness of the face, an arm, or leg, especially on one side of the body

Sudden trouble seeing

Sudden trouble walking, dizziness, loss of balance or coordination

Loss of consciousness (fainting)

There is also risk of serious heart problems such as heart attack, stroke, heart failure, and a higher chance of death if patients are treated with an ESA to a hemoglobin level above 12 g/dL.

They also will no longer base discounts for Neulasta® (pegfilgrastim) and Neupogen© (filgrastim) on purchases of Aranesp, a process known as bundling.  Neulasta and Neupogen help raise white cell counts lowered by chemotherapy and are designed to prevent infection resulting from treatment.

Nancy Roach, Chairperson of the C3: Colorectal Cancer Coalition, told the New York Times,

It’s a step in the right direction.

In addition, she told C3 Research News that

C3 supports fair pricing policies for drugs used in cancer treatment that don’t interfere with physicians making the best decision for their patients based on evidence of safety and effectiveness.

Although rebates and discounts are offered by others in the pharmaceutical industry, there was criticism of Amgen’s pricing policies as evidence emerged showing potential safety problems when the drug was used in ways other than indicated on its FDA-approved label.

An Amgen spokesperson told the New York Times that perceptions that physicians might be over-prescribing Aranesp were not true.

Nevertheless, we believe these contracting changes, along with other modifications, help to clear up those possible misperceptions.

For cancer patients, Aranesp is used to prevent blood transfusions in patients who are receiving chemotherapy. An erythropoetin stimulating agent (ESA), it boosts red cell counts.  Other ESAs include PROCRIT® and EPOGEN® (epoetin alfa).  PROCRIT is sold by Ortho Biotech, EPOGEN by Amgen.

Aranesp, Epogen, and Procrit are not appropriate for cancer patients who are not receiving chemotherapy, and their use should be restricted to the lowest dose possible to prevent blood transfusion.  Recent labeling changes also restrict use of ESAs to patients whose cancer treatment is not aimed at a cure.  The dosage and administration section of the revised labels state that “Therapy should not be initiated at hemoglobin levels ≥ 10 g/dL.

A revised Medication Guide for patients was also released in August, 2008 reflecting the new labeling and potential for faster tumor growth, shorter survival, and serious cardiovascular side effects.