New Guidelines Address Treatment of Chemotherapy-Related Anemia

October 26, 2007 — The American Society of Clinical Oncology and the American Society of Hematology have released new clinical practice guidelines on the use of epoetin and darbepoetin. The guidelines, published in the October 22 Online First issue of the Journal of Clinical Oncology, recommend initiating an erythropoiesis-stimulating agent for chemotherapy-related anemia.
Similar evidence-based guidelines on the use of epoetin were first published in 2002. These latest recommendations expand the scope of the guidelines to address the use of darbepoetin and the thromboembolic risk associated with these agents.
"Since the first guidelines were issued, there have been black box warnings issued by the US Food and Drug Administration [FDA],"co-author Alan Lichtin, MD, from the Cleveland Clinic Foundation in Ohio told Medscape Oncology. "We wanted to alert clinicians of these risks and I would say that's the biggest change to the guidelines."
Led by J Douglas Rizzo, MD, from the Medical College of Wisconsin in Milwaukee, the committee reviewed and analyzed data published since 2002 to July 2007. They used MEDLINE and the Cochrane Collaboration Library databases to conduct their searches.
The committee included both epoetin alfa and beta in their analysis, although epoetin beta is not commercially available in the United States. Although there are no published comparative analyses of epoetin alfa and beta, the FDA considers these agents to be part of the same pharmacologic class.
"Biochemical differences between the agents do not translate into differences in their pharmacodynamic properties when they are used at the recommended doses. This is reflected in the product labeling," the committee writes. Therefore, the new recommendations on initiation, dosing, indications, and benefits apply to both epoetin alfa and beta.
Epoetin and Darbepoetin Considered Equivalent in Efficacy and Safety
The committee reports that epoetin and darbepoetin are equivalent in efficacy and safety. They base this on a systematic review comparing outcomes in patients with chemotherapy-induced anemia and on the drugs' identical cancer-related indications, warnings, and cautions in the FDA-approved package inserts.
But when treating chemotherapy-induced anemia, the committee urges clinicians to first consider other correctable causes of anemia before initiating therapy erythropoiesis-stimulating agents.
"At a minimum," they write, "one should take a thorough drug exposure history, carefully review the peripheral blood smear (and, in some cases, the bone marrow), consider iron, folate, and B12 deficiency where indicated, and assess for occult blood loss and renal insufficiency."
The committee also reported on the threshold for initiating erythropoiesis-stimulating agents. If the hemoglobin concentration approaches or falls below 10 g/dL, they recommend increasing the hemoglobin and decreasing transfusions. They note that red-blood-cell transfusion is also an option, depending on the severity of the anemia or clinical circumstances.
For patients with declining hemoglobin, but less severe anemia — those with a concentration of less than 12 g/dL but which has never fallen near 10 g/dL — the committee suggests the decision of whether to use epoetin or darbepoetin immediately or wait until the hemoglobin levels fall closer to 10 g/dL should be determined by clinical circumstances.
The group suggests that conclusive evidence is lacking to suggest that initiating erythropoiesis-stimulating agents at hemoglobin levels greater than 10 g/dL for most clinical circumstances either spares more patients from transfusion or substantially improves quality of life.
They note that starting doses and modifications based on response should follow the product's package insert. Continuing erythropoiesis-stimulating agents after 6 to 8 weeks in the absence of response, assuming appropriate dose increase has been attempted in nonresponders, does not seem to be beneficial, and therapy should be discontinued.
The committee recommends monitoring iron stores and supplementing iron intake for patients receiving treatment. And, erythropoiesis-stimulating agents should be used cautiously with chemotherapy or in clinical states associated with elevated risk for thromboembolic complications. The committee also cautions against using these agents in patients with cancer who are not receiving chemotherapy because recent trials report increased thromboembolic risks and decreased survival in these circumstances.
Agents Boost Thromboembolic Risk
Clinicians should carefully weigh the risks of thromboembolism in patients receiving these agents, the guidelines urge. "Randomized clinical trials and systematic reviews of available randomized clinical trials demonstrate an increased risk of thromboembolism in patients receiving epoetin or darbepoetin."
Specific risk factors for thromboembolism have not been defined in these trials, the committee notes, and clinicians should use caution and clinical judgment when considering use of these agents. Established general risk factors include history of thromboses, surgery, and prolonged periods of immobilization or limited activity. There are no data regarding concomitant use of anticoagulants or aspirin to modulate this risk.
The committee reports there is evidence that supports the use of epoetin or darbepoetin in patients with anemia associated with low-risk myelodysplasia, but no published high-quality studies support its exclusive use in patients with anemic myeloma, non-Hodgkin's lymphoma, or chronic lymphocytic leukemia in the absence of concurrent chemotherapy.
"A number of questions remain," Dr. Lichtin told Medscape Oncology during an interview. "For example, do tumor growth enhancements occur with the use of erythropoiesis-stimulating agents?" This key question, he says, will have to be answered by future studies.
Dr. Lichtin points out problems in previous work, including quality-of-life data suggesting that as hemoglobin levels rose, patients benefited. "We've since observed a downside to elevated hemoglobin levels and I think this may open up a new field of inquiry down the road."
The complete guidelines can be accessed on the Journal of Clinical Oncology Web site at http://www.jco.org.
Several committee members, including Dr. Lichtin, have disclosed various financial relationships with Amgen, a maker of epoetin and darbepoetin, and Johnson and Johnson.
J Clin Oncol. Published online October 22, 2007.