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Clear-cut evidence for routine use of ESA agents remains elusive in meta-studies

Clear-cut evidence for routine use of ESA agents remains elusive in meta-studies

ABSTRACT: A recent meta-analysis of multiple ESA studies did not unearth specific risk factors, but clinicians still need to proceed with caution. Experts discuss three distinct approaches to ESA application.

When it comes to erythropoiesis-stimulating agents in cancer patients, there are three distinct schools of thought: These agents are quite straightforward; they are nothing short of a "minefield or morass"; or they are somewhere in between.

Guidelines from medical societies—including ASH/ASCO, NCCN, and EORTC/EMEA in the EU—are in no short supply. This makes it fairly easy for those who approach ESAs in a straightforward manner: Follow these guidelines, which should be viewed in the context of Black Box warnings on ESAs issued by the FDA.

But the situation becomes somewhat murkier when the individual studies that led to the Black Box warnings are more closely scrutinized by people who have declared ESAs a minefield.

The ongoing controversy over ESAs was reignited with a meta-analysis presented at ASH 2008 in San Francisco (abstract LBA-6), which did not find any specific risk factors associated with the agents.

Senior author Andreas Engert, MD, professor at the University of Cologne in Germany, said that although the investigators looked at the patient-specific data in detail, no risk factors emerged.

"Obviously, patients who had no chemotherapy or treatment fared worse. The question for the majority of patients is whether a risk group can be identified," said Dr. Engert, who has served as a consultant for Roche, Amgen, and Johnson & Johnson.

"We cannot answer the question of whether a particular subgroup of cancer patients on chemotherapy is at higher risk. All groups were at risk on our model," he added. Oncology News International spoke with the authors of the meta-analysis, as well experts in all three ESA camps, about their respective takes on the use of the agents and why the current restrictions may go too far.

Early warnings
In 2007, the FDA issued a Black Box warning stating that ESAs are associated with excess mortality and/or accelerated tumor growth. The label change was based on multiple studies, which critics say utilized higher-than-currently-recommended doses of ESAs and treated patients to higher-than-currently-recommended hemoglobin (Hb) target levels. Summaries of the studies, including CHOIR and CREATE, were provided in a statement by John K. Jenkins, MD, director of the office of new drugs at FDA's Center for Drug Evaluation and Research (www.fda.gov/ola/2007/esa062607.html).

In 2008, two additional studies of women with breast cancer and gynecologic cancer (PREPARE and GOG-191, respectively) showed an increased risk of mortality when the drugs were used for chemotherapy-induced anemia (CIA). In both of those studies, high doses of ESAs were used and patients were treated to target level of Hb > 12 g/dL. Later in 2008, based on all studies to date, the FDA said that labels for ESAs had to carry warnings about the following risks: shortened survival, tumor progression, or recurrence, and serious cardiovascular and thrombovascular events in patients with cancer. Label changes stipulated use of the lowest possible dose of ESA to avoid red blood cell transfusions. ESAs are only to be used for anemia due to chemotherapy and only in patients who are not deemed curable.

The label also states that ESAs should be discontinued after the completion of chemotherapy.

How to treat patients
Alan Lichtin, MD, a staff hematologist/oncologist at the Cleveland Clinic Foundation, was involved with developing the ASH/ASCO guidelines. He said there are basically three options for a patient who is becoming more and more anemic on chemotherapy: hand-holding, transfusions, and ESAs. "ESAs are only indicated for patients on chemotherapy without a curative intent. Adjuvant chemotherapy for a curable malignancy is not a setting for ESAs," he stated. Dr. Lichtin believes that oncologists should stick to the guidelines and Black Box warnings. "If you don't, you expose your patients to risk, and your judgment could be called into question."

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