Use of ESAs should be restricted to indications, experts say

Strict evidence-based criteria should be used when prescribing erythropoiesis-stimulating agents (ESAs) for cancer, as ESAs appear to activate signaling pathways that are important in altering tumor behavior and treatment response, experts said.

ESAs were approved for certain patients with anemia at a time when the safety of the blood supply came into question. Since the approval of these agents, the target threshold for defining chemotherapy-induced anemia has been pushed higher, resulting in expanded use of ESAs, said Deborah Schrag, MD, MPH, Dana Farber Cancer Institute. The agents have also been used increasingly outside the scope of their indications. The increased use has occurred despite a lack of data to support an improved quality of life through correction of anemia using ESAs, she said. The only definitively demonstrated result of ESA use is a decreased rate of transfusion.

Postmarketing regulatory reviews followed reports of worse progression-free survival (PFS) in treated patients with cancer who received ESAs compared with those who received placebo. In May 2007, boxed warnings and safety-related changes to package inserts were established. In March 2008, FDA issued a safety advisory stating that ESAs were not to be used in the context of curative therapy.

There is evidence that tumor cells may use the erythropoietin system for growth, prolonging the tumor's survival, said Fadlo R. Khuri, MD, Winship Cancer Institute, Emory University, Atlanta. Adequately powered randomized clinical trials in patients with treated head and neck cancer and breast cancer demonstrated higher locoregional progression of cancer and worse overall survival in recipients of ESAs compared with recipients of placebo. Although the data are incomplete, "we have 3 studies in the curative setting that suggest harm," he said.

Randomized, placebo-controlled clinical trials in which ESAs were studied in untreated patients with cancer-related anemia mirrored the results (worse overall survival and worse disease-free survival) from the treated cancer population.

Further studies have suggested that erythropoietin receptors on cancer cells may explain the worse prognosis observed with ESAs in patients with cancer. In radiotherapy-treated patients with head and neck cancer, those with erythropoietin receptor-positive disease demonstrated significantly worse results when treated with epoetin beta versus those treated with placebo, noted Dr Khuri.

Histologic studies have demonstrated that concomitant erythropoietin and erythropoietin receptor expression correlates with an advanced stage of disease, more extensive tumor angiogenesis, and worse patient survival.

"I would not give these drugs as adjuvant therapy or neoadjuvant therapy where erythropoietin expression is present," said Dr Khuri.

FDA has taken the position that improvement of the symptoms associated with anemia has not been established with the use of ESAs, said Jennifer L. Malin, MD, PhD, Division of General Internal Medicine-Health Services Research, University of California, Los Angeles. The Agency for Health Care Research and Quality states that quality-of-life measures tend to favor ESAs, although the evidence is not sufficient. A review by the U.K. National Institute for Clinical Effectiveness demonstrated an improvement in health-related quality of life in 13 of 20 clinical trials of ESAs, although the improvement was not significant in 3 of the 13 studies.