Erythropoietic‐stimulating agents: the cancer progression controversy and collateral damage to the blood supply

I n 1994, the FDA approved an erythropoieticstimulating agent (ESA; recombinant human erythropoietin [rHuEPO]) to partially reverse the anemia in cancer patients who were receiving chemotherapy. The early trials were carried out on relatively small numbers of patients with a variety of nonmyeloid malignancies. Although not every patient responded to the drug, and there was a lag period before the full effect of the drug was seen, transfusion requirements decreased by approximately 50% in the ESA-treated patients compared to those who were treated with placebo. Approval of the drug was based on this claim and came with relative ease, since there was a rapidly growing body of clinical experience being generated in the nephrology community that demonstrated that the drug was safe and certainly efficacious. As experience with these drugs grew in the oncology setting, the emphasis shifted away from simple transfusion avoidance to quality-of-life issues. This evolution culminated in several large, community-based, openlabel studies that purported to show that quality-of-life variables improved as the hemoglobin (Hb) was increased in response to treatment. However, the one randomized, placebo-controlled trial that was carried out in the United States failed to show statistical significance in an intentto-treat analysis. In contrast, a similar trial in the United Kingdom did show improvement in quality of life and even suggested an overall survival benefit in the patients who received an ESA. At the same time, there was growing evidence in preclinical and in observational studies in man that anemia was an independent risk factor for disease progression in patients with head and neck cancer. Other studies showed that correcting anemia in animals with established tumors led to improved outcomes in response to either radioor chemotherapy. These data understandably led to attempts to duplicate the preclinical and observational studies in patients by increasing the Hb to levels nearer (or even exceeding) normal while simultaneously administering radiation or chemotherapy. The first such trial was published in 2003 and, contrary to all expectations, the outcomes in head and neck cancer were demonstrably worse in the patients who received an ESA. Not only was there poorer locoregional cancer control, but overall survival was poorer and there was an increased incidence of adverse vascular events in those patients who received the ESA. This study was followed shortly by a study in breast cancer that was stopped early because of increased mortality in the ESA arm. More studies followed—a mixture of those that either were neutral as to the effect of the ESA or suggested poorer outcomes in those who received an ESA. In short, no study, properly powered and evenly balanced, has shown improved outcomes as a result of giving an ESA. The appearance of the adverse clinical trial results galvanized the FDA to call into question the safety of this class of drug for this indication. The Oncology Drug Advisory Committee (ODAC) reviewed the results of the clinical trials on two occasions and, in its last set of recommendations in 2008, came down hard on the continued use of ESAs to combat chemotherapy-induced anemia. But even before that, the FDA had mandated a “black-box” warning in the package inserts of the ESAs although, originally, there was no call to reduce the allowable upper limit of Hb (12 g/dL)—just a firm warning not to exceed that level. A parallel effort to limit the exposure of patients to ESAs took form in 2007 when the Centers for Medicare and Medicaid Services (CMS) issued its own restrictions. Now, not only was an acceptable Hb level eliminated, but the recommendation was to start ESA treatment only when the Hb decreased below 10 g/dL. At the same time, reimbursement for the drug for Medicare patients would cease at the same Hb level—a “catch 22” if there ever was one! In lock step, the FDA mandated additional restrictions on the use of ESAs for this clinical indication and introduced further changes to the package insert. In so doing, they invoked a relatively new law (the FDA Amendments Act of 2007) that gave the FDA authority to effectively write the package insert without concurrence of the manufacturer. And that’s where we stand. There are several issues entangled in all of this and the article by Vekeman and colleagues in this issue of TRANSFUSION addresses one of them. With such restrictions on the use of ESAs, what will the impact on the US blood supply be? Although the study makes some estimates of depletion of the “marginal blood supply,” there are actual data emerging that address this. Studies presented at ASCO last year and at the recent meeting of ASH suggest that the transfusion of red blood cell products to TRANSFUSION 2009;49:824-826.