Anemia is a common problem for patients with cancer, whether or not they are receiving therapy for the disease. Anemia is defined as a decrease in the number of red blood cells and can contribute to fatigue, require blood transfusions for relief of symptoms, pose a danger to those with underlying heart disease, and possibly even decrease the effectiveness of cancer therapy, such as radiation therapy. Erythropoietin is the body's natural hormone, which stimulates the bone marrow to produce more red blood cells. In the mid 1980's, researchers were able to clone the human erythropoietin gene, and two years later, epoetin alfa was tested in humans. Researchers found that this laboratory-produced version of erythropoietin resulted in increased red blood cell production, and in 1989, Epogen was approved by the US Food and Drug Administration (FDA). In 1993, the drug gained approval for use in patients undergoing cancer therapy.
Fast forward to 2004, when after many years of using these supportive care agents, two studies raise concerns of possible tumor progression and increased risk of death with their use. The FDA convened to discuss the results of these studies and address the associated risks. Two large, randomized, placebo-controlled trials found a decrease in survival among patients treated with erythropoiesis stimulating agents (ESAs) and a possible increase in tumor progression. Laboratory studies had long demonstrated tumor growth with erythropoietin as a possibility, given the presence of erythropoietin receptors on various types of cancer cells. The trials had used target hemoglobin levels higher than what is needed to avoid blood transfusion, which is not the approved usage. Many felt these studies were inconclusive, given the safety record of these agents and the use of higher than advised target hemoglobin levels. As a result of this meeting, the FDA mandated warning labels be added to product packaging describing the risk of tumor promotion and decreased survival and requested the manufacturers perform clinical trials to address these concerns further.
In December 2006, the Danish Head and Neck Cancer Study Group closed a trial involving ESAs early, due to an increased risk of death in the treatment arm. Radiation therapy achieves its best results when cancer tissue is well oxygenated. Anemia corresponds with low hemoglobin, which results in less oxygen getting to tissues and possibly, a decrease in the effectiveness of radiation therapy. The Danish study attempted to increase hemoglobin levels with ESAs in order to improve oxygenation and, in turn, outcomes. At an interim analysis, the investigators found a 10% increase in locoregional disease progression and a statistically non-significant trend towards poorer survival in the treatment arm.
In January 2007, Amgen reported the preliminary results of a trial involving 989 anemic cancer patients not receiving therapy, with a target hemoglobin of 12g/dl. The results found that darbepoetin alfa did not reduce the need for transfusions and resulted in increased mortality for patients receiving the drug compared with placebo. Concerns over these two studies led a Canadian research group to analyze their study of epoetin alfa on quality of life in non small cell lung cancer patients who were not receiving active treatment earlier than expected. They had enrolled 70 patients, with a target hemoglobin of 12-14g/dl. The m edian time to death in those treated with epoetin alfa was 68 days, which was significantly shorter than the 131 days in those treated with placebo. The majority of deaths were attributed to disease progression. In addition, this study found no decrease in the transfusion requirements or increase in quality of life in the treatment group.
In February 2007, Roche suspended a phase II study of a pegylated epoetin beta in stage III and IV non small cell lung cancer patients undergoing first line chemotherapy (target hemoglobin 11-13g/dl). Interim analysis found a higher than expected number of deaths in the treatment arms. We await further information on this study. In the same month, Ortho Biotech reported the preliminary results of a study utilizing epoetin alfa in patients undergoing elective spinal surgery to avoid transfusion (target hemoglobin 10-13g/dl). The treatment group was found to be more than twice as likely to develop deep vein thrombosis. Further analysis of this study is also expected. In addition, two studies using ESAs in chronic renal failure related anemia found increased risk of cardiovascular events (death, stroke, congestive heart failure and myocardial infarction) when higher hemoglobin levels were targeted (>12g/dl).
The Oncology Drug Advisory Committee (ODAC) met on May 10 th, 2007 to discuss questions raised by these recently released results and make recommendations to the FDA. ODAC members recommended that the FDA:
Concerns were expressed at this meeting by clinicians and advocates involved in the care of myelodysplastic syndrome, aplastic anemia and other diseases affecting bone marrow function. Because anemia in these patients is functionally different, they urged ODAC and the FDA to distinguish between bone marrow failure and anemia in other cancers when instituting further regulations. We will have to wait and see what steps the FDA takes in response to this meeting.
While these results and recommendations are sure to spur future research and ongoing evaluation of the safety of these agents, what are clinicians and patients to do with the information we have? The FDA advises clinicians and patients to remember that ESAs are given to reduce the need for red blood cell transfusions and not to treat symptoms such as fatigue. The risks and benefits of ESAs must be weighed against the risks and benefits of blood transfusions in each individual case when deciding whether or not to use the agents. The use of evidenced based guidelines, such as those developed by the National Comprehensive Cancer Network may be helpful in guiding the decision to treat with ESAs. In those who choose to use ESAs, it is imperative that doses be adjusted to maintain a hemoglobin level that does not exceed 12-13g/dl. In addition, the cost of these agents is not insignificant to the patient or health care system and must be considered in the overall risk benefit analysis.
Patients and clinicians must understand that no data exists to support claims of improvement in quality of life or fatigue. The manufacturers of these agents frequently used direct consumer marketing to promote these unsupported claims, a fact that concerns many patient advocacy groups.
Studies have found a decrease in the use of ESAs by oncologists in the months since the negative study results were publicized. There are likely to be changes in Medicare reimbursement for these agents as a result as well. We await the FDA's response to the past year's study results and ODAC recommendations. Follow-up studies addressing the concerns are sure to come, as the role of supportive care therapies is further defined, so stay tuned.