Drug Criteria & Outcomes: The Two Faces of ESAs: Beneficial or Detrimental?
Drug Criteria & Outcomes
The Two Faces of ESAs: Beneficial or Detrimental?
By Kristy Bryant, PharmD Candidate, Harrison School of Pharmacy, Auburn University
Chemotherapy-induced anemia (CIA) is a very prevalent side effect associated with chemotherapy and affects more than half of all patients with cancer. Patients with CIA endure additional extreme fatigue as well as a decrease in quality of life and worsened long-term outcomes.
Erythropoietin stimulating agents (ESAs) are the current treatment option for CIA, and include epoetin alfa (Epogen®, Procrit®) and darbepoetin alfa (Aranesp®). These agents stimulate the division and differentiation of committed erythroid progenitors in the bone marrow increasing red blood cell production.
The goal of ESA treatment is to avoid blood transfusions by maintaining appropriate Hgb levels between 10 and 12 g/dL. Exceeding Hgb levels of 12 g/dL can lead to serious cardiovascular complications such as myocardial infarction, stroke, and death. ESAs are only indicated for CIA while concomitantly on chemotherapy and these agents should be stopped once chemotherapy has been discontinued.
Black box warning
The FDA recently announced safety concerns associated with ESAs in the treatment of CIA. On Nov. 8, 2007, the black box warning on ESA product labels was strengthened based on adverse safety results from six studies. The black box warning currently addresses the adverse outcomes associated with treatment that include shortened time to tumor progression, shortened overall survival, and increased deaths as a result of disease progression. The FDA revisions state: "Data are not sufficient to exclude the possibility of shortened survival and tumor progression in cancer patients when ESAs are dosed to reach a (Hb) level between 10 and 12 g/dL."
The following is a list of trials whose results have paved the way for this recent ESA safety warning: BEST, ENHANCE, 20010103, 20000161, EPO-CAN-20, DAHANCA 10, PREPARE, and GOG-191. Several of the most relevant trials are summarized below.
Trials supporting black box revisions
The EPO-CAN-20 trial involved patients with non-small-cell lung cancer (NSCLC). The trial was suspended early based on data showing increased mortality in the active treatment arm and negative overall survival results of two additional studies. The authors concluded that this study reaffirms the efficacy of epoetin alfa with regards to increasing Hgb levels. An unplanned safety analysis suggests decreased overall survival in patients with advanced NSCLC treated with epoetin alfa. Concern over the routine use of epoetin alfa for disease-related anemia in patients with NSCLC remains.
The ENHANCE trial involved patients with advanced head and neck cancer. The authors concluded that epoetin corrects anemia but does not improve cancer control or survival, and that disease control may even be impaired.
The BEST trial involved patients with metastatic breast cancer, and was suspended early due to increased mortality in the arm being treated with an ESA. The authors concluded that the use of epoetin alfa to achieve high Hgb targets was associated with increased mortality.
There are currently two ongoing trials that also contributed to the new FDA warnings: the PREPARE study (breast cancer) and the GOG-191 study (cervical cancer). Both of these trials present higher death rates and/or tumor progression in patients receiving ESAs versus those given placebo.
A review article from the Cochrane database examined safety and efficacy involving multiple types of cancer. The authors concluded that ESAs are effective for prevention or treatment of anemia but are associated with increased risk for thromboembolic events and do not increase survival.
Clinical practice guidelines
Based on recent literature and FDA label revisions regarding ESA therapy, the American Society of Clinical Oncology (ASCO) along with the American Society of Hematology (ASH) updated their 2007 clinical practice guidelines.
Even though these organizations proceeded with the updates, they made a point to discuss the design flaws of the current literature from which the revisions were derived. Several of the trials contained imbalances of baseline characteristics, which lead to the randomization of "sicker" patients into the active treatment arms. In addition, multiple studies were suspended early due to increased mortality without a definitive cause identified.
ASCO and ASH acknowledged the "difficulty in interpreting their results and applying them to current clinical practice" based on the study weaknesses. The following list includes a brief highlight of the 2007 revisions related to ESA safety concerns:
- With regard to CIA threshold for initiating ESA therapy, epoetin or darbepoetin should be used with a Hgb that is approaching or has fallen below 10 g/dL, to increase Hgb levels and decrease transfusions
- Based on current literature reviews, there is an increased risk of thromboembolic events associated with ESA therapy in this population and extra caution should be taken in patients with an increased risk
- Harm in relation to increased risk of death and serious cardiovascular complications has been linked to treating to a goal Hgb >12 g/dL. Dose modification must be considered once a patient's Hgb nears this level.
Conclusion
ESA agents have proven to be beneficial and effective in raising Hgb levels and treating CIA in cancer patients. Unfortunately, there are now a total of eight trials that allude to safety concerns for patients being treated for CIA with these agents.
Key recommendations for health care providers include initiating ESA therapy with a Hgb that is near or below 10 g/dL, not to exceed Hgb levels >12 g/dL, as well as communicating to patients the safety concerns regarding tumor progression, shortened overall survival, and increased deaths associated with disease progression. In addition, it is very important to remember that ESAs should be stopped once chemotherapy has been discontinued.
The FDA is conducting an ongoing safety review to evaluate risks and benefits associated with ESA treatment of CIA. In addition, they warn medical professionals to evaluate this risk-to-benefit ratio regarding the best overall care for their patients.
Resources
- Wright JR, Ung YC, Julian JA, et al. Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia. J Clin Oncol 2007;25:1027-1032; Epub 2007 Feb 20.
- Henke M, Laszig R, Rube C, et al. Erythropoietin to treat head and neck cancer patients with anemia undergoing radiotherapy: Randomized, double-blind, placebo-controlled trial. Lancet 2003;362:1255-1259.
- Rizzo JD, Somerfield MR, Hagerty KL, et al. Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update. J Clin Oncol 2008;26:132-149; Epub 2007 Oct 22. Erratum in: J Clin Oncol 2008;26:1192.
- Bohlius J, Wilson B, Seidenfeld J, et al. Review: Erythropoietin or darbopoetin for patients with cancer. Cochrane Database Syst Rev 2006;3:CD003407.
- Food and Drug Administration. Available at: www.fda.gov. Updated Jan. 3, 2008. Accessed Jan. 7, 2008.
- Cancer Consultants web site. Available at: http://professional.cancerconsultants.com. Accessed Jan. 17, 2008.
- Micromedex web site. Available at: http://www.thomsonhc.com/home/dispatch. Accessed Jan. 14, 2008.
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