Editor’s Note: In February, JAMA published a meta-analysis led by Charles L. Bennett, MD, a member of the Oncology News International Editorial Advisory Board, suggesting that ESA use is associated with increased mortality. Here, Dr. Bennett and co-author Simone N. Boyle elaborate on the findings.
The FDA approved the use of erythropoietin-stimulating agents in cancer patients receiving chemotherapy 15 years ago, but only recently has significant attention forced a re-examination of the controversy over ESA use in these patients. Mounting clinical evidence associates ESA use with increased mortality rates, and laboratory evidence has shown the drugs can promote tumor growth.
These findings are making it increasingly difficult to ignore the controversy surrounding ESA use in the oncology setting. This increased scrutiny may lead to changes in standard clinical practice. The two agents receiving the attention are Procrit (epoetin) and Aranesp (darbepoetin alfa).
Resolutions in the debate surrounding ESAs remain elusive largely because research has been inconclusive and inconsistent. More than 50 large phase III clinical trials have evaluated the use of ESAs within the cancer setting; however, these trials produced conflicting results.
Several meta-analyses of these trials aimed to clarify safety information. While the meta-analyses demonstrated increased risk with ESA use, these results were not statistically significant.
The most recent meta-analysis published in February,1 the first since 2006, shows a statistically significant increased mortality risk with ESAs for the treatment of cancer-related anemia. This report included 13 trials and 5,369 patients (for a total of 51 trials and 13,611 patients) that had not been included in previous meta-analyses. Some of the trials included cancer patients not receiving chemotherapy (not an approved ESA indication).
The biological basis for this clinical observation is not entirely understood, although laboratory evidence is growing more comprehensive. The initial laboratory debate focused largely on whether ESA toxicity in cancer patients results from hemoglobin levels greater than12 g/dL or if there is a more direct toxicity. Evidence now supports a more direct effect.
This evidence hinges on four central questions:
• Are erythropoietin receptors (EpoR) present on tumors?
• Are the downstream effects of these receptors also present in tumors?
• What is the role of EpoR in the facilitation of tumor progression?
• What is the role of EpoR in increased resistance to chemotherapy?
Researchers have identified EpoR on a wide range of tumor cells, including breast, head and neck, lung, cervical, ovarian, prostate, endometrial, renal, and gastric cancer, as well as neuroblastomas, gliomas, melanomas, and lymphomas.2 Of the studies looking for the presence of EpoR in the aforementioned cancer types, 88% confirmed the presence of EpoR.3
Interestingly, these results vary from cancer type to cancer type. For some cancers, head and neck or prostate for example, EpoR is identified in 100% of studies conducted. However, for other cancer types, such as renal or ovarian, this percentage is lower (67% and 83%, respectively).3
While evidence supporting the presence of EpoR on tumor cells has increased, there are a few studies that negate this evidence. A primary argument made in these studies is that the methods used by previous investigators were nonspecific, claiming that the antibodies utilized were equally likely to identify ubiquitous heat shock proteins as EpoR.4
1. Bennett CL, Silver SM, Djulbegovic B, et al: Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA 299:914-924, 2008.
2. Jelkmann W: Erythropoietin after a century of research: Younger than ever. Eur J Haematol 78:183-205, 2007.
3. Kuykendal A, Bennett CL, McCoy J, et al: Tumor progression and mortality associated with administration of erythropoiesis stimulating agents (ESAs) to cancer patients: Is toxicity due to ESAs or elevated hemoglobin (Hb) levels? 2008 ASCO Annual Meeting Proceedings (J Clin Oncol supplement, in press).
4. Farrell F, Lee A: The erythropoietin receptor and its expression in tumor cells and other tissues. Oncologist 9(suppl 5):18-30, 2004.
5. Henke M, Verma A, Acs G: Erythropoietin receptors on cancer cells: Exciting perspectives, difficult to appreciate. Blood 108:1107-1108; 2006 (author reply pp 1108-1109).
6. Li J, Vesey DA, Johnson DW, et al: Erythropoietin reduces cisplatin-induced apoptosis in renal carcinoma cells via a PKC dependent pathway. Cancer Biol Ther 6(12):1944-1950, 2007.
7. Lai SY, Grandis JR: Understanding the presence and function of erythropoietin receptors on cancer cells. J Clin Oncol 24:4675-4676, 2006.