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Journal of Clinical Oncology, Vol 26, No 18 (June 20), 2008: pp. 3096-3097 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.4872
Reconsideration of American Society of Clinical Oncology/American Society of Hematology Erythropoiesis-Stimulating Agent GuidelinesDivision of Medical Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
Lymphoma Tumor Group, Division of Medical Oncology, British Columbia Cancer Agency and Department of Advanced Therapeutics, BC Cancer Research Centre, Vancouver, British Columbia, Canada To the Editor: The recommendations of the American Society of Clinical Oncology/American Society of Hematology (ASCO/ASH) 2007 Clinical Practice Guideline Update on the Use of Epoetin and Darbopoetin1 are based on published trials. They state that "for patients with chemotherapy induced anemia, the Committee continues to recommend initiating an erythropoiesis-stimulating agent (ESA) as hemoglobin approaches or falls below 10 g/dL, to increase hemoglobin and decrease transfusions. There is no evidence showing increased survival as a result of ESA treatment." The ASH/US Food and Drug Administration (FDA) Drug Update issued on November 8, 2007, which included new "boxed warnings" based on published and more recent unpublished data, is far more cautionary.2 It states, "Clinical trials conducted in patients with cancer have shown either decreased overall survival and/or an increased rate of tumor progression when ESAs are used in advanced breast, head and neck, lymphoid, and non–small-cell lung malignancies. These trials were conducted to achieve hemoglobin levels greater than or equal to 12 g/dL. The new labeling emphasizes that clinical studies have not been conducted to exclude ESA-associated tumor progression or shortened survival when ESAs are dosed to achieve lower hemoglobin levels."
It is notable that the pharmaceutical industry, ASCO/ASH, and the FDA have based their concerns and recommendations on the level of hemoglobin as though that were the fundamental problem. One can understand why this paradigm is advantageous to industry, given that it suggests that the adverse outcomes associated with ESAs are a consequence of the drug doing exactly what it is supposed to do: increase the hemoglobin, free of unintended consequences. Indeed, when this class of drug was developed, it was hoped that ESAs would be specific for erythropoiesis and not have serious adverse effects. However, the data from multiple randomized trials and meta-analyses of these trials suggest otherwise. The decreased cancer survival, increased tumor progression, increased thrombotic events, and hypertension associated with ESAs cannot be easily explained by the modest increases in hemoglobin observed in the randomized trials. The meta-analysis shows that the median hemoglobin increase is only 1 to 1.5 g/dL.3 ASCO/ASH and the FDA do acknowledge a dose effect for ESAs in that the adverse outcomes are worse when the hemoglobin is "pushed" to induce levels above 12 g/dL, and much worse when the intended level is How does one push the hemoglobin? It is accomplished by more intense dosing of ESAs. The potential risks of such increased intensity are clearly documented in a trial of chronic kidney disease,4 where patients were randomly assigned to receive a dose of epoetin alfa to achieve a hemoglobin level of 13.5 g/dL, versus a dose targeted to achieve a level of 11.3 g/dL. This trial reported more deaths, hospitalizations, and incidents of congestive heart failure, myocardial infarctions, and strokes in the group targeted for the higher hemoglobin without any improvement in quality of life. The mean dose of epoetin alfa for patients in the high hemoglobin group who reached the target level was 10,694 U per week; for those who did not reach the target, the mean dose was 12,884 U per week (P < .001). The mean dose of epoetin alfa for patients in the low hemoglobin group who reached the target level was 6,067 U per week; for those who did not reach the target level, the mean dose was 11,098 U per week (P < .001). For cancer clinical trials, the actual level of ESAs delivered is not reported for individual trials or meta-analyses. Apparently journal reviewers, those that perform meta-analyses, ASCO/ASH ESA committees, and the FDA have not asked for provision of this crucial information. Compared with chronic renal disease patients, ESAs work less well for cancer patients and it is likely that delivered ESA doses are higher, regardless of the level of hemoglobin targeted, and very high when the highest hemoglobin levels are targeted. The adverse events that cancer patients experience when prescribed low doses of ESAs are disconcerting and potentially severe when they receive high doses of ESAs. What sort of conclusions about ESAs should a clinician scientist draw from this dose-response relationship? The risk/benefit ratio for an antineoplastic drug must be favorable for it to be used. This ratio should be more favorable for a supportive care drug such as an ESA, and the agent should assist rather than interfere with the anticancer therapy. ESAs increase the median hemoglobin for cancer patients only 1 to 1.5 g/dL, and on average, decrease red cell transfusions by only one unit.3 The available clinical trial data suggest that the effect of ESAs on survival is detrimental.2,3,5,6 Moreover, the FDA suggests that these agents do not mitigate fatigue, improve quality of life, or decrease the symptoms of anemia.2 We will not soon have additional data on the safety of ESA dosing targeting lower levels of hemoglobin. It would be helpful to perform a meta-analysis using individual patient data that documents the actual delivery of ESAs and the actual hemoglobin achieved. While awaiting such information, it is difficult to understand why the ASCO/ASH committee continues to recommend ESAs for cancer patients with anemia from chemotherapy.1 Indeed, the recommendation seems to be at variance with ASCO's Core Values.7 Presently there are no data documenting what effects the widespread use of ESAs has had on patients receiving chemotherapy with curative intent such as adjuvant chemotherapy. It is clearly possible that interpretation of randomized trials of potentially beneficial new treatments may have been undermined by the widespread use of ESAs. Until better data are available, and considering the additional information that has recently emerged even as the ASCO/ASH guidelines were being drafted, ASCO and ASH should consider recommending that this type of supportive care be suspended. First do no harm. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. 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, 26:132-149, 2008 2. US Food and Drug Administration: Information on Erythropoiesis Stimulating Agents (ESA) (marketed as Procrit, Epogen, and Aranesp). www.fda.gov/cder/drug/infopage/RHE/default.htm 3. Bohlius J, Wilson J, Seidenfeld J, et al: Recombinant human erythropoietins and cancer patients: Updated meta-analysis of 57 studies including 9,353 patients. J Natl Cancer Inst 98:708-714, 2006 4. Singh AK, Szczech L, Tang KL, et al: Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 355:2085-2098, 2006 5. Raftopoulos H, Gralla R, Emilio B: Assessing the role of erythroid stimulating agents (ESAs): A comprehensive review of benefits and risks based on 8 randomized studies in 2,023 patients with respiratory cancers. Presented at the 12th World Conference on Lung Cancer, Seoul, Korea, September 2-6, 2007 6. Bennett CL, Silver SM, Djulbegovic B, et al: Venous thromboembolism and mortality associated with recombinant erythropoetin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA 299:914-923, 2008 7. Pentz RD, Joffe S, Emanuel EJ, et al: ASCO core values. J Clin Oncol 24:5780-5782, 2006
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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14 g/dL.
