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Erythropoiesis-Stimulating Agents in Cancer

Department of Medicine, Duke University Medical Center, Durham, NC

To the Editor:

The American Society of Clinical Oncology/American Society of Hematology Clinical Practice Guideline Update on erythropoiesis-stimulating agents (ESAs) provides specific target hemoglobin (Hb) values as it recommends ESA administration in cancer patients with chemotherapy-induced anemia.¹ It is noteworthy that the final, published version of the guideline introduces ambiguous dosing criteria and that the Update Committee has not used this opportunity to formulate individualized recommendations for patients in special clinical circumstances with specific tumor types when ESAs are given outside of a clinical trial.

Initiating ESA therapy at Hb less than 12 g/dL is broadly recommended, with the acknowledgment that there is no conclusive evidence that ESA initiation at Hb levels greater than 10 g/dL reduces transfusions or improves quality of life. To guide therapy continuation, the clinician is again provided with specific Hb values, recommending that ESAs be withheld when Hb level exceeds 12 g/dL and restarted at a lower dose when Hb decreases to 11 g/dL (Table 6).¹ These arbitrary Hb level recommendations are derived from meta-analysis results of clinical trials, the majority of which were not powered for survival outcomes and enrolled patients with heterogeneous tumor types treated with a variety of chemotherapy regimens. Based on the recent US Food and Drug Administration announcement of ESA product label revisions in November 2007, the first version of the guideline published online in October 2007 was revised to include a second set of recommendations in the appendix of the final article, in which the arbitrary Hb level recommendations were deleted (Table 6A). The presence of two different ESA dosing regimens in the same guideline leads to uncertainty as to which of these regimens is actually endorsed and recommended by the Update Committee.

In the updated 2007 American Society of Clinical Oncology/American Society of Hematology guidelines, the findings of the recent randomized clinical trials—the majority of which enrolled patients with homogenous tumor types and that reported unfavorable progression-free and/or overall survival associated with ESA use—were considered difficult to interpret and inapplicable to current clinical practice because these trials targeted Hb levels greater than 12 g/dL, and because adequately powered and well-designed trials are lacking to detect differences in tumor response and survival in chemotherapy-treated cancer patients receiving ESAs to achieve and maintain Hb levels close to 12g/dL.¹ Although the reasons for the reported detrimental effect on progression-free and/or overall survival in ESA trials targeting Hb greater than 12 g/dL remain elusive and there is no conclusive evidence that ESAs directly promote cancer progression, the true effect on survival of ESAs when prescribed in patients with a specific tumor type to target Hb less than 12 g/dL remains uncertain. Furthermore, for certain patient groups, an arbitrary Hb level of 11.9 g/dL may not necessarily represent a significantly safer level compared with an Hb level of 12.1 g/dL, particularly if the adverse outcomes associated with ESAs are related to potential nonhematopoietic systemic effects that remain to be characterized. For these reasons, the clinician is faced with the challenge of individualized therapy decisions in special clinical circumstances until new evidence from ongoing and future trials are available; it is hoped that these will demonstrate the safety of ESAs with respect to survival outcomes when used in accordance with these updated guidelines and Hb values, in specific tumor types, in either the metastatic or adjuvant setting.

Examples of specific clinical circumstances for individualized decision making and informed consent before embarking on ESA therapy might include patients with metastatic breast cancer or advanced non–small-cell lung cancer receiving palliative chemotherapy, even though the target Hb in the randomized clinical trials was greater than 12 g/dL.^2-4 The guidelines could have formulated individualized considerations for anemic head and neck cancer patients receiving chemoradiation therapy, even though the patients in the trials were treated with radiation therapy alone and ESAs to a target Hb of greater than 12 g/dL.^5,6 Individualized, tumor type–specific considerations for other groups of patients may be justified, given the apparent absence of a significant detrimental effect of ESAs in small-cell lung cancer patients as reported in published and unpublished trials.^7,8 The fact is that more than a decade after the US Food and Drug Administration's approval of epoetin alfa for cancer patients with chemotherapy-induced anemia, the optimal administration of this useful drug and its analogs in supportive cancer care is not settled. The performance of additional meta-analyses emphasized as a research priority by the Update Committee is not likely to provide answers to the key questions regarding ESA use in cancer patients. Focusing efforts to guide ESA therapy with specific target Hb values may be important, but until more clinical data are available, patients will be better served if they are well informed of the current limitations of our knowledge in special clinical circumstances so that they can actively participate in the decision-making process while individualized treatment plans for concomitant antitumor therapy and supportive care are formulated.

AUTHOR'S 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[Abstract/Free Full Text]

2. Leyland-Jones B: Breast cancer trial with erythropoietin terminated unexpectedly. Lancet Oncol 4:459-460, 2003[CrossRef][Medline]

3. Leyland-Jones B, Semiglazov V, Pawlicki M, et al: Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: A survival study. J Clin Oncol 23:5960-5972, 2005[Abstract/Free Full Text]

4. 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 25:1027-1032, 2007[Abstract/Free Full Text]

5. Henke M, Laszig R, Rube C, et al: Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: Randomised, double-blind, placebo-controlled trial. Lancet 362:1255-1260, 2003[CrossRef][Medline]

6. Overgaard J: Interim analysis of DAHANCA 10: Study of the importance of novel erythropoiesis stimulating protein (Aranesp) for the effect of radiotherapy in patients with primary squamous cell carcinoma of the head and neck. http://www.dahanca.dk/get_media_file.php?mediaid=125

7. Grote T, Yeilding AL, Castillo R, et al: Efficacy and safety analysis of epoetin alfa in patients with small-cell lung cancer: A randomized, double-blind, placebo-controlled trial. J Clin Oncol 23:9377-9386, 2005[Abstract/Free Full Text]

8. Amgen: Aranesp(R) "145 Study" shows no difference in survival in patients with small-cell lung cancer. http://www.amgen.com/media/media_pr_detail.jsp?year=2007&releaseID=987476

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  J. Douglas Rizzo, Mark R. Somerfield, Karen L. Hagerty, Jerome Seidenfeld, Julia Bohlius, Charles L. Bennett, David F. Cella, Benjamin Djulbegovic, Matthew J. Goode, Ann A. Jakubowski, Carole B. Miller, Mark U. Rarick, David H. Regan, and Alan E. Lichtin
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