Erythropoietin Use in Breast Cancer Patients with Normal Hemoglobin Levels May Lead to Increased Mortality
Erythropoietin Use in Breast Cancer Patients with Normal Hemoglobin Levels May Lead to Increased Mortality
Abstract & Commentary
By William B. Ershler, MD, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC and is Editor of Clinical Oncology Alert. Dr. Ershler is on the speaker’s bureau for Amgen and does research for Ortho Biotech.
Synopsis: In a large, multicenter trial, the use of recombinant erythropoietin to maintain hemoglobin levels above anemic levels in chemotherapy treated patients with metastatic breast cancer, survival was reduced in those on the study drug. This trial, initially published in preliminary form 1 year ago is presented in more detail in this report. The question of optimal use of erythropoietic agents in the context of overall survival needs additional intense investigation.
Source: Leyland-Jones B, 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. 2005;23:5960-5972.
Several studies have demonstrated the beneficial effects of maintaining normal hemoglobin levels with the use of recombinant erythropoietin (eg, epoetin alfa) in cancer patients who develop chemotherapy-related anemia. By increasing hemoglobin, transfusion requirements are reduced and quality of life, particularly in those domains related to fatigue and energy level, are increased.1 The use of this agent has clearly increased quality of life in cancer patients with anemia.2,3
Anemia is, itself, an important risk factor for shortened survival in patients with cancer.4 Thus, the question arose whether prevention of anemia in patients with cancer would be associated with improved outcomes, most notably, survival.
The current, industry-sponsored, large-scale multi-center trial was conducted from June 2000 through April 2002 at which time the study was prematurely terminated in accordance with a recommendation from the independent Data Monitoring Committee because of higher mortality in the group treated with epoetin alfa.
Nine hundred thirty-nine women with stage IV metastatic breast cancer were enrolled in the study (469 randomized to adjunctive treatment with epoetin alfa and 470 to placebo). For the most part, patients were not anemic at the beginning of study, but if/when their hemoglobin fell below 12 g/dL they were started on a drug (either epoetin alfa at 40,000 IU or placebo) administered weekly by subcutaneous injection. The subjects in the study drug group had the dose of epoetin adjusted to maintain their hemoglobin between 12 and 14 g/dL.
At the time of termination of study, the anticipated number of patients had been enrolled (939). The interim data analysis showed that a total of 249 patients died within 12 months of random assignment. Of these, 28% or 138 were in the epoetin alfa group and 23% or 111 were in the placebo group. By Kaplan-Meier analysis, there was a lower overall 12-month survival for the study drug group (70%) compared to the placebo group (76%). The leading causes of mortality were listed as disease progression (27% in the treatment group and 22% in the placebo group), chemotherapy toxicity (1.7% in the treatment group and 0.2% for the placebo group), and venous thromboembolism (1.3% for the treatment group and 0.6% for the placebo group). Although almost twice as many subjects in the treatment group achieved hemoglobin levels greater than 14 g/dL at some point during the study, the reduced 12-month survival in the treatment group did not appear to be related to the actual hemoglobin levels as the mean hemoglobin levels did not change significantly from the baseline. Furthermore, optimal tumor response and time to disease progression were similar between groups. Thus, the reason for the difference in mortality between groups could not be determined, even after additional examinations of both study data and chart review.
Commentary
In the decade and a half that recombinant erythropoietin has been available for treatment of anemia, among those that seem to have benefited the most are patients receiving marrow toxic chemotherapy. Thus, several large trials have demonstrated improved quality of life and physical function in those who have anemia corrected by epoetin alfa, and this occurs even in the absence of tumor regression.
Inasmuch as mild-to-moderate anemia is a negative prognostic factor, it seems reasonable to question whether correction of anemia would improve survival. There are a number of mechanisms whereby this might be explained. For example, increased red cell mass might improve both drug and oxygen delivery to tumor cells and patients with less anemia associated fatigue might be able to maintain full-dose chemotherapy schedules. Thus, the announcement of the termination of this trial because of an apparent opposite effect of epoetin treatment came as quite a surprise. As it turns out, most of the excess deaths were due to early disease progression, but there was also an imbalance in deaths as a result of chemotherapy toxicity and thromboembolic events.
As discussed in the accompanying editorial5 it would be tempting to attribute these results to bad luck—a statistical fluke or some imbalance in randomization, although, as pointed out, this was a large trial in which it is more than likely that such imbalance would be washed out by sheer numbers.
Furthermore, additional concern was raised in a different, albeit methodologically criticized trial initially published at about the same time as the announcement of the termination of the current effort. In that trial in which a different erythropoietin preparation (epoetin beta) was used to maintain relatively high (> 14 g/dL in women and >15 g/dL in men) hemoglobin levels in radiotherapy-treated head and neck cancer patients, locoregional progression-free survival was poorer in those receiving study drug.6
These, and a few other reports indicating potential increased risk of thromboembolic events have raised concerns and both the FDA and industrial providers have responded by mailings to physicians and by alterations in the prescribing information for each of the commercially available agents. The recommendations currently have been adjusted such that the target hemoglobin should be no more than 12 g/dL and the drug withheld if the level is 13 g/dL or higher.
The question remains; does correcting hemoglobin in anemic cancer patients improve survival? For now, it is probable that maintaining hemoglobin levels above 13 g/dL is more likely to have adverse consequences and be associated with shorter rather than longer survival in patients with cancer. Certainly we need to learn more about the biology of erythropoietin and no longer assume that it is the totally safe drug that we initially thought it was.
References
1. Cella D, et al. Epoetin alfa treatment results in clinically significant improvements in quality of life in anemic cancer patients when referenced to the general population.. J Clin Oncol. 2003;21:366-373.
2. Demetri GD, et al. Quality-of-life benefit in chemotherapy patients treated with epoetin alfa is independent of disease response or tumor type: results from a prospective community oncology study. Procrit Study Group. J Clin Oncol. 1998;16:3412-3425.
3. Glaspy J, et al. Impact of therapy with epoetin alfa on clinical outcomes in patients with nonmyeloid malignancies during cancer chemotherapy in community oncology practice. Procrit Study Group. J Clin Oncol. 1997;15:1218-1234.
4. Caro JJ, et al. Anemia as an independent prognostic factor for survival in patients with cancer: a systemic, quantitative review. Cancer. 2001;91:2214-2221.
5. Steensma DP, Loprinzi CL. Erythropoietin use in cancer patients: a matter of life and death? J Clin Oncol. 2005;23:5865-5868.
6. Henke M, et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet. 2003;362:1255-1260.
In a large, multicenter trial, the use of recombinant erythropoietin to maintain hemoglobin levels above anemic levels in chemotherapy treated patients with metastatic breast cancer, survival was reduced in those on the study drug. This trial, initially published in preliminary form 1 year ago is presented in more detail in this report. The question of optimal use of erythropoietic agents in the context of overall survival needs additional intense investigation.Subscribe Now for Access
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