ESA Treatment in the Adjuvant Management of Breast Cancer: A Resurfacing Controversy

Financial Disclosure: Clinical Oncology Alert’s Editor, William Ershler, MD; nurse planner, Irene Q. Flores, RN, BSN OCN; peer reviewer, V.R. Veerapalli, MD; executive editor, Leslie Coplin; and managing editor, Neill Kimball report no financial relationships relevant to this field of study

Synopsis: High-risk, early breast cancer patients treated on a dose-intense chemotherapy protocol were randomized to receive thrice weekly epoetin alfa or not. As compared with controls, hemoglobin levels were maintained and fewer red cell transfusions were required. Furthermore, there did not appear to be any detriment in progression-free or overall survival. However, venous thrombotic events occurred more frequently. The use of erythropoiesis-stimulating agents in the adjuvant setting remains unsettled.

Source: Moebus V, et al; on behalf of the AGO Breast Study Group. Adding epoetin alfa to intense dose-dense adjuvant chemotherapy for breast cancer: Randomized clinical trial. J Natl Cancer Inst 2013;105:1018-1026.

There remains significant controversy over the use of erythropoiesis-stimulating agents (ESA) in the management of patients with cancer, primarily over concerns of the possible enhancement of tumor proliferation resulting in shorter progression-free and overall survival (OS) and the more clearly demonstrated increased risk of venous thrombotic events.1-4 Because of these concerns, ESAs currently are not recommended for patients being treated with curative intention. Yet, the large literature, including meta-analyses, are inconclusive regarding the tumor progression and survival risks for chemotherapy-induced anemia (CIA), particularly when published FDA guidelines are followed.2,5

For patients with breast cancer receiving intensive adjuvant chemotherapy, symptomatic anemia and need for red cell transfusion are common occurrences, and prior studies have shown ESA efficacy in reducing CIA.6,7 In the current report, Moebus and colleagues within the Arbeitsgemeinschaft Gynokologische Onkologie (AGO) Breast Study Group chose to reexamine the efficacy and safety of epoetin alfa (Epo) when used in the treatment of CIA in high-risk breast cancer patients receiving intensive adjuvant chemotherapy.

The study was an adjunct to the AGO Phase 3 randomized trial that tested dose intensity and density for 1284 patients with four or more positive nodes. The overall AGO trial compared 5-year, relapse-free survival (RFS) of intense dose-dense (IDD) sequential chemotherapy with epirubicin (E), paclitaxel (T), and cyclophosphamide (C) (IDD-ETC) every 2 weeks vs conventional scheduled epirubicin/cyclophosphamide followed by paclitaxel (EC ➝ T; every 3 weeks) as adjuvant treatment in high-risk breast cancer patients. At a median follow-up of 5 years, RFS (70% vs 62%; P < 0.001) and OS (82% vs 77%; P = 0.03) were in favor of IDD chemotherapy, and at 10 years, these benefits were still maintained.8

The current report describes an additional objective of this trial: to evaluate the safety and efficacy of Epo for those patients in the IDD arm. For this, the investigators performed a second randomization among the 643 patients in the IDD ETC arm to either receive Epo or not. Thus, 324 patients were assigned to the Epo group and 319 were assigned to the control group. Epo (150 IU/kg) was given three times a week to maintain a hemoglobin (Hb) level of 12.5-13 g/dL. Patients with an Hb of < 9.0 g/dL were considered for transfusions on both arms of the study. The median duration of Epo administration was 18 weeks. Epo avoided the decrease in Hb level (no decrease in the Epo group vs -2.20 g/dL change for the control group; P < 0.001). Furthermore, Epo treatment significantly reduced the percentage of subjects requiring red blood cell transfusion (12.8% vs 28.1%; P < 0.0001).

With regard to the issue of tumor progression, Epo treatment did not negatively impact 5-year RFS (71% vs 72%; P = 0.86) or OS (83% vs 81%; P = 0.89) for control and Epo groups, respectively. Yet, toxicity was observed in that the rate of observed venous thromboembolic events was significantly worse for those treated with Epo (7% vs 3%; P = 0.03).

COMMENTARY

This report, demonstrating both efficacy and apparent safety with regard to tumor progression will, no doubt, rekindle discussions about the use of ESAs, particularly for those patients receiving "curative-intent" aggressive chemotherapy, for whom the development of symptomatic anemia and the need for red cell transfusions are common. The editorials that accompany this paper provide an excellent frame of reference. Whereas Leyland-Jones offers an eloquent history of the use of and controversies with ESA treatment in oncology practice,9 Dang and colleagues from Memorial reframe the question in the context of the current report.10 Both editorials point out that the controversy is by no means resolved and that even well-constructed meta-analyses have offered conflicting conclusions. But as Dang et al point out, the current report is insufficient to resolve certain critical safety concerns. One issue pertained to basic statistical interpretation and it was their conclusion that the analysis undertaken was insufficient to establish safety equivalence between Epo and control groups with regard to progression and survival. They suggest that to do this, a much larger sample size would be required. They also point out the very high transfusion requirement in the control group (28%), considerably higher than in other dose-/schedule-intense adjuvant breast cancer trials, and suggest this might be the consequence of the very high dose of cyclophosphamide used in the IDD-ETC regimen.

There are, of course, other issues, including the non-controversial, ESA-associated occurrence of venous thromboembolic events, a finding apparent in just about every ESA oncology clinical trial. And then, there is the issue of expense. But, these are to be countered by improved measures of quality of life and reduced transfusion requirements (also expensive and not without risks). Thus, the controversy remains unresolved. Nonetheless, it is encouraging to find positive results regarding ESA use for cancer patients treated with curative intention. The paper will not cause a paradigm shift, but it reminds us that the issue isn’t dead either. As personalized medicine is upon us, future research should be directed at providing guidelines on which patients are at greatest risk for adverse consequences of ESA treatment. The current report raises hope that the dogma insisting the avoidance of ESAs in "curative-intent" patients might not be irreversible, but additional studies are needed.

References

1.  Aapro M, et al. Effects of erythropoietin receptors and erythropoiesis-stimulating agents on disease progression in cancer. Br J Cancer 2012;106:1249-1258.

2.  Glaspy J, et al. Erythropoiesis-stimulating agents in oncology: A study-level meta-analysis of survival and other safety outcomes. Br J Cancer 2010;102:301-315.

3.  Bohlius J, et al. Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: A meta-analysis of randomised trials. Lancet 2009;373:1532-1542.

4.  Tonelli M, et al. Benefits and harms of erythropoiesis-stimulating agents for anemia related to cancer: A meta-analysis. CMAJ 2009;180:E62-E71.

5.  Food and Drug Administration. Epoetin alfa label. Available at: www.accessdata.fda.gov/scripts/cder/drugsatfda/. Accessed July 18, 2013.

6.  Chang J, et al. Weekly epoetin alfa maintains hemoglobin, improves quality of life, and reduces transfusion in breast
cancer patients receiving chemotherapy. J Clin Oncol 2005;23:
2597-2605.

7.  Shasha D, et al. Once-weekly dosing of epoetin-alpha increases hemoglobin and improves quality of life in anemic cancer patients receiving radiation therapy either concomitantly or sequentially with chemotherapy. Cancer 2003;98:1072-1079.

8.  Moebus V, et al. Intense dose-dense sequential chemotherapy with epirubicin, paclitaxel, and cyclophosphamide compared with conventionally scheduled chemotherapy in high-risk primary breast cancer: Mature results of an AGO phase III study. J Clin Oncol 2010;28:2874-2880.

9.  Leyland-Jones B. Erythropoiesis stimulating agents: A personal journey. J Natl Cancer Inst 2013;105:999-1001.

10.  Dang C, et al. Epoetin alfa: To give or not to give. J Natl Cancer Inst 2013;105:1001-1002.