Elsevier

Clinical Breast Cancer

Volume 20, Issue 6, December 2020, Pages 439-447
Clinical Breast Cancer

Original Study
Impact of Granulocyte Colony-Stimulating Factor (G-CSF) and Epoetin (EPO) on Hematologic Toxicities and Quality of Life in Patients During Adjuvant Chemotherapy in Early Breast Cancer: Results From the Multi-Center Randomized ADEBAR Trial

https://doi.org/10.1016/j.clbc.2020.03.008Get rights and content

Abstract

Background

Hematologic toxicities are one of the greatest challenges in adjuvant chemotherapy for breast cancer. This analysis of the ADEBAR trial aims to evaluate application and effect of granulocyte colony-stimulating factor (G-CSF) and epoetin alfa (EPO) on hematologic parameters and fatigue in patients with breast cancer during chemotherapy.

Patients and Methods

In the ADEBAR trial, 1493 patients with node-positive primary breast cancer were randomized to either 6 × 5-fluorouracil, epirubicin, and cyclophosphamide (FEC120) or 4 × epirubicin and cyclophosphamide followed by 4 × docetaxel (EC-DOC). Co-medication with G-CSF or EPO was applied to treat chemotherapy-induced leukopenia or anemia. Fatigue was assessed at baseline and after one-half of the chemotherapy.

Results

In total, 899 patients could be included in the analysis. There was no evidence for an association between leucocyte or hemoglobin levels and application of G-CSF and EPO in the preceding cycle, respectively. Hemoglobin levels (B = −0.41; P < .001) were affected by treatment regimen. Fatigue during chemotherapy was mostly affected by the level of fatigue before the start of chemotherapy (B = 0.41; P < .001). Patients with G-CSF application in the preceding cycle showed an increased fatigue score (B = 5.43; P = .02).

Conclusion

We showed that fatigue during adjuvant chemotherapy was mostly affected by the level of fatigue present before the start of chemotherapy. This result suggests that the level of fatigue before the start of treatment should be included as an important factor when deciding on type and toxicity of chemotherapy in early breast cancer.

Introduction

Breast cancer is one of the most common malignancies in women and the second leading cause of cancer-related death among females worldwide.1 Across Europe, this malignant disease accounts for 28% of all cancer cases. Adjuvant chemotherapy has been shown to reduce the risk of cancer recurrence for patients with high-risk breast cancer.2 However, side effects of chemotherapy may cause problems that can even be life-threatening. Therefore, it is of great importance to identify effective and well-tolerated chemotherapy regimens in combination with the use of co-medications to reduce side effects.

Hematologic toxicities, such as leucopenia and anemia, and their complications are a great challenge in adjuvant chemotherapy for breast cancer. It has been shown that neutropenia especially is the main side effect of anthracycline and taxane-based chemotherapy, as observed for example in the Early Breast Cancer Trialists' Collaborative Group (EBCTCG).3, 4, 5

Prophylactic or secondary administration of granulocyte colony-stimulating factor (G-CSF) in cytotoxic therapy regimes is considered necessary in order to avoid delays and dose reductions owing to neutropenia and to avoid neutropenic sepsis. International guidelines recommend the use of G-CSF when the risk of febrile neutropenia (FN) is 20% or higher.6 High overall FN risk may arise from high-risk chemotherapy alone or from intermediate-risk chemotherapy combined with individual risk factors (eg, age, prior FN).6,7 However, prophylactic G-CSF may cause symptoms such as bone pain, which may be marked and sometimes debilitating, thus limiting the quality of life (QoL) during therapy.8 Furthermore, administration of G-CSFs in the adjuvant setting may increase the risk of long-term damages such as myelodysplasia or leukemia.9,10

Anemia is often associated with fatigue, a major determinant of QoL.11 Erythropoiesis-stimulating agents are widely used for managing anemia in patients with cancer.12,13 Erythropoiesis-stimulating agents, and in particular epoetin (EPO), established their efficacy in terms of increase of hemoglobin levels,12,14, 15, 16 reduction of red blood cell transfusion requirements,12,14, 15, 16 and improvement of patients' QoL.11,12,14,16, 17, 18 Moreover, EPOs decrease the risks of viral infections in comparison with red blood cell transfusions and provide a more sustained correction of anemia.12

EPO and G-CSF are well-studied concerning their indication for application, physical effects, and side effects on patients. However, their effect on QoL in patients with breast cancer during adjuvant cytotoxic therapy is not yet well-known. In particular, fatigue has been shown to be one of the most prevalent indicators of reduced QoL in patients with cancer,19 but detailed studies on the relation of blood parameters, co-medication, and fatigue of patients with breast cancer receiving adjuvant chemotherapy are rare. Indeed, health-related QoL is not only important for outcome research, but is also considered a predictive baseline variable for clinical outcomes.20

Thus, the aim of the current analysis in the setting of the prospective, multicenter ADEBAR trial was to evaluate a potential association between hematologic parameters (leucocyte and hemoglobin levels), application of the stimulating factors/co-medication G-CSF and EPO during chemotherapy, and fatigue.

Section snippets

Patients

In the randomized, multicenter, open-label, phase III ADEBAR trial, women with high-risk primary invasive breast cancer aged between 18 and 70 years with ≥ 4 involved axillary lymph nodes (pN2-3), tumor size between pT1-4, and no evidence of metastatic disease (M0) were included.21,22 Furthermore, a complete R0 resection of the primary invasive tumor with resection margins free of invasive carcinoma and completion of axillary lymphadenectomy (with ≥ 10 removed nodes) no longer than 5 weeks ago

Results

In total, 1493 patients were randomized to treatment in the ADEBAR trial between September 2001 and May 2005. After exclusion of non-evaluable patients (no documentation, no chemotherapy, other reasons), 1364 patients could be included in the full analysis set (689 receiving EC-Doc, 675 receiving FEC120).22 Of those, 899 patients had valid data on fatigue at time point t4/t5 (ie, before cycle 4 for the FEC120 arm and before cycle 5 for the EC-DOC arm) (see Figure 1) and were thus included in

Discussion

Multi-agent chemotherapy in breast cancer, as received by patients in the adjuvant ADEBAR trial, has a spectrum of side effects including leucopenia, anemia, and fatigue. In this study, we investigated both – the relationship between leucocyte levels, G-CSF application, and fatigue and the relationship between hemoglobin levels, EPO application, and fatigue – using 2 separate but identical analytical approaches. A shared result of both analyses was that we found no significant association

Conclusions

Chemotherapy-induced side effects represent a major concern in treatment of patients with breast cancer. In the adjuvant ADEBAR trial for patients with high-risk, node-positive, early breast cancer, both the occurrence of leucopenia or anemia and the rate of consecutive application of G-CSF or EPO were in a range comparable with the literature. Rather surprisingly, leucocyte levels as well as hemoglobin levels measured after patients had received one-half of the scheduled chemotherapy cycles

Disclosure

S.S. reports fees from Pfizer and personal fees from Lilly outside the submitted work. N.H. reports personal fees from Amgen, Astra Zeneca, and Novartis during the conduct of the study and personal fees from Roche and Sandoz outside the submitted work. B.R. reports grants from Sanofi Aventis, Pharmacia, Amgen, Novartis, and Astra Zeneca during the conduct of the study. J.H. reports personal fees from Lilly, Roche, MSD, Astra Zeneca, Pfizer, Abbvie, and Eisai; grants and personal fees from

Acknowledgments

This study was supported by Amgen, Astra Zeneca, Novartis, Sanofi-Aventis, and Wilex.

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