Abstract
Background/Aim: Eribulin is an effective chemotherapeutic agent for advanced and metastatic breast cancer. However, severe neutropenia occurs in 30-40% of patients and interferes with the recommended treatment schedule. Neutropenia is a major cause of treatment interruptions, delays, or even relative dose reductions. This study aimed to examine the risk factors for severe neutropenia after eribulin treatment. Patients and Methods: We retrospectively evaluated 263 patients with metastatic breast cancer who had received eribulin therapy. Risk factors for severe neutropenia in the first cycle were evaluated. Results: Severe neutropenia in cycle 1 occurred in 50% of the patients. Multivariate analysis suggested six risk factors for severe neutropenia: low baseline neutrophil count and body mass index, high aspartate aminotransferase and bilirubin levels, creatinine clearance (CrCl) less than 50 ml/min, and eribulin dose of 1.4 mg/m2. Conclusion: This is one of the few studies to simultaneously examine both hepatic and renal functions in relation to severe neutropenia induced by eribulin. We have provided important information to support the close monitoring of patients with these risk factors and subsequent dosage adjustments, if necessary.
Metastatic breast cancer (MBC) is responsible for approximately 500,000 deaths worldwide (1), with a 5-year survival rate of approximately 27%. The survival rate of patients with MBC has reportedly improved (2). The treatment goals for MBC are to prolong survival and maintain the quality of life by controlling symptoms and minimizing treatment toxicity (3).
In Japan, eribulin is indicated for the treatment of patients with MBC who have received at least two prior chemotherapy regimens. Prior therapy must include anthracyclines and taxanes as adjuvants or for metastatic diseases. The recommended dose is 1.4 mg/m2 of eribulin mesylate, administered intravenously over approximately 5 min on days 1 and 8 of a 21-day cycle (4, 5). Metabolism accounts for only a small percentage of eribulin clearance. When 2 mg of 14C-eribulin mesylate was administered to a patient, the radioactivity derived from eribulin was almost entirely accounted for by the unchanged parent compound (6).
Hepatic impairment affects the disposition of eribulin, decreasing its clearance and prolonging its elimination half-life, thereby increasing its exposure (7). Therefore, the U.S. eribulin package insert recommends that the dose of eribulin mesylate be reduced from 1.4 to 1.1 mg/m2 in patients with mild (Child-Pugh A) hepatic impairment and 0.7 mg/m2 in patients with moderate (Child-Pugh B) hepatic impairment (7, 8). Renal excretion is a minor route of eribulin elimination, with less than 10% of the drug excreted in its unchanged form (6). The safety and tolerability of repeated doses of eribulin in moderate [creatinine clearance (CrCl) 30-50 ml/min] or severe impairment (CrCl 15-29 ml/min) were also examined; a reduced dose of eribulin to 1.1 mg/m2 simulated the same exposure as 1.4 mg/m2 in normal (CrCl ≥80 ml/min) (9).
Severe neutropenia is a side effect that interferes with the continuation of eribulin, requiring withdrawal or dose reduction. Eribulin dose adjustment is necessary to avoid severe neutropenia during hepatic and renal dysfunction. However, no study has examined the effects of hepatic or renal dysfunction or dosage on neutropenia. There is a need to better understand the clinical applications of eribulin and to collect information to determine the optimal treatment plan. Therefore, we aimed to explore the risk factors associated with eribulin-induced neutropenia based on the clinical and laboratory data of Japanese patients.
Patients and Methods
This retrospective study enrolled patients with MBC who had received eribulin between August 2011 and February 2023 at the Breast Surgery Department of the Hokkaido Cancer Center. All patients met the following baseline criteria: (i) age ≥20 years, (ii) Eastern Cooperative Oncology Group performance status 0-2, (iii) ability to complete the first cycle of treatment, and (iv) sufficient information from the medical records. Eight covariates were included in the multivariate analysis. This study was approved by the Ethical Review Committee of Hokkaido Cancer Center (approval number: 05-06) and conducted in accordance with the Declaration of Helsinki. The committee waived the requirement for informed consent from participants because of the retrospective nature of this study. The treatment regimen consisted of eribulin (1.4 mg/m2 on days 1 and 8) administered every three weeks. As previously reported, the dose was reduced to 1.1 and 0.7 mg/m2 depending on the severity of the side effects.
Assessment of adverse effects. The required patient information was obtained from the medical records. Adverse reactions were evaluated according to the Common Terminology Criteria for Adverse Events, version 5.0. The primary endpoint was the detection of risk factors for the development of severe neutropenia during cycle 1. The secondary endpoints were progression-free survival (PFS) and overall survival (OS) in the presence or absence of severe neutropenia during the first cycle. Severe neutropenia was defined as grade ≥3 neutropenia requiring eribulin dose reduction and/or treatment interruption.
Statistical analysis. Multivariate analyses were performed using logistic regression to identify the independent risk factors associated with severe neutropenia. The following covariates were used in the analyses: age, neutropenia (10-12), aspartate aminotransferase (AST) (7), alanine aminotransferase (ALT) (7), total bilirubin (7), hemoglobin (13, 14), platelets (15, 16), and body mass index (BMI) (13, 17, 18). The evaluated pretreatment covariates were established based on previous reports on availability, prior evidence, and biological validity. For continuous variables, cutoff values were calculated using receiver operating characteristic (ROC) analysis.
From previous reports (9, 19), renal dysfunction at baseline (creatinine clearance less than 50 ml/min) and eribulin initial dose adjustment (1.4 mg/m2 or 1.1 mg/m2) have been reported to be associated with severe eribulin-induced neutropenia. In the present study, we combined these factors and added the covariate of creatinine clearance less than 50 ml/min at 1.4 mg/m2 (20). Statistical significance was set at p<0.05.
Results
Patient characteristics. Of the 311 patients, 263 were enrolled according to the study’s eligibility criteria (Figure 1). Table I shows the patient characteristics, including age, body surface area, BMI, and baseline laboratory values. Thirty percent of the patients were aged ≥65 years. The percentages of patients with neutrophil, hemoglobin, and platelet counts lower than the normal lower limit at baseline were 3%, 44%, and 13%, respectively. Five percent of patients received reduced-dose therapy from the beginning.
Flowchart of patient selection.
Patient characteristics.
Frequency of severe neutropenia during eribulin treatment. Severe neutropenia occurred in 50% (n=132) of the patients during the first cycle of eribulin treatment; 35% discontinued treatment on day 8, and 50.3% delayed treatment for the first cycle on day 15 or the second cycle on day 1. The relative dose intensity calculated for the first cycle was 85.0% (Table II).
Frequency and details of severe adverse effects in eribulin treatment.
The effects of creatinine clearance and eribulin dose on the development of grade 3 or higher neutropenia were also confirmed. The results showed that the incidence of neutropenia was 50% when CLcr was >50 ml/min and eribulin was 1.4 mg/m2. In contrast, treatment with CLcr <50 ml/min and 1.4 mg/m2 eribulin resulted in an increase of up to 80%. Furthermore, the rates were 17% for CLcr <50 ml/min and 1.1 mg/m2 of eribulin (Figure 2).
Creatinine clearance rates at different eribulin doses.
Multivariate analysis of risk factors associated with severe neutropenia. Optimal cutoff values for predicting grade ≥3 neutropenia were analyzed using ROC analysis. Age, baseline neutrophil count, AST, ALT, total bilirubin, hemoglobin, platelet values, and BMI were 63, 2900, 3.9, 42, 38, 0.56, 12.4, 20.4, and 26.5, respectively. The AUC of the baseline values were 0.54, 0.60, 0.62, 0.55, 0.54, 0.67, 0.54, 0.61, and 0.52, respectively.
The final multivariate model yielded six factors: (a) neutropenia at baseline (<2,900), (b) high AST level (>42), (c) bilirubin level at baseline (>0.56), (d) BMI (<26.5), (e) creatinine clearance (CrCl) less than 50 ml/min, and (f) eribulin dose of 1.4 mg/m2 (Table III).
Multivariable analysis for the occurrence of grade 3/4 neutropenia during the first cycle.
Survival. In the study population, 263 PFS events and 205 deaths were recorded based on the cutoff dates. The median PFS in patients who were administered eribulin was 3.4 (95%CI=2.9-3.9) and 3.4 (95%CI=3.1-4.7) months; p=0.58 (Figure 3A). The median OS observed in patients receiving eribulin was 13.9 (95%CI=11.3-19.0) and 14.4 (95%CI=11.8-20.0) months; p=0.76 (Figure 3B).
A) Comparison of progression-free survival with/without-neutropenia of grade≥3 group. The median progression-free survival observed in included patients receiving with-neutropenia of grade≥3 group and without-neutropenia of grade≥3 group was 3.4 (95%CI=2.9–3.9) months and 3.4 (95%CI=3.1–4.7) months, respectively; p=0.58. B) Comparison of overall survival with/without-neutropenia of grade≥3 group. The median overall survival observed in included patients receiving with-neutropenia of grade≥3 group and without-neutropenia of grade≥3 group was 13.9 (95%CI=11.3–19.0) months and 14.4(95%CI=11.8–20.0) months, respectively; p=0.76.
Discussion
Eribulin is an effective therapeutic option for MBC (4, 5, 8). However, severe neutropenia occurs in 30-40% of patients, leading to treatment interruptions, delays, and dose reductions (4, 5). Neutropenia is also a risk factor for infection (especially febrile neutropenia), as eribulin is often administered as an outpatient therapy. Considering that risk factors should be evaluated in advance of severe neutropenia to ensure safe continuation of therapy, this study evaluated the factors associated with severe neutropenic vocalization during eribulin therapy. Severe neutropenia during the first cycle occurred in 50% of the patients, a similar frequency to that in previous reports (4, 5, 8). Our study showed that neutropenia at baseline, abnormal liver function-related laboratory values (high AST and bilirubin levels), and creatinine clearance of less than 50 ml/min at 100% dose (1.4mg/m2) were risk factors for severe neutropenia in the first cycle. Interestingly, liver and renal function factors were extracted simultaneously. Baseline neutropenia has been suggested as a factor in previous studies because of the residual effects of prior therapy and may be a factor for drugs with strong hematologic toxicity, such as anthracyclines and taxanes. In their logistic analysis, the authors used neutropenia at baseline (<2,900), which had a decisive influence on the results. A previous study reported that a baseline neutrophil count of <3,000 was a risk factor for severe neutropenia, which supports our results (10, 12). High AST and bilirubin levels are risk factors for liver dysfunction. Because eribulin is excreted mainly in its unchanged form and the main route of excretion is biliary excretion, delayed excretion may occur at high bilirubin levels (6). Furthermore, elevated bilirubin levels are reportedly associated with increased toxicity and a greater need for dose modification in patients with MBC (19). In addition, as a portion of eribulin is metabolized by CYP3A4, the area under the blood concentration-time curve is higher in patients with hepatic dysfunction than in those with normal hepatic function (7, 20). Therefore, a reduced dose is recommended for patients with Child-Pugh classes A and B (7, 19). Therefore, we considered it theoretically consistent that high AST and bilirubin levels were identified as risk factors in this study. Furthermore, creatinine clearance <50 ml/min alone was not identified as a risk factor for severe neutropenia in this study, although it has been reported as a risk factor for severe neutropenia in prior renal function-adjusted studies (12). However, in an additional validation of this study, the frequency of severe neutropenia was 80% when the drug was used at 100% without a dose reduction in creatinine clearance of <50 ml/min; whereas the incidence decreased to 17% when the dose was reduced. Thus, the use of 100% creatinine without dose reduction when the creatinine clearance is less than 50 ml/min is expected to be strongly associated with severe neutropenia (Figure 2).
This study has several limitations, including its retrospective design, which may have led to confounding errors and biases. The current study had a single treatment group with no comparators, which may limit its generalizability to other locations or populations. Hence, the findings should be interpreted with caution.
Conclusion
To our knowledge, this is the first study to simultaneously analyze hepatic and renal dysfunction, as well as eribulin dose, as factors associated with severe neutropenia. This study reports real-world experiences in an Asian country (Japan) and enhances the current knowledge on eribulin for the treatment of MBC. This study identified four risk factors associated with severe neutropenia. Both hepatic and renal function factors have been demonstrated to be important considerations in eribulin treatment. Therefore, patients with these risk factors should be carefully monitored, as they may develop severe neutropenia.
Acknowledgements
The Authors thank all the patients who participated in this study and their families, as well as the staff of the Pharmacy and Breast Surgery Department of Hokkaido Cancer Center, Sapporo, Japan.
Footnotes
Authors’ Contributions
ST designed the study, interacted with patients, collected the data, performed the statistical analysis, and drafted the manuscript. YH, KM, YK, YF, KS, MY, HM, NT, KW, and HH designed the study, interacted with patients, and critically reviewed the manuscript. All Authors read and approved the final manuscript.
Conflicts of Interest
The Authors declare no conflicts of interest in association with the present study.
- Received September 27, 2023.
- Revision received October 21, 2023.
- Accepted October 23, 2023.
- Copyright © 2024 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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