Abstract
Background
Breast cancer patients receiving myelosuppressive chemotherapy are at high risk of febrile neutropenia (FN). Long-acting G-CSFs are recommended for FN prevention, but evidence for mecapegfilgrastim in the dose-dense setting remains limited.
Methods
This multicenter, prospective, observational, real-world study was conducted at 43 centers in China. Patients with breast cancer who received 2-weekly or 3-weekly chemotherapy with mecapegfilgrastim (6 mg) as prophylaxis for chemotherapy-induced neutropenia were enrolled. The primary outcome was the incidence of FN, defined as an oral temperature of > 38.3 °C or two consecutive readings of > 38.0 °C for 2 h and an absolute neutrophil count (ANC) of < 0.5 × 109/l, or expected to fall below 0.5 × 109/L. The secondary outcomes included severe neutropenia and adverse events (AEs).
Results
Between June 2019 and March 2022, a total of 757 patients were enrolled. After 1:2 propensity score matching, 36 patients were included in the 2-weekly group and 71 patients were included in the 3-weekly group. In the first cycle, FN, grade 3/4 neutropenia, and grade 4 neutropenia occurred in 0 (0%; 95% CI, 0.0-9.6%), 9 (25.0%; 95% CI, 13.8–41.1%), and 4 (11.1%; 95% CI, 4.4–25.3%) patients in the 2-weekly group, and in 2 (2.8%; 95% CI, 0.8–9.7%), 11 (15.5%; 95% CI, 8.9–25.7%), and 5 (7.0%; 95% CI, 3.0-15.4%) patients in the 3-weekly group. Across all cycles, the corresponding incidences were observed in 0 (0.0%), 11 (30.6%), and 5 (13.9%) patients in the 2-weekly group, and 2 (2.8%), 14 (19.7%) and 7 (9.9%) patients in the 3-weekly group. Dose hold (≥ 5 days) occurred in 7 patients (19.4%) in the 2-weekly group and 5 patients (7.0%) in the 3-weekly group. The incidence of grade 3/4 treatment-emergent adverse events (TEAEs) was 26.7% in the 2-weekly and 33.3% in the 3-weekly groups. No patients had serious AEs in either group. No treatment-related deaths were reported.
Conclusion
Mecapegfilgrastim was associated with a low incidence of FN and manageable safety profiles in patients with breast cancer receiving 3-weekly or 2-weekly chemotherapy. Nevertheless, further studies with larger sample sizes are warranted to confirm these findings.
Keywords: Febrile neutropenia, Neutropenia, Supportive care, Breast cancer, Mecapegfilgrastim
Introduction
Worldwide, breast cancer is one of the most commonly diagnosed malignancies [1]. Most of the breast cancer patients need to receive myelosuppressive chemotherapy treatment, which leads to a high risk of incidence of myelosuppression-associated symptoms [2].Furthermore, 2-weekly chemotherapy is preferred over 3-weekly chemotherapy in the treatment of breast cancer in many circumstances, causing increased myelosuppression [3–5].
Febrile neutropenia (FN), one of the most serious complications induced by myelosuppressive chemotherapy and frequently leads to dose reduction, discontinuation of anticancer treatment, thus increase morbidity and mortality of cancer patients [6, 7]. To reduce the incidence of FN, the National Comprehensive Cancer Network (NCCN) guidelines recommend granulocyte colony–stimulating factors (G-CSFs) as a standard of care for patients who received myelosuppressive chemotherapy [8].
A retrospective study compared the effectiveness between pegfilgrastim, a long-acting G-CSF, and filgrastim, a short-acting G-CSF, in 1058 patients with breast cancer who received 2-weekly chemotherapy regimens. The results showed that the incidence of FN was comparable in the two groups (pegfilgrastim: 4.3% versus filgrastim: 3.4%), while pegfilgrastim associated with lower incidence rate of severe neutropenia, dose reduction, and treatment delay [9]. Furthermore, several clinical studies demonstrated feasibility and safety of pegfilgrastim in breast cancer patients who were treated with 2-weekly chemotherapy [10, 11].
Mecapegfilgrastim (HHPG-19 K), a novel long-acting G-CSF, is a biosimilar to pegfilgrastim, has been approved for the treatment of chemotherapy-induced myelosuppression in China [12, 13]. However, there is a lack of evidence of the efficacy of mecapegfilgrastim in breast cancer patients who received 2-weekly chemotherapy regimens, and the risk of FN compare to 3-weekly chemotherapy.
Hence, in the present prospective real-world study, we aimed to investigate the effectiveness and safety of mecapegfilgrastim in patients with breast cancer treated with dd chemotherapy.
Methods
Study design and patient population
This multicenter, prospective, observational, real-world study was conducted at 43 centers in China. Informed consents were obtained from all patients before their enrollment. The study protocol was approved by Harbin Institute of Hematology and Oncology (No. 2019-006).
Main eligibility criteria included: age ≥ 18 years old; have breast cancer confirmed by pathological or histological assessment; received 2-weekly (2-weekly group) or 3-weekly chemotherapy (3-weekly group); and willingness to receive mecapegfilgrastim treatment as prescribed by clinicians.
Patients were excluded if they were pregnancy, lactation, or allergy to mecapegfilgrastim, recombinant human granulocyte colony-stimulating factor (rhG-CSF), pegylated rhG-CSF (PEG-rhG-CSF) or other similar biological agents.
Treatment and assessment
Chemotherapy regimens were performed according to investigators’ decision.
According to general clinical practice, mecapegfilgrastim (6 mg) was subcutaneously administered after each chemotherapy cycle.
Routine blood examinations were performed on day 7 and 14 every treatment cycle.
Outcomes
The primary outcome of this real-world study was the incidence of FN, defined as an oral temperature of > 38.3 °C or two consecutive readings of > 38.0 °C over 2 h, in the presence of an absolute neutrophil count (ANC) of < 0.5 × 109/L or an expected to fall below 0.5 × 109/L. Patients were instructed to measure their body temperature daily and to contact the study center if fever or related symptoms occurred. FN events were identified based on laboratory results from both scheduled and unscheduled visits, as well as hospital medical records.
The secondary outcomes were severe neutropenia, defined as ANC < 1.0 × 109/L, and adverse events (AEs) according to Common Terminology Criteria for Adverse Events (version 5.0). All grade ≥ 3 AEs were independently reviewed by two investigators in a blinded manner during data analysis using predefined criteria. Causality was assessed according to categories (definite, probable, possible, unlikely, unrelated, or unassessable) recommended by CTCAE.
Statistical analysis
Propensity score matching (PSM) was performed to reduce baseline confounding between patients receiving 2-weekly and 3-weekly chemotherapy regimens. Propensity scores for receiving the 2-weekly regimen were estimated for each patient using a logistic regression model, incorporating covariates including age, ECOG performance status, baseline FN risk, and the use of anthracycline-containing regimens. Patients were then matched using a 1:2 nearest-neighbor matching approach without replacement, with a caliper width of 0.2. After matching, covariate balance for key variables included in the propensity score model was assessed using standardized mean differences (SMDs), with an absolute SMD < 0.1 considered indicative of acceptable balance between groups. Patients with missing values in ECOG performance status or baseline FN risk were excluded prior to PSM analysis. Categorical variables were presented as numbers and percentages, while continuous variables were presented as mean and standard deviation. In the matched cohort, count outcomes such as the number of chemotherapy delays and FN events were compared between groups using the nonparametric Wilcoxon rank-sum test. Corresponding 95% confidence intervals (CIs) were calculated using the Clopper–Pearson method. The main analyses were done in the full analysis set, which included all patients who received at least one dose of mecapegfilgrastim. Safety analyses were done in the safety analysis set, including all patients who received at least one dose of mecapegfilgrastim and one safety assessment. All analyses were conducted using R software, with a two-sided significance level of α = 0.05.
Results
Patient characteristics
Between June 2019 and March 2022, a total of 757 patients were enrolled in the present study. Of these, 44 patients received 2-weekly chemotherapy and 713 patients received 3-weekly chemotherapy. After PSM, a total of 36 patients were included in the 2-weekly group and 71 patients were included in the 3-weekly group. The baseline characteristics between the two groups were generally well balanced (Table 1). The mean age was 47.9 years in the 2-weekly group and 48.1 years in the 3-weekly group. Chemotherapy-related FN risks were classified as low, moderate, and high in 0 (0), 16 (44.4%) and 20 (55.6%) patients in the 2-weekly group, and in 0 (0), 31 (43.7%) and 40 (56.3%) patients in the 3-weekly group, respectively. The median ANC was 3.61 × 109/L in the 2-weekly group and 3.40 × 109/L in the 3-weekly group.
Table 1.
Baseline characteristics before and after propensity score matching
| Characteristics | Before matching | After matching | ||||
|---|---|---|---|---|---|---|
| 2-weekly chemotherapy (n = 44) |
3-weekly chemotherapy (n = 713) |
P value | 2-weekly chemotherapy (n = 36) |
3-weekly chemotherapy (n = 71) |
P value | |
| Sex (n, %) | ||||||
| Female | 44 (100) | 709 (99.4) | 1.000 | 36 (100) | 71 (100) | 1.000 |
| Male | 0 (0) | 4 (0.6) | 0 (0) | 0 (0) | ||
| Age (mean (SD)) | 47.59 (9.37) | 51.40 (10.14) | 0.015 | 47.94 (9.95) | 48.14 (10.94) | 0.928 |
| FN risk | 0.097 | 1.000 | ||||
| Low | 0 (0) | 63 (8.8) | 0 (0) | 0 (0) | ||
| Moderate | 23 (52.3) | 364 (56.1) | 16 (44.4) | 31 (43.7) | ||
| High | 20 (45.5) | 263 (36.9) | 20 (55.6) | 40 (56.3) | ||
| Unknown | 1 (2.3) | 23 (3.2) | 0 (0) | 0 (0) | ||
| ECOG | 0.871 | |||||
| 0–1 | 37 (84.1) | 689 (96.9) | 36 (100) | 71 (100) | 1.000 | |
| ≥ 2 | 0 (0) | 5 (0.7) | 0 (0) | 0 (0) | ||
| Unknown | 7 (15.9) | 19 (2.7) | 0 (0) | 0 (0) | ||
| Clinical stage (n, %) | 0.003 | |||||
| I | 1 (2.3) | 92 (12.9) | 1 (2.8) | 7 (9.9) | 0.024 | |
| II | 7 (15.9) | 232 (32.5) | 7 (19.4) | 26 (36.6) | ||
| III | 15 (34.1) | 123 (17.3) | 15 (41.7) | 11 (15.5) | ||
| IV | 3 (6.8) | 60 (8.4) | 2 (5.6) | 7 (9.9) | ||
| Unknown | 18 (40.9) | 206 (28.9) | 11 (30.6) | 20 (28.2) | ||
| Absolute neutrophil count (median, 109/L) | 3.46 | 3.53 | 0.646 | 3.61 [2.60, 5.92] | 3.40 [2.66, 4.69] | 0.481 |
| White blood cell count (median, 109/L) | 5.84 | 5.55 | 0.421 | 5.97 [4.49, 8.07] | 5.34 [4.50, 7.32] | 0.528 |
| Prior chemotherapy | 1.000 | 0.403 | ||||
| Yes | 22 (50) | 361 (50.6) | 18 (50.0) | 28 (39.4) | ||
| No | 22 (50) | 352 (49.4) | 18 (50.0) | 43 (60.6) | ||
| Prior radiotherapy | 0.939 | 0.860 | ||||
| Yes | 2 (4.5) | 43 (6.0) | 1 (2.8) | 4 (5.6) | ||
| No | 42 (95.5) | 670 (94.0) | 35 (97.2) | 67 (94.4) | ||
| Surgery within 6 months | 0.071 | 0.588 | ||||
| Yes | 16 (36.4) | 368 (51.6) | 15 (41.7) | 35 (49.3) | ||
| No | 28 (63.6) | 345 (48.4) | 21 (58.3) | 36 (50.7) | ||
| Chemotherapy regimen in first cycle | ||||||
| Containing doxorubicin/epirubicin | 30 (68.2) | 269 (37.7) | < 0.001 | 25 (69.4) | 49 (69.0) | 1.000 |
| Containing taxanes | 8 (18.2) | 166 (23.3) | 0.551 | 6 (16.7) | 21 (29.6) | 0.224 |
FN febrile neutropenia, ECOG Eastern Cooperative Oncology Group
Incidence of FN and severe neutropenia
After matching, in the first treatment cycle, no patients (0.0%; 95% CI 0–9.6%) experienced FN in the 2-weekly group, whereas FN occurred in 2 patients (2.8%; 95% CI 0.8–9.7%) in the 3-weekly group (P = 0.55). Grade 3/4 neutropenia occurred in 9 patients (25.0%; 95% CI 13.8–41.1%) in the 2-weekly group and 11 patients (15.5%; 95% CI 8.9–25.7%) in the 3-weekly group (P = 0.29). Grade 4 neutropenia was observed in 4 patients (11.1%; 95% CI 4.4–25.3%) in the 2-weekly group and 5 patients (7.0%; 95% CI 3.0–15.4%) in the 3-weekly group, respectively (P = 0.48). Across all treatment cycles, FN was observed in 0 patients (0.0%; 95% CI 0–9.6%) in the 2-weekly group and in 2 patients (2.8%; 95% CI 0.8–9.7%) in the 3-weekly group (P = 0.55). Grade 3/4 neutropenia occurred in 11 patients (30.6%; 95% CI 18.0–46.9%) in the 2-weekly group and 14 patients (19.7%; 95% CI 12.1–30.4%) in the 3-weekly group (P = 0.23), while grade 4 neutropenia was observed in 5 (13.9%; 95% CI 6.1–28.7%) and 7 (9.9%; 95% CI 4.9–19.0%) patients in the 2-weekly and 3-weekly groups, respectively (P = 0.53). Dose hold (≥ 5 days) occurred in 7 patients (19.4%; 95% CI 9.8–35.0%) in the 2-weekly group and 5 patients (7.0%; 95% CI 3.0–15.4%) in the 3-weekly group (P = 0.10) (Table 2).
Table 2.
Febrile neutropenia and grade 3/4 neutropenia
| First cycle | P | Any cycle | P | |||
|---|---|---|---|---|---|---|
| 2-weekly (n = 36) | 3-weekly (n = 71) | 2-weekly (n = 36) | 3-weekly (n = 71) | |||
| Febrile neutropenia, n (%) | 0 (0% [0.0-9.6%]) | 2 (2.8% [0.8–9.7%]) | 0.55 | 0 (0.0% [0.0-9.6%]) | 2 (2.8% [0.8–9.7%]) | 0.55 |
| Grade 3/4 neutropenia, n (%) | 9 (25.0% [13.8–41.1%]) | 11 (15.5% [8.9–25.7%]) | 0.29 | 11 (30.6% [18.0-46.9%]) | 14 (19.7% [12.1–30.4%]) | 0.23 |
| Grade 4 neutropenia, n (%) | 4 (11.1% [4.4–25.3%]) | 5 (7.0% [3.0-15.4%]) | 0.48 | 5 (13.9% [6.1–28.7%]) | 7 (9.9% [4.9–19%]) | 0.53 |
| Dose hold (≥ 5 days), n (%) | NA | NA | 7 (19.4% [9.8–35%]) | 5 (7.0% [3.0-15.4%]) | 0.10 |
Safety
During the first cycle, the incidence of grade 3/4 TEAEs was 26.7% in the 2-weekly and 33.3% in the 3-weekly groups. The most common grade 3/4 TEAEs in the 2-weekly group were white blood cell count decreased (25.0%) and neutrophil count decreased (22.2%). In the 3-weekly group, the most common grade 3/4 TEAEs were neutrophil count decreased (14.1%), followed by white blood cell count decreased (9.9%) (Table 3). Treatment-related adverse events (TRAEs) were uncommon. No grade 3/4 TRAEs were observed in either group (Table 4). No patients had serious AEs in either group. No treatment-related deaths were reported.
Table 3.
Treatment-emergent adverse events
| First cycle | ||||
|---|---|---|---|---|
| 2-weekly (n = 36) | 3-weekly (n = 71) |
|||
| Grade 1–2 | Grade 3–4 | Grade 1–2 | Grade 3–4 | |
| Anemia | 17 (47.2) | 2 (5.6) | 12 (16.9) | 3 (4.2) |
| White blood cell count decreased | 9 (25.0) | 9 (25.0) | 14 (19.7) | 7 (9.9) |
| Neutrophil count decreased | 8 (22.2) | 8 (22.2) | 8 (11.3) | 10 (14.1) |
| Lymphocyte count decreased | 6 (16.7) | 2 (5.6) | 2 (2.8) | 4 (5.6) |
| Platelet count decreased | 4 (11.1) | 1 (2.8) | 2 (2.8) | 1 (1.4) |
| Nausea | 3 (8.3) | 0 (0) | 13 (18.3) | 0 (0) |
| Vomiting | 2 (5.6) | 0 (0) | 6 (8.5) | 0 (0) |
| Bone marrow suppression | 0 (0) | 2 (5.6) | 0 (0) | 1 (1.4) |
Table 4.
Treatment-related adverse events
| First cycle | ||||
|---|---|---|---|---|
| 2-weekly (n = 36) | 3-weekly (n = 71) |
|||
| Grade 1–2 | Grade 3–4 | Grade 1–2 | Grade 3–4 | |
| Bone pain | 0 (0) | 0 (0) | 2 (2.8) | 0 (0) |
| Vomiting | 0 (0) | 0 (0) | 1 (1.4) | 0 (0) |
| Nausea | 0 (0) | 0 (0) | 1 (1.4) | 0 (0) |
| White blood cell count decreased | 0 (0) | 0 (0) | 1 (1.4) | 0 (0) |
| Neutrophil count decreased | 0 (0) | 0 (0) | 1 (1.4) | 0 (0) |
| Lymphocyte count decreased | 0 (0) | 0 (0) | 1 (1.4) | 0 (0) |
Discussion
With the development of supportive care, chemotherapy-induced side effects have been alleviated, and the interval between chemotherapy cycles were shorten, especially for patients with high-risk malignancies. Currently, the 2-weekly regimens such as doxorubicin and cyclophosphamide (AC) has been recommended for the treatment of breast cancer in NCCN guidelines, which has a higher risk to cause myelosuppression symptoms such as FN and neutropenia as compared with traditional 3-weekly regimens [14, 15].
To our knowledge, this is the largest observational prospective study that evaluated real-world evidence of effectiveness of mecapegfilgrastim in breast cancer patients who received 2-weekly and 3-weekly chemotherapy in China. The primary outcome was the incidence of FN in the first cycle. After PSM, FN occurred in 0 patients (0%; 95% CI, 0-9.6%) in the 2-weekly group and in 2 patients (2.8%; 95% CI, 0.8–9.7%) in the 3-weekly group during the first cycle. Severe neutropenia occurred in 9 (25.0%; 95% CI, 13.8–41.1%) and 11 (15.5%; 95% CI, 8.9–25.7%) patients in the 2-weekly and 3-weekly groups during the first cycle, respectively. Notably, although severe neutropenia appeared numerically more frequent in the 2-weekly group, this did not correspond to a higher observed incidence of FN. Treatment delays were observed in 7 (19.4%; 95% CI, 9.8–35.0%) and 5 (7%; 95% CI, 3-15.4%) patients in the 2-weekly and the 3-weekly groups, respectively, across all cycles. No statistically significant differences in efficacy were observed between the two groups. However, the relatively small sample size and descriptive nature of the analysis may limit the robustness of these observations. The TEAEs and TRAEs were manageable in both groups and no treatment-related deaths occurred. The current findings were in line with our previously published analyses [16, 17].
In clinical practice, while neutropenia alone may not cause any specific symptoms, FN is a serious complication that can be life-threatening, impacts patients’ quality of life, leads to hospitalization, and increases patients’ economic burden [18, 19]. The efficacy of mecapegfilgrastim in breast cancer patients who received 3-weekly chemotherapy has been investigated in a randomized, active-controlled, multicenter, phase III study. The results showed that the incidence of FN and severe neutropenia was 4.5% and 50.45% in patients who received 100 µg/kg mecapegfilgrastim, and 0.0% and 50.91% in patients who received 6 mg dose mecapegfilgrastim [12]. Compared with this clinical trial, our study showed a similar FN rate, but a numerically lower incidence of severe neutropenia, which might be attributed to the less frequent blood count monitoring in real-world practice. In the randomized phase III study, blood samples were assessed within 24 h before the initiation of chemotherapy and on days 1, 3, 5, 7, 8, 9, 10, 11, 13, 15, 17 and 21 during the first cycle, whereas in our study, routine blood counts were generally assessed on days 7 and 14. Consequently, patients who experienced only brief periods of grade ≥ 3 neutropenia could have recovered by the time of scheduled assessments, resulting in an underestimation of the true incidence. Although the effectiveness of mecapegfilgrastim in patients with breast cancer who received 2-weekly chemotherapy have not been investigated, several observational studies have evaluated other long-acting G-CSF such as pegfilgrastim and lipegfilgrastim in this population. In the first treatment cycle, the incidence of FN in these studies ranged from 1.1% to 5.0%, and the incidence of severe neutropenia ranged from 1.7% to 33.3% [9, 11, 20, 21]. The results from the above studies were consistent with corresponding results from our study. In addition, 19.4% and 7.0% of patients experienced treatment delays in the 2-weekly group and the 3-weekly group in our study, respectively. Unfortunately, because of different definitions and counting methods of dose delay and infection, a comparison between the data from this study and those from previous studies was unable to be conducted. Furthermore, since only data from observational studies are available in this field, they may be subject to inevitable biases caused by selection and recording.
In terms of safety, the proportion of grade 3/4 TRAEs and serious AEs were low in either group. A randomized, phase II clinical trial involving patients with breast cancer who received 3-weekly chemotherapy followed by 100 µg/kg pegfilgrastim showed that 45% of patients experienced bone pain [22]. Moreover, in a randomized, phase III clinical trial investigating pegfilgrastim in patients with breast cancer who received 3-weekly chemotherapy, 57.0% of patients experienced AEs related to chemotherapy or pegfilgrastim. One (1.2%) patient had an SAE [23]. However, the proportion of patients experienced grade 3/4 AEs in the above two studies was not reported. In an observational real-world study that enrolled patients with non-myeloid malignancies and received mecapegfilgrastim prophylaxis for chemotherapy, the incidence of study drug-related grade ≥ 3 AEs was 1.0%, and the SAEs was 0.1%, which is consistent with our findings [17].
There are several limitations in the present study. First, selection bias was inevitable due to the nature of the observational design. Second, although matching improved the comparability between groups, the sample size of the 2-weekly cohort was relatively small, which may affect the stability and precision of the estimates. In particular, the absence of FN events in the 2-weekly group may be influenced by the small sample size and the low incidence of FN, and could be attributable to random variation. Third, although a higher incidence of grade 3/4 neutropenia was observed in the 2-weekly group, this did not translate into FN events, and this discordance cannot be definitively explained in the current study. Fourth, the AEs of specific chemotherapy regimens were not anayzed.
Conclusion
Mecapegfilgrastim was associated with a low incidence of FN and a manageable safety profile in patients with breast cancer who received 3-weekly or 2-weekly chemotherapy. However, these findings should be interpreted in the context of the observational study design and the limited sample size.
Acknowledgements
We thank Liu Yang (Department of Medical Affairs, Jiangsu Hengrui Pharmaceuticals Co., Ltd.) for data interpretation and Yunning Yang (Department of Medical Affairs, Jiangsu Hengrui Pharmaceuticals Co., Ltd.) for medical writing assistance according to Good Publication Practice Guidelines. We thank Do Wang for statistical support (Department of Medical Affairs, Jiangsu Hengrui Pharmaceuticals Co., Ltd.) for statistical support.
Authors’ contributions
Yuihua Xu and Jun Ma designed the study and supervised the study; Yanxia Shi write the original article; Peifen Fu and Yongsheng Wang edited the manuscript; data were collected and analyzed by all authors.
Funding
None.
Data availability
Data supporting the findings of this study are available from the corresponding author upon reasonable request.
Declarations
Ethics approval and consent to participate
The study protocol was approved by the ethics committees of Harbin Institute of Hematology and Oncology (No. 2019-006) and was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines.
Consent for publication
Not Applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ruihua Xu and Jun Ma contributed equally as corresponding authors.
Contributor Information
Ruihua Xu, Email: xurh@sysucc.org.cn.
Jun Ma, Email: drmajun123@163.com.
References
- 1.Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17–48. [DOI] [PubMed] [Google Scholar]
- 2.Patel K, West HJ. Febrile Neutropenia. JAMA Oncol. 2017;3(12):1751. [DOI] [PubMed] [Google Scholar]
- 3.Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003;21(8):1431–9. [DOI] [PubMed] [Google Scholar]
- 4.Del Mastro L, De Placido S, Bruzzi P, De Laurentiis M, Boni C, Cavazzini G, et al. Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer: an open-label, 2 × 2 factorial, randomised phase 3 trial. Lancet. 2015;385(9980):1863–72. [DOI] [PubMed] [Google Scholar]
- 5.Ding Y, Ding K, Yang H, He X, Mo W, Ding X. Does dose-dense neoadjuvant chemotherapy have clinically significant prognostic value in breast cancer? A meta-analysis of 3,724 patients. PLoS ONE. 2020;15(5):e0234058. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Crawford J, Dale DC, Lyman GH. Chemotherapy-induced neutropenia: risks, consequences, and new directions for its management. Cancer. 2004;100(2):228–37. [DOI] [PubMed] [Google Scholar]
- 7.Klastersky J, de Naurois J, Rolston K, Rapoport B, Maschmeyer G, Aapro M, et al. Management of febrile neutropaenia: ESMO Clinical Practice Guidelines. Ann Oncol. 2016;27(suppl 5):v111–8. [DOI] [PubMed] [Google Scholar]
- 8.Griffiths EA, Roy V, Alwan L, Bachiashvili K, Baird J, Cool R, et al. NCCN Guidelines® Insights: Hematopoietic Growth Factors, Version 1.2022. J Natl Compr Canc Netw. 2022;20(5):436–42. [DOI] [PubMed] [Google Scholar]
- 9.Kourlaba G, Dimopoulos MA, Pectasides D, Skarlos DV, Gogas H, Pentheroudakis G, et al. Comparison of filgrastim and pegfilgrastim to prevent neutropenia and maintain dose intensity of adjuvant chemotherapy in patients with breast cancer. Support Care Cancer. 2015;23(7):2045–51. [DOI] [PubMed] [Google Scholar]
- 10.Jones RL, Walsh G, Ashley S, Chua S, Agarwal R, O’Brien M, et al. A randomised pilot Phase II study of doxorubicin and cyclophosphamide (AC) or epirubicin and cyclophosphamide (EC) given 2 weekly with pegfilgrastim (accelerated) vs 3 weekly (standard) for women with early breast cancer. Br J Cancer. 2009;100(2):305–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Wang X, He Y, Wang T, Xie Y, Li J, Ouyang T, et al. Efficacy of pegfilgrastim to support neoadjuvant dose-dense epirubicin and cyclophosphamide chemotherapy in breast cancer. Support Care Cancer. 2019;27(8):3019–25. [DOI] [PubMed] [Google Scholar]
- 12.Xu F, Zhang Y, Miao Z, Zeng X, Wu B, Cai L, et al. Efficacy and safety of mecapegfilgrastim for prophylaxis of chemotherapy-induced neutropenia in patients with breast cancer: a randomized, multicenter, active-controlled phase III trial. Ann Transl Med. 2019;7(18):482. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Yan B, Zhang W, Lu F, Chen Z-L, Han B-H, Jiang L-Y. Safety of polyethylene glycol recombinant human granulocyte colony-stimulating factor in treating non-small cell lung cancer patients at I b stage. Asian Pac J Trop Med. 2013;6(11):912–5. [DOI] [PubMed] [Google Scholar]
- 14.Gradishar WJ, Moran MS, Abraham J, Abramson V, Aft R, Agnese D, et al. NCCN Guidelines® Insights: Breast Cancer, Version 5.2025. J Natl Compr Canc Netw. 2025;23(11):426–36. [DOI] [PubMed] [Google Scholar]
- 15.Gradishar WJ, Moran MS, Abraham J, Abramson V, Aft R, Agnese D, et al. NCCN Guidelines® Insights: Breast Cancer, Version 4.2023. J Natl Compr Canc Netw. 2023;21(6):594–608. [DOI] [PubMed] [Google Scholar]
- 16.Ma J, Huang H, Fu P, Xu N, Mao C, Cheng G, et al. Prophylaxis of neutropenia with mecapegfilgrastim in patients with non-myeloid malignancies: a real-world study. Ann Transl Med. 2021;9(10):893. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Qin S, Shi Y, Fu P, Xu N, Mao C, Chen Y, et al. Mecapegfilgrastim prophylaxis for neutropenia in patients with non-myeloid malignancies: A Chinese nationwide real-world study. BMC Cancer. 2025;25(1):742. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Lee S, Knox A, Zeng ISL, Coomarasamy C, Blacklock H, Issa S. Primary prophylaxis with granulocyte colony-stimulating factor (GCSF) reduces the incidence of febrile neutropenia in patients with non-Hodgkin lymphoma (NHL) receiving CHOP chemotherapy treatment without adversely affecting their quality of life: cost-benefit and quality of life analysis. Support Care Cancer. 2013;21(3):841–6. [DOI] [PubMed] [Google Scholar]
- 19.Boccia R, Glaspy J, Crawford J, Aapro M. Chemotherapy-Induced Neutropenia and Febrile Neutropenia in the US: A Beast of Burden That Needs to Be Tamed? Oncologist. 2022;27(8):625–36. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Kiechle M, Schem C, Lüftner D, Hipp J, Stetzer E, Köhler U. Prophylaxis of Neutropenia with Lipegfilgrastim in Breast Cancer Patients with Dose-Dense Chemotherapy: Results of a Noninterventional Study on Therapeutic Routine in Germany (NADENS). Breast Care (Basel). 2022;17(5):508–13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Mądry R, Popławska L, Haslbauer F, Šafanda M, Ghizdavescu D, Benkovicova J, et al. Results of a prospective dose intensity and neutropenia prophylaxis evaluation programme (DIEPP) in cancer patients at risk of febrile neutropenia due to myelosuppressive chemotherapy. Wien Klin Wochenschr. 2016;128(7–8):238–47. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Holmes FA, Jones SE, O’Shaughnessy J, Vukelja S, George T, Savin M, et al. Comparable efficacy and safety profiles of once-per-cycle pegfilgrastim and daily injection filgrastim in chemotherapy-induced neutropenia: a multicenter dose-finding study in women with breast cancer. Ann Oncol. 2002;13(6):903–9. [DOI] [PubMed] [Google Scholar]
- 23.Green MD, Koelbl H, Baselga J, Galid A, Guillem V, Gascon P, et al. A randomized double-blind multicenter phase III study of fixed-dose single-administration pegfilgrastim versus daily filgrastim in patients receiving myelosuppressive chemotherapy. Ann Oncol. 2003;14(1):29–35. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data supporting the findings of this study are available from the corresponding author upon reasonable request.