Zou et al.

BMC Cancer (2021) 21:661

https://doi.org/10.1186/s12885-021-08364-9

RESEARCH ARTICLE Open Access

A clinical study of pegylated recombinant

human granulocyte colony stimulating
factor (PEG-rhG-CSF) in preventing
neutropenia during concurrent
chemoradiotherapy of cervical cancer
Dongling Zou, Mingfang Guo and Qi Zhou*

Abstract
Purpose: To evaluate the effectiveness and safety of pegylated recombinant human granulocyte colony stimulating
factor (PEG-rhG-CSF) in preventing neutropenia during chemoradiotherapy in patients with cervical cancer.
Methods: From August 2018 to April 2020, 60 patients who were pathologically confirmed as cervical cancer were
randomly divided into two groups at a ratio of 2:1: PEG-modified-rhG-CSF experimental group and control group.
The primary endpoints were the incidence of grade 3–4 neutropenia. Secondary endpoints included the duration
of grade 3–4 neutropenia, the incidence of grade 4 neutropenia, the incidence of febrile neutropenia (FN), delay
rate of chemotherapy, prolonged time of chemotherapy, time to complete radiotherapy and safety.
Results: The incidence of grade 3–4 neutropenia in the experimental group was significantly lower than the
control group (10% vs. 77.78%, P < 0.001). However, there was no statistical significance between the two groups in
the duration of grade 3–4 neutropenia (3.75 days vs. 5.07 days, P = 0.871). The experimental group was better than
the control group in the incidence of grade 4 neutropenia, the incidence of FN and delay rate of chemotherapy,
and the difference was statistically significant (P < 0.05). Besides, the prolonged time of chemotherapy and the time
to complete radiotherapy in the experimental group were less than those in the control group, but the difference
was not statistically significant (P > 0.05). The incidence of adverse events in the experimental group and control
group were 55.00 and 94.44%, respectively, and the difference was statistically significant (P = 0.003).
Conclusion: PEG-rhG-CSF preventive treatment used in the course of chemoradiotherapy for patients with cervical
cancer can reduce the incidence of neutropenia and improve the incidence of delayed chemotherapy cycles.
Trial registration: ClinicalTrials.gov, NCT04542356. Registered 9 September 2020 - Retrospectively registered.
Keywords: Cervical Cancer, Concurrent Radiochemotherapy, Neutropenia, Pegylated recombinant human
granulocyte colony stimulating factor

* Correspondence: [email protected]
Chongqing University Cancer Hospital, Shapingba district, Chongqing
400030, China

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Zou et al. BMC Cancer (2021) 21:661 Page 2 of 7

Introduction approved by the Clinical Research Management

Cervical cancer is the third most common cancer among Committee of Chongqing Cancer Hospital (No. 2019-
women in the world, and the most common cancer among linshen-027). The study received informed consent
women in Eastern and Central Africa [1, 2]. According to signed by all patients.
reports, the incidence and mortality of cervical cancer are
incredibly high, accounting for about 86% of the deaths Patients
from cervical cancer worldwide. According to the 2018 The inclusion criteria were: women aged 18–70 years;
International Federation of Gynecology and Obstetrics pathologically confirmed and previously untreated with
(FIGO) staging recommendation, the preferred treatment surgery Stage IIb-IIIb cervical cancer; Expected survival
for patients with stage IIB ~ IVA cervical cancer is concur- time ≥ 8 months; Eastern Cooperative Oncology Group
rent radiotherapy and chemotherapy (chemoradiotherapy). (ECOG) performance score ≤ 1. The bone marrow
Studies have shown that compared with the same dose of hematopoietic function is normal, the absolute neutro-
radiotherapy, the five-year overall survival rate of chemora- phil count (ANC) ≥ 1.8 × 109/L, platelet count (PLT)
diotherapy has increased by 6% [3]. Chemoradiotherapy ≥ 100 × 109/L, hemoglobin (Hb) ≥ 90 g/L and white
can improve the efficacy and survival rate of cervical cancer, blood cell count (WBC) ≥4.0 × 109/L. All patients
but it increases the incidence of acute blood adverse reac- showed no obvious cardiac dysfunction through the
tions, such as acute blood toxicity and neutropenia [4]. ECOG examination. All patients must agree to take ef-
Neutropenia caused by chemoradiotherapy is often fective contraceptive measures during the study period
treated with recombinant human granulocyte colony and within 6 months after stopping treatment, and fe-
stimulating factor (rhG-CSF) in clinical practice [5–7]. male patients of childbearing age must have a negative
The circulating half-life (t1/2) of rhG-CSF is about 3–6 urine pregnancy test before treatment.
h and requires daily administration [8–10]. Pegylated
modified recombinant human granulocyte colony stimu-
Randomization and study treatment
lating factor (PEG-modified-rhG-CSF) is the long-acting
According to the principle of 2:1 randomization, patients
form of rhG-CSF with t1/2 of about 42–62 h, which is a
were divided into the experimental group and the control
covalent combination of rhG-CSF and polyethylene
group. Patients in the experimental group were treated
glycol (PEG) [9, 11]. PEG-rhG-CSF mainly acts on
with PEG-rhG-CSF for primary prevention during concur-
hematopoietic cells, including promonocytes, eosino-
rent chemoradiotherapy. Patients in the control group
phils, lymphocytes, erythrocytes, and megakaryocytes, by
were treated with rhG-CSF when ANC < 1 × 109/L
binding to G-CSF receptor on the cell surface, thereby
occurred during concurrent chemoradiotherapy.
stimulating cell proliferation, differentiation, and activa-
tion of terminal cell functions, without altering the ag-
gregation and bind pattern compared with rhG-CSF [9]. Study procedures
A multicenter prospective study indicated that the use of Chemoradiotherapy regimen
PEG-rhG-CSF for primary prevention can significantly The chemotherapy regimen was TP regimen: paclitaxel 150
reduce the incidence of febrile neutropenia (FN) caused mg/m2 on day 1 + cisplatin 35 mg/m2 on day 1–2. TP regi-
by chemotherapy [12]. Although PEG-rhG-CSF for pri- men was repeated every 3 weeks as a chemotherapy cycle,
mary prevention can benefit patients, most of the and radiotherapy was followed 24 h after the end of chemo-
evidence comes from chemotherapy, there are few clin- therapy at each cycle. If patients experience intolerance with
ical practice studies on concurrent chemoradiotherapy cisplatin, other platinums such as carboplatin can be used in-
[13–15]. This current study firstly analyzed the efficacy stead. All patients received two 3-week cycles of TP chemo-
and safety of PEG-rhG-CSF in the prevention of neutro- therapy. Radiotherapy was given on the second day of
penia caused by chemoradiotherapy in patients with cer- chemotherapy at each cycle. The radiotherapy regimen is ex-
vical cancer. The results may provide a basis for the ternal beam radiotherapy (EBRT): 95% of planning tumor
clinical application of PEG-rhG-CSF in the treatment volume (PTV) received the prescribed dose of 45Gy/25
process of chemoradiotherapy cycle in patients with times, 5 times/week.
cervical cancer.
Dosing regimen
Patients and methods The experimental group was injected subcutaneously
From August 2018 to April 2020, a total of 60 patients with 6 mg PEG-rhG-CSF (Qilu Pharmaceutical Co., Ltd.)
with cervical squamous cell carcinoma diagnosed by 2 h after the end of radiotherapy at each cycle. The con-
histopathology and who were not initially treated with trol group was not given PEG-rhG-CSF for treatment. If
surgery (stage IIb-IIIb) were enrolled (clinical trials the patient has an ANC < 1 × 109/L, 5μg/kg/d rhG-CSF
registration number NCT04542356). The study was (Qilu Pharmaceutical Co., Ltd.) was given for treatment
Zou et al. BMC Cancer (2021) 21:661 Page 3 of 7

Table 1 Baseline analysis

Characteristics Experimental group (N = 40) Control group (N = 18) Statistics P
Age 54.25 ± 7.48 54.17 ± 7.56 t = 0.04 0.969
Classification of diseases – –
CSEC 40 (100.00%) 18 (100.00%)
FIGO staging χ2 = 5.01 0.025
IIB 19 (47.50%) 3 (16.67%)
IIIA+IIIB 21 (52.50%) 15 (83.33%)
ECOG score χ2 = 0.13 0.719
0 13 (32.50%) 5 (27.78%)
1 27 (67.50%) 13 (72.22%)
ANC baseline (×109) 4.26 ± 1.38 4.32 ± 1.74 t = 0.14 0.889
2
Body surface area (m ) 1.54 ± 0.11 1.56 ± 0.17 t = 0.44 0.666
Second cycle precursor body surface area (m2) 1.54 ± 0.11 1.56 ± 0.17 t = 0.44 0.666
CSEC cervical squamous epithelium carcinoma, ANC Absolute neutophil count

subcutaneously, and both chemotherapy and radiother- the baseline absolute neutrophil count (ANC) was
apy were stopped until ANC ≥ 2 × 109/L. (4.26 ± 1.38) × 109/L and (4.32 ± 1.74) × 109/L (P = 0.889).
According to FIGO staging, there were 19 patients with
Study outcomes stage IIB and 21 patients with IIIA+IIIB in the experi-
The primary outcome was the incidence of grade 3–4 mental group. The control group included 3 patients
neutropenia (defined as ANC < 0.5 × 109/L). The second- with stage IIB and 15 patients with IIIA+IIIB. There was
ary outcomes were the duration of grade 3–4 neutro- no significant difference between the two groups of pa-
penia (according to National Cancer Institute (NCI) tients in various baseline indicators. All patients received
common toxicity criteria, V4.03), the incidence of grade
4 neutropenia, the completion time of radiotherapy,
Table 2 Exposure analysis
delay rate of chemotherapy, prolonged time of chemo-
Experimental group Control group
therapy, the incidence of FN and safety. (N = 39) (N = 18)
First cycle
Statistical analysis
Paclitaxel amount (mg)
Data analysis was performed using SAS9.4 software. For con-
tinuous data, if it obeys a normal distribution, the measured Median (Q1,Q3) 235.00 (220.00, 240.00) 225.00 (210.00, 240.00)
data were analyzed by t-test and the data were expressed as Mean ± SD 231.67 ± 16.69 227.94 ± 24.73
mean ± standard deviation. If it does not obey the normal Paclitaxel dose (mg/m2)
distribution, analyze the measured data were analyzed by Median (Q1,Q3) 150.07 (149.34, 151.90) 149.33 (144.83, 150.00)
non-parametric rank sum test and the data were expressed Mean ± SD 150.91 ± 7.26 146.78 ± 6.68
as the median (Q1, Q3). For classified data, the measurement
Cisplatin amount (mg)
data were analyzed by χ2 test, and the data were expressed in
frequency (percentage). P < 0.05 indicates that the difference Median (Q1,Q3) 106.00 (100.00, 110.00) 100.00 (100.00, 110.00)
was statistically significant. Mean ± SD 105.66 ± 9.70 102.89 ± 9.68
Cisplatin dose (mg/m2)
Results Median (Q1,Q3) 69.18 (67.11, 70.51) 68.49 (66.12, 69.18)
Patients
Mean ± SD 68.73 ± 3.44 66.47 ± 5.14
A total of 60 patients were included in this study be-
Second cycle
tween August 2018 and April 2020. Forty patients were
randomly assigned to the experimental group and 20 pa- Whether to adjust the dose in the second cycle
tients were randomly assigned to the control group. Yes 0 0
However, two patients in the control group withdrew No 39 (100.00%) 18 (100.00%)
due to lack of treatment compliance. Table 1 summa- Whether to remedy the use of short-acting rhG-CSF
rizes the baseline characteristics of the patients. The Yes 3 (7.69%) 18 (100.00%)
average age of the experimental group and the control
No 36 (92.31%) 0
group were 54.25 years and 54.17 years, respectively, and
Zou et al. BMC Cancer (2021) 21:661 Page 4 of 7

the second cycle of chemoradiotherapy without adjusting difference between the two groups was not statisti-
the dose, which was the same as the first cycle of che- cally significant (P = 0.871) (Table 3).
moradiotherapy. In the second cycle of chemoradiother-
apy, all patients in the control group used rhG-CSF for The incidence of grade 4 neutropenia and the incidence of
salvage treatment, while only 3 people in the experimen- FN
tal group used rhG-CSF and all of them received The incidence of grade 4 neutropenia in the experimen-
prophylactic PEG-rhG-CSF (Table 2). tal and control groups was 7.5 and 33.33%, respectively.
The incidence of grade 4 neutropenia in the experimen-
tal group was reduced by 25.83%, which was significantly
Efficacy lower compared with the control group (P = 0.034).
The incidence and duration of grade 3–4 neutropenia Similarly, FN didn’t occurre in the experimental
The primary endpoint, the incidence of grade 3–4 group (0%) and occurred in 3 patients (16.67%) in the
neutropenia, was significantly lower in experimental control group, and the difference was also signifi-
group (4/40; 10%) than that in the control group (14/ cantly lower in experimental group compared with
18; 77.78%) (P < 0.001) (Table 3 and Fig. 1). The aver- control group (P = 0.026) (Table 3).
age duration of grade 3–4 neutropenia in the experi-
mental group was 3.75 days and in the control group Time to complete radiotherapy, delay rate of chemotherapy
was 5.07 days. Although the duration of grade 3–4 and prolonged time of chemotherapy
neutropenia in the experimental group tended to There was no statistically significant difference in the
decrease compared with the control group, the mean ± SD time to complete radiotherapy (P = 0.375),

Table 3 Analysis of endpoints

Endpoints Experimental group (N = 40) Control group (N = 18) Statistics P
Whether grade 3/4 neutropenia occurs χ2 = 26.64 < 0.001
Yes 4 (10.00%) 14 (77.78%)
No 36 (90.00%) 4 (22.22%)
The duration of grade 3–4 neutropenia a Z = 0.16 0.871
n 4 14
Median (Q1,Q3) 3.5 (3.0,4.5) 3.5 (3.0,9.0)
Whether grade 4 neutropenia occurs χ2 = 4.50 0.034
Yes 3 (7.50%) 6 (33.33%)
No 37 (92.50%) 12 (66.67%)
Whether FN occurs 0.026
Yes 0 3 (16.67%)
No 40 (100.00%) 15 (83.33%)
Whether chemotherapy is delayed χ2 = 12.35 < 0.001
Yes 5 (12.50%) 11 (61.11%)
No 35 (87.50%) 7 (38.89%)
Prolonged time of chemotherapy b Z = 1.94 0.052
n 5 11
Median (Q1,Q3) 4.0 (3.0,6.0) 9.0 (7.0,11.0)
Time to complete radiotherapy c t = 0.89 0.375
n 40 18
Mean ± SD 43.55 ± 6.91 45.22 ± 5.80
Whether bone pain occurs χ2 = 1.99 0.159
Yes 1 (2.50%) 3 (16.67%)
No 39 (97.50%) 15 (83.33%)
a
Calculate the duration of 3/4 degree arrhythmia for subjects who have developed 3/4 degree arrhea
b
Calculate the delay time of chemotherapy for subjects who have delayed chemotherapy
c
Calculate the duration between the begining and the ending of radiotherapy in the concurrent chemoradiotherapy cycle of the subjects
Zou et al. BMC Cancer (2021) 21:661 Page 5 of 7

Fig. 1 Summarized data presenting the analysis of endpoints

which was 43.55 ± 6.91 days in the experimental group reactions across the two groups, the higher reported ad-
and 45.22 ± 5.80 days in the control group. Besides, the verse events included vomiting, bone marrow suppres-
delay rate of chemotherapy in the experimental group sion, diarrhea, and fever (Table 4).
(12.5%) was significantly lower than that of the control
group 61.11% (P < 0.001). The average prolonged time of Discussion
chemotherapy in the experimental group was 4.8 days, Concurrent chemoradiotherapy is an important treat-
and the control group was 8.9 days. Although the experi- ment for cervical cancer, but chemoradiotherapy has dir-
mental group had a decreasing trend compared with the ect or indirect killing effect on neutrophils, thereby
control group, the difference was not statistically signifi- increasing hematological toxicity. RhG-CSF is an effect-
cant (P = 0.052) (Table 3). ive drug to prevent neutropenia caused by tumor radio-
therapy [16]. PEG-rhG-CSF is a PEGylated form of rhG-
Safety CSF, which has shown good efficacy and safety in
Adverse events preclinical studies, and it is a long-acting preparation
The total incidence of adverse reaction events in the [17, 18]. Studies have shown that PEG-rhG-CSF and
experimental group and the control group were 22/40 rhG-CSF are equally effective in preventing
(55%) and 17/18 (94.44%), respectively, indicating PEG- chemotherapy-induced neutropenia [19]. However, there
rhG-CSF reduced side effects (P = 0.003). Of adverse are few studies on the preventive use of PEG-rhG-CSF
Zou et al. BMC Cancer (2021) 21:661 Page 6 of 7

Table 4 Analysis of adverse reactions

Adverse events Experimental group (N = 40) Control group (N = 18) 合计(N = 58)
At least one adverse reaction occurred 22 (55.00%) 17 (94.44%) 39 (67.24%)
χ2 8.77
P 0.003
Vomiting 17 (42.50%) 10 (55.56%) 27 (46.55%)
Bone marrow suppression 8 (20.00%) 12 (66.67%) 20 (34.48%)
diarrhea 5 (12.50%) 0 (0.00%) 5 (8.62%)
Fever 1 (2.50%) 2 (11.11%) 3 (5.17%)
Anemia 1 (2.50%) 1 (5.56%) 2 (3.45%)
Hypokalemia 1 (2.50%) 0 (0.00%) 1 (1.72%)
Myocardial ischemia 0 (0.00%) 1 (5.56%) 1 (1.72%)
dizziness 1 (2.50%) 0 (0.00%) 1 (1.72%)
Decreased platelets 1 (2.50%) 0 (0.00%) 1 (1.72%)

in concurrent chemoradiation. On this basis, a random- group. The most common adverse reactions of PEG-
ized controlled trial was used to evaluate the efficacy rhG-CSF in the experimental group were vomiting, bone
and safety of PEG-rhG-CSF in preventing neutropenia marrow suppression, diarrhea, and fever [9]. The adverse
during radiotherapy and chemotherapy of cervical can- effects of rhG-CSF are similar to those of conventional
cer in this study. doses of rhG-CSF, which reflect the drug characteristics
The main factor affecting the risk of infection after of granulocyte colony stimulating factor [19]. The inci-
chemoradiotherapy is the incidence and duration of dence of vomiting was 42.50%, and the incidence of
grade 3–4 neutropenia [20]. In this study, the incidence other adverse reactions was less than 20%, and most of
of grade 3–4 neutropenia in the experimental group was them were less than 5%. This indicates that the adverse
less than that in the control group, and the difference events are from the standard treatment (radiotherapy/
was statistically significant (P < 0.05). However, there chemotherapy/chemoradiotherapy) and that this is not
was no significant difference in the duration of grade 3– due to PEG-rhG-CSF, and that these adverse events are
4 neutropenia between the test group and the control reduced by PEG-rhG-CSF. In addition, due to the long-
(P = 0.871). In addition, no one in the test group devel- acting effect of PEG-rhG-CSF, it can reduce the number
oped FN, and only 3 people in the control group devel- of subcutaneous injections in the entire process of radio-
oped FN. The two groups had statistical differences in therapy and chemotherapy, thereby reducing the pain
the incidence of FN (P = 0.026). This result is consistent caused by multiple injections [23, 24].
with other research results at home and abroad, In conclusion, our research showed that PEG-rhG-
indicating that PEG-rhG-CSF has the effect of reducing CSF can be used in concurrent chemoradiotherapy-
FN [21, 22]. induced neutropenia preventive therapy. PEG-rhG-CSF
Besides, compared with the control group, preventive has good safety, low incidence of adverse reactions and
use of PEG-rhG-CSF can also significantly reduce grade simple application. A single dose of PEG-rhG-CSF can
4 neutropenia and the incidence of chemotherapy delay, effectively reduce the occurrence of grade III/IV neutro-
which is consistent with previous published study [9]. penia, FN and delayed chemotherapy in patients with
There was no statistical difference in the prolonged time cervical cancer chemotherapy. It provides a new option
of chemotherapy and the time to complete radiotherapy for cervical cancer patients to control neutropenia
between the two groups, but the prolonged time of during chemotherapy.
chemotherapy and radiotherapy was statistically shorter
in the experimental group compared with that of the Authors’ contributions
control group. This may be related to the use of rhG- DZ participated in the sequence alignment and drafted the manuscript. MG
participated in the acquisition of radiotherapy data. QZ and DZ participated
CSF for rescue treatment after the occurrence of degree in the design of the study.The authors read and approved the final
3 neutropenia in the control group [20] and the small manuscript.
sample size of the research data.
The incidence of adverse reactions between the experi- Funding
mental group and the control group is significantly dif- This study was supported by the CSCO-Qilu cancer research fund project
(Grant No. Y-Q201801–066) and the Science and Technology Research Pro-
ferent in this study. The incidence of adverse reactions gram of Chongqing Municipal Education Commission (Grant
in the experimental group is less than that in the control No.KJQN201900106).
Zou et al. BMC Cancer (2021) 21:661 Page 7 of 7

Availability of data and materials 12. Lee KHKJ, Lee MH, Han HS, Lim JH, Park KU, Park IH, et al. A randomized,
The data are available from the corresponding author upon reasonable multicenter, phase II/III study to determine the optimal dose and to
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Declarations cancer patients: KCSG PC10–09. Support Care Cancer. 2016 Apr;24(4):1709–
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Consent for publication 016/S1098-3597(06)80055-4.
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specific PEGylated rhG-CSF: optimization of PEG molecular weight. J
Competing interests Biotechnol. 2009;142(3–4):259–66. https://doi.org/10.1016/j.jbiotec.2009.05.
This study was supported by the Qilu pharmaceutical Co. Ltd. 012.
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Received: 16 December 2020 Accepted: 17 May 2021 multicenter phase III study of single Administration of Mecapegfilgrastim
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