1 Introduction

Cervical cancer ranks as the fourth most prevalent malignancy among women worldwide and stands as the leading cause of cancer-related mortality in developing countries [1, 2]. The treatment of cervical cancer is based on the FIGO staging system outlined in the 2018 edition. Radiotherapy combined with platinum-based chemotherapy is the standard treatment approach for stage IB3 and IIA2-IVA cervical cancer. Additionally, this therapeutic modality can be employed for patients with early to mid-stage cervical cancer who are not suitable candidates for hysterectomy [3]. However, due to its localized effect, radiotherapy alone fails to yield satisfactory curative outcomes. Conversely, the curative effect of radiotherapy combined with synchronous chemotherapy is better than that of radiotherapy alone, significantly enhancing the overall survival rate and local control rate of cervical cancer patients [4,5,6]. Concurrent chemoradiotherapy builds upon precision radiotherapy combined with chemotherapy by effectively targeting hidden metastatic cells throughout the body while simultaneously shrinking tumors and eradicating distant metastases. Consequently, this comprehensive treatment strategy offers improved therapeutic benefits and prognostic outcomes for patients. However, since both radiation and drugs exert inhibitory effects on bone marrow function, toxicity superimposition will increase the probability of blood toxicity in patients [7,8,9,10]. Grade ≥ 3 blood toxicity serves as a dose-limiting factor during concurrent chemoradiotherapy, since 87% of patients with concurrent chemoradiotherapy will have grade ≥ 3 blood toxicity [7]. The incidence of grade 3-4 leukopenia/neutropenia ranges from 10% to 50% [11], representing the most common restrictive hematological toxicity of cervical cancer associated with concurrent chemoradiotherapy, inducing febrile neutropenia, toxic shock from infection, and even death [12]. Simultaneously, it can lead to the interruption of radiotherapy, aggravate the anxiety among cervical cancer patients, and even cause secondary infections and a decline of immune function, ultimately impacting treatment efficacy and patient survival [13,14,15]. Patients whose treatment was interrupted due to myelosuppression had a significantly lower overall survival rate compared to those who did not experience treatment interruption [16, 17]. In recent years, some studies have shown that pegylated recombinant human granulocyte stimulating factor (PEG-rhG-CSF) can reduce the incidence of leukopenia/neutropenia during concurrent chemoradiotherapy for cervical cancer [18,19,20]. Therefore, reasonable prevention and management of leukopenia/neutropenia in patients with malignant tumors during concurrent chemoradiotherapy is of significant importance. Promptly addressing associated hematological toxicities is essential to ensure completion of chemoradiotherapy within the planned timeframe and prescribed dosage. Therefore, based on multiple clinical data from domestic and foreign research, the National Comprehensive Network (NCCN) Guidelines for Hematopoietic Growth Factors (2023.V1) and multiple domestic guidelines agreed to recommend that PEG-rhG-CSF could be used for the treatment of leukopenia/neutropenia with caution and reference to chemotherapy-related principles during concurrent chemoradiotherapy [12, 21, 22].

Recombinant human granulocyte colony-stimulating factor (rhG-CSF) was the most commonly used drug for clinical treatment and prevention of leukopenia/neutropenia in the past. Due to its short half-life (only 3-6 h), repeated administration was necessary to achieve a curative effect [15, 23]. PEG-rhG-CSF is a long-acting preparation of granulocytic stimulating factor that exhibits similar efficacy to the short-acting preparation. PEG-rhG-CSF acts on hematopoietic cells after binding to the surface receptors of hematopoietic cells to promote cell proliferation, differentiation, and activation. It possesses a long half-life and long-lasting effect, and has the advantages of "self-regulation" and less toxic side effects [24,25,26,27]. Several studies have demonstrated the significant benefits of PEG-rhG-CSF in preventing and treating chemotherapy-induced leukopenia/neutropenia [28,29,30,31]. However, whether it can be utilized for primary prevention of concurrent chemoradiotherapy-induced leukopenia/neutropenia remains unexplored.

The recommended dose of PEG-rhG-CSF approved for primary and secondary prophylaxis of leukopenia/neutropenia after chemotherapy alone is 100 μg/kg once per chemotherapy cycle, with an interval between subsequent chemotherapies of ≥ 14 days. However, there is no standard for the dose used in concurrent chemoradiotherapy for cervical cancer. Currently, the commonly used dose of PEG-rhG-CSF during concurrent chemoradiotherapy is 100 μg/kg, which aligns with the recommended dose used in chemotherapy. The relatively expensive price of PEG-rhG-CSF contributes to difficult clinical promotion and poor patient compliance. Since the myosuppression effect of radiotherapy is weaker than that of chemotherapy, concurrent chemoradiotherapy enhances the efficacy, while the dose of chemotherapy when radiotherapy is combined with chemotherapy is mostly lower than that of chemotherapy alone. Therefore, the recommended dose of PEG-rhG-CSF for post-chemotherapy leukopenia/neutropenia is not necessarily appropriate for concurrent chemoradiotherapy, which remains to be explored. The purpose of this study was to investigate the effect of different doses of PEG-rhG-CSF on the prevention of leukopenia/neutropenia during concurrent chemoradiotherapy of cervical cancer, especially low dose (50 μg/kg) for primary prevention, aiming to provide a more rational treatment plan for the prevention of leukopenia/neutropenia of cervical cancer during concurrent chemoradiotherapy.

2 Data and methods

2.1 Research design

This study was a single-center prospective clinical study. Patients with cervical cancer who received initial radical radiotherapy combined with platinum-based chemotherapy every 3 weeks in the Affiliated Cancer Hospital of Dalian University of Technology (Liaoning Cancer Hospital) from June 2020 to January 2023 were enrolled. This prospective clinical study focused on the efficacy of different doses of PEG-rhG-CSF on the prevention of leukopenia/neutropenia.

The sample size was determined as follows. In the pre-trial, the effect size (f) of the primary outcome measure (reduced values of leukocytes & neutrophils) was all close to low, and in the formal trial, the one-way random ANOVA test was employed to calculate the study sample size, effect size f = 0.15, α=0.05, β=0.85, and N=3, yielded a sample size of 163 cases per group. Considering a potential maximum sample loss of 20%, a total of 204 cases per group were deemed necessary. However, in clinical practice (the real world), on the premise of respecting the wishes of patients, we found that the proportion of patients who chose the P 0, P 50, and P 100 regimens was about 3/2/2. To ensure greater clinical relevance in our study population distribution, we increased the sample size for the P0 group to 306 cases (i.e., P 0=204*1.5=306 cases), while maintaining P 50 and P 100 groups at 204 cases each; resulting in a total cohort of 714 cases.

Randomization was performed according to allocation rules as follow. Three table tennis balls with the number "1", two balls with the number "2", and two balls with the number "3" were put in a closed and opaque cloth bag. Whenever a patient was enrolled to be assigned, the person responsible for randomization randomly took out a table tennis ball, read out the number on the ball. The numbers 1, 2, 3 on the balls indicated that the patient correspondingly joined the P 0, P 50, P 100 group. When all seven table tennis balls were removed, they were put back together until all 714 patients in this study were enrolled.

Eligible participants were randomly allocated into the control group (P 0) and experimental groups. The experimental groups were further categorized based on the dose of PEG-rhG-CSF, including the low-dose group (P 50, 50 μg/kg) and the high-dose group (P 100, 100 μg/kg). All participants were enrolled voluntarily and signed an informed consent form, which was reviewed and approved by the hospital ethics committee.

2.2 Inclusion and exclusion criteria

2.2.1 Inclusion criteria

(1) Locally advanced cervical squamous cell carcinoma, adenocarcinoma, and adenosquamous cell carcinoma diagnosed by histological pathology (2) Age: 18~75 years (3) Patients with stage IB3 or IIA 2-IVA according to FIGO stage (International Union of Obstetrics and Gynecology) 2018 clinical stage criteria (4) Receiving concurrent chemoradiotherapy treatment (5) The estimated survival period of 8 months; Physical strength status (KPS) score of 80 points; The ECOG score less than 2 points (6) Normal bone marrow hematopoiesis, white blood cell count (WBC )≥ 3.5×109 /L, neutrophil (ANC) ≥ 1.8×109/L, Platelet count (PLT)≥ 90×109/L; hemoglobin (HB)≥ 90g/L (7) During concurrent chemoradiotherapy, no other drugs that raise leukocytes/neutrophils were used except PEG-rhG-CSF and rhG-CSF.

2.2.2 Exclusion criteria

(1) Serious heart, lung, liver, kidney, and other vital organ diseases (2) Patients with abnormal coagulation function, bleeding tendency, or receiving thrombolysis or anticoagulation therapy (3) Combined with an uncontrollable infection, body temperature ≥38°C (4) Combined with other site malignancies or hematological diseases (5) Radiotherapy is preceded by chemotherapy/targeting/immunotherapy (6) A history of chemotherapy and/or radiation therapy.

2.2.3 Study groups

The study was divided into experimental groups and a control group. The control group, designated as P 0, did not receive any drugs for the prevention of leucopenia/neutropenia during chemoradiotherapy, while the experimental group received PEG-rhG-CSF treatment after each chemotherapy session to prevent leucopenia/neutropenia. The drug dosage administered was calculated as 50 μg/kg and 100 μg/kg, respectively.

2.3 Chemoradiotherapy regimen

Chemotherapy regimen: Cisplatin 50-60 mg/m2 (or carboplatin AUC 4-5), IV, day 1; paclitaxel 135 mg/m2, IV, day 1; repeated every 3 to 4 weeks for a total of 2 cycles of chemotherapy.

Radiation therapy protocol: external irradiation with conformal intensity modulated radiation therapy (IMRT) at the prescribed dose of 50 Gy (25 times, once a day, five times a week) in the planned target area (PTV), 2 Gy per time; for paraintrauterine invasion, 10 to 14 Gy (5-7 times) can be added locally; and enlarged pelvic lymph nodes, 12 to 14 Gy (5-7 times) can be added locally. Brachytherapy was performed after the end of external irradiation. The brachytherapy source was Iridium 192, prescribed to administer more than 90% of the volume of the high-risk clinical target area (HR-CTV), at a dose of 30 Gy (5 times), twice a week. The schematic diagram of radical concurrent chemoradiotherapy is shown in Fig. 1.

Fig. 1
figure 1

Schematic diagram of radical concurrent chemoradiotherapy

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2.4 Administration and monitoring protocol of PEG-rhG-CSF, rhG-CSF

Patients in the test group were injected with PEG-rhG-CSF 24 h to 48 h after each chemotherapy [Shiyao Group (Shandong) Biopharmaceutical Co., LTD., S20110014, specification: 3mg / dose: 1 ml (pre-filling)]. The dosages of P 50 group and P 100 group were calculated at 50 μg/kg and 100 μg/kg each time and were injected subcutaneously, once per chemotherapy cycle, twice in total. PEG-rhG-CSF was administered more than 14 days before the next chemotherapy. Control patients will not receive PEG-rhG-CSF injections after chemotherapy. Patients with ANC <1.0×109 / L or WBC < 2.0×109 / L in the three groups could be injected 100 μ g rhG-CSF [Qilu Pharmaceutical Co., Ltd., S19990049; Specification: 6.0106 IU (100 μ g): 0.6 mL] subcutaneously once daily until ANC≥ 1.8×109 / L or WBC 3.5×109 / L. The normal reference value of ANC was between 1.8×109 / L and 6.3×109 / L, and the normal reference value of WBC was between 3.5×109 / L and 9.5×109 / L.

2.5 Observation method

Maximum body temperature was recorded after chemotherapy or on the day of trial drug administration and daily thereafter. Venous blood was collected at 3, 7, 10, 14, and 17 days after chemotherapy or PEG-rhG-CSF administration. If grade 3 or higher leukopenia/neutropenia occurred, blood routine changes were monitored the next day.

2.6 Efficacy and safety evaluation indicators

2.6.1 Efficacy evaluation index

Several indexes were compared in all three groups during concurrent chemoradiotherapy, such as the lowest values, incidence and recovery time of neutropenia and leukopenia, FN incidence, and time of radiotherapy interruption due to leukopenia/neutropenia.

2.6.2 Evaluation of adverse reactions

NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 was used to evaluate major adverse events, including osteoarticular myalgia and drug-induced fever.

2.6.3 Total cost of treatment

The total cost of in-patient/out-patient treatment with concurrent chemoradiotherapy was calculated, and the difference of total cost of treatment among the three groups was compared.

2.7 Statistical analysis

The Kolmogorov-Smirnov test (K-S method) was used for normality testing, and Levene's test was used for homogeneity of variance. The measurement data conforming to the normal distribution were described by means and standard deviation, analyzed by one-way ANOVA and the LSD method for pairwise comparison in groups, while the measurement data and rank data that did not follow the normal distribution were described by median (P 25, P 75) and analyzed by the median test or K test and pairwise comparison between groups. The counting data were described by frequency and composition ratio, and the Pearson χ2 test was used, and the P value was not corrected for pairwise comparison. Binary logsitic regression was used to analyze the OR of grade 3-4 leukopenia/neutropenia between different treatment protocols. All statistical analyses were performed using IBM SPSS 23.0 statistical software, using a two-sided test, with a P < 0.05 representing a statistically significant difference.

3 Results

3.1 Baseline characteristics of the patients

According to the inclusion and exclusion criteria, a total of 714 patients were enrolled, with 306 in the control group and 204 in each experimental group. Due to side effects or other reasons, random loss occurred, to be exact, 37 cases (12.1%) in the P 0 group, 16 cases (7.8%) in the P 50 group and 17 cases (8.3%) in the P 100 group. Ultimately, there were 188 cases in the P 50 group, 187 cases in the P 100 group, and 269 cases in the P 0 group (control group). There were no significant differences observed among the three groups regarding age, tumor stage, and tumor type (P > 0.05) as shown in Table 1.

Table 1 Comparison of general data between the two groups
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3.2 Efficacy evaluation

3.2.1 Minimum values of leukocytes and neutrophils

There were significant differences in leukocyte and neutrophil reduction values among the three groups (F=12.768, P<0.001; F=11.282, P<0.001). Pairwise comparison (LSD) showed that the lowest WBC value in the P 50 group (2.97±1.66×109/L, P < 0.001) and the P 100 group (3.05±1.62±1.26×109/L, P < 0.001) was markedly higher than that in P0 group. The lowest neutrophils in the P 50 group (1.99±1.40×109/L, P < 0.001) and the P 100 group (2.02±1.26×109/L, P < 0.001) were significantly higher than that in the P 0 group (1.56±0.93×109/L). There was no significant difference between the P 50 group and the P 100 group in the lowest value of leukocytes and neutrophils (P > 0.05; P > 0.05) (Table 2, Fig. 2).

Table 2 Comparison between groups with reduced values of leukocytes & neutrophils (×10-9/L,‾x ± s)
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Fig. 2
figure 2

Results of the study

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3.2.2 The occurrence of grade 3-4 leukopenia and neutropenia

There were significant differences in the occurrence of grade 3-4 leukocytes and neutrophilia among the three groups (χ2=14.594, P=0.001; χ2=7.782, P=0.020). Pairwise comparison between groups revealed that grade 3-4 leukopenia in the P 0 group (110/269,40.9%)was observably higher than that in the P 50 group ((52/188,27.7%, P=0.004) and the P 100 group (48/187,25.7%, P=0.001). The grade 3-4 neutropenia in the P 0 group (81/269,30.1%) was remarkably higher than that in the P 50 group ((38/188,20.2%, P=0.018) and the P 100 group (39/187,20.9%, P=0.027). There was no statistical difference between the P 50 group and the P 100 group in the occurrence of grade 3-4 leukopenia and neutropenia (P > 0.05; P > 0.05) (Table 3, Fig. 2).

Table 3 Comparison between groups with reduced grade III-IV leukocytes & neutrophils [n, (%)]
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3.3 Clinical indicators

3.3.1 Recovery time of grade 3-4 leukopenia and neutropenia

Significant differences were recorded between the three groups in the recovery time of grade 3-4 leukopenia and neutropenia (F=77.567, P<0.001; F=31.113, P<0.001). The pairwise comparison (LSD) indicated that the recovery time of grade 3-4 leukopenia in the P 0 group (9.70±2.51 days) was notably higher than that in the P 50 group (5.85±2.31 days, P<0.001) and the P 100 group (5.46±1.99 days, P<0.001). The recovery time of grade 3-4 neutropenia in the P 0 group (9.05±3.32 days) was noticeably higher than that of the P 50 group (5.71±2.45 days, P<0.001) and the P 100 group (5.23±2.11 days, P<0.001). There was no difference in the recovery time of grade 3-4 leukopenia and neutropenia between the P 50 and the P 100 group (P > 0.05; P > 0.05) (Table 4).

Table 4 Comparison between groups of recovery time for reduced grade III-IV leukocytes & neutrophils (d, ‾x ± s)
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3.3.2 Comparison of the occurrence of the FN

There was no significant difference in FN occurrence (P 0 group: 6/269, 2.2%; P 50 group: 2/188, 1.1; P 100 group: 4/187, 2.1%) between the three groups (χ2=0.924, P=0.630) (Table 5).

Table 5 Comparison between groups of grade III-IV myelosuppression, moderate to severe bone pain, and drug-induced fever [n (%)]
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3.3.3 Grade 3-4 leukopenia / neutropenia and adverse reactions

The incidence of grade 3-4 leukopenia / neutropenia was significantly different among the three groups (χ2=16.729, P<0.001). The comparison showed that the occurrence of grade 3-4 leukopenia / neutropenia in the P 0 group (118/269,43.9%) was significantly higher than that in the P 50 group (57/188, 30.3%, P=0.003) and the P 100 group (50/187, 26.7%, P<0.001). There was no difference between the P 50 group and the P 100 group in the occurrence of grade 3-4 reduction of leukocytes/neutrophils (P > 0.05; P > 0.05). There were significant differences between the three groups in the occurrence of moderate to severe osteoarticular myalgia (χ2=6.492, P=0.039). The comparison showed that the occurrence of severe osteoarticular myalgia in the P 0 group (120/269, 44.6%) was significantly higher than that in the P 50 group (57/188, 42.0%, P=0.039) and the P 100 group (65/187, 34.8%, P<0.035). There was no statistical difference in the occurrence of bone pain between the P 50 group and the P 100 group (P > 0.05; P > 0.05). There was no statistical significant difference in the occurrence of drug-induced fever between the three groups (P 0 group:10/269, 3.7%; P 50 group: 11/188, 5.9%; P 100 group:16/187, 8.6%, χ2=4.775, P=0.092) (Table 5).

3.3.4 Radiotherapy interruption time

There was a significant difference in the duration of radiotherapy interruption between the three groups (Z=27.056, P<0.001). The pairwise comparison showed that the interruption time of radiotherapy in the P 0 group [0(0, 10) d] was conspicuously higher than that in the P 50 group ([0(0,7) d] P<0.001) and the P 100 group ([0(0,7) d], P<0.001). There was no significant difference between the P 50 group and the P 100 group (P > 0.05; P > 0.05) (Table 6, Fig. 2).

Table 6 Comparison between groups of radiotherapy interruption time in patients with grade III-IV myelosuppression
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3.4 Medical expenses

There was no significant difference in medical expenses (including outpatient) between the three groups (χ2=3.751, P=0.153) (Fig. 2).

3.5 Comparison of the efficacy of high and low dose PEG-rhG-CSF in the prevention of leukopenia/neutropenia

In Binary logsitic regression analysis, the severity of leukopenia / neutropenia (non-grade 3-4 = 0, grade 3-4 = 1) was considered as the dependent variable, whereas the diagnosis and treatment regimen (P 0 group, P 50 group, P 100 group) were the independent variables. In addition, age, tumor classification, and tumor stage were the control variables. In contrast to the P0 group, the risk of grade 3-4 leukopenia/neutropenia in the P50 group was OR (95% CI)=0.557(0.376, 0.825), P=0.004, while that in the P100 group was OR (95% CI) = 0.467 (0.312, 0.699), P< 0.001. On the other hand, compared with the P100 group, the risk of grade 3-4 leukopenia/neutropenia in the P50 group was OR(95%CI)=1.192 (0.761, 1.868), P=0.443. Namely, there was no significant difference in the prevention effect of grade 3-4 leukopenia/neutropenia between the two groups (Fig. 2).

4 Discussion

Concurrent chemoradiotherapy is the standard treatment for patients with advanced cervical cancer and inoperable early cervical cancer. Compared with radiotherapy or chemotherapy alone, it offers significant advantages and is an important measure to improve the long-term survival of patients. Although the acute side effects of concurrent chemoradiotherapy can be tolerated, more than 50% of proliferative bone marrow is located in cervical cancer radiotherapy areas such as pelvis and lumbar vertebrae [32], in order that about 60% of patients treated by concurrent chemoradiotherapy will develop grade II and above neutropenia, with up to a 12% probability of death resulting from grade III and IV bone marrow suppression [33, 34]. As a result, severe leukopenia/neutropenia poses a major limitation to concurrent chemoradiotherapy, making prevention of grade 3 and 4 leukopenia/neutropenia during treatment essential for successful completion and long-term survival. Previous attempts at using short-acting drugs to prevent leukopenia/neutropenia have yielded unsatisfactory results. These unsatisfactory results probably resulted from the fact that these short-acting drugs were required to be continuously used for a long time and there might be serious drug reactions such as bone pain, giving rise to the poor patient's compliance. PEG-rhG-CSF is characterized by a longer half-life, in contrast to the short-acting drugs that raises white blood cells. It has been currently approved to use in patients at risk of developing clinically significant febrile leukocyte/neutropenic myelosuppression following anti-tumor chemotherapy, so as to reduce the incidence of infection. Clinically, PEG-rhG-CSF has has found widespread application in the prevention of bone marrow suppression in patients after simple chemotherapy. Due to its single-use convenience and alleviation of pain from repeated injections for patients, PEG-rhG-CSF demonstrates satisfactory efficacy following each chemotherapy session. Despite a slightly higher cost, patient compliance remains high. Currently, the recommended dosage is 100 μg/kg. Furthermore, PEG-rhG-CSF exhibits superior efficacy and safety compared to the widely used recombinant human granulocytic stimulating factor (rhG-CSF) in many aspects. Specifically, PEG-rhG-CSF offers an extended duration of action and incorporates a self-regulation mechanism, resulting in enhanced convenience while reducing patient discomfort associated with repeated injections and ultimately improving the quality of life for cancer patients [23, 35,36,37].

However, in the early stage, PEG-rhG-CSF was only approved for the prevention and treatment after simple chemotherapy [37,38,39]. Although clinical research results in recent years have shown that PEG-rhG-CSF has achieved certain efficacy in the treatment of leukopenia/neutropenia induced by concurrent chemoradiotherapy in patients with cervical cancer, it is worth noting that most of these research results were derived from a limited sample size, leading to inconsistent conclusions. Concurrent chemoradiotherapy is the combination of chemotherapy and radiotherapy. Chemotherapy synchronizes the tumor cell cycle, inhibits cell damage and repair after radiotherapy, thereby enhancing radiotherapy sensitivity. Concurrent chemoradiotherapy intensifies therapeutic effectiveness and avoids delay in targeting local and distant metastatic lesions to improve the curative effect. It should be noted that the mechanism and probability of myelosuppression caused by concurrent chemoradiotherapy are different from those of chemotherapy alone. Moreover, even if the same chemotherapy regimen is used, there exists a disparity in the dosage administered for standalone chemotherapy versus concurrent chemoradiotherapy, resulting in varying degrees of bone marrow suppression. Currently, only prophylactic regimens and dosages of long-acting leukopenia drugs are available for standalone chemotherapy, while standardized medication protocols to prevent potential bone marrow suppression during concurrent chemoradiotherapy are lacking. The efficacy of PEG-rhG-CSF in the prevention of leukopenia / neutropenia induced by concurrent chemoradiotherapy requires further verification. Currently, the recommended dosage is mainly for patients treated by chemotherapy alone, and there is no standard dose for concurrent chemoradiotherapy. Therefore, exploring the efficacy and appropriate dose of PEG-rhG-CSF for the prevention of leukopenia/neutropenia during concurrent chemoradiotherapy of cervical cancer is of great necessity to help cervical cancer patients successfully complete the treatment.

First of all, PEG-rhG-CSF could effectively prevent the occurrence of leukopenia/neutropenia during concurrent chemoradiotherapy of cervical cancer. Compared with the non-prophylactic group (P0 group), prophylactic administration of PEG-rhG-CSF at both doses of 50 μg/kg or 100 μg/kg significantly declined the incidence of leukopenia/neutropenia during concurrent chemorotherapy, especially significantly reduced the incidence of over grade 3 leukopenia/neutropenia, and stabilized bone marrow function status. In other words, the application of PEG-rhG-CSF enabled concurrent chemoradiotherapy safer, especially for out-patient chemoradiotherapy, and reduced the hospitalization rate and length of stay of inpatients. Both doses of PEG-rhG-CSF were able to alleviate the severity of leukopenia/neutropenia. What’s more, the lowest value of leukopenia/neutropenia of both test groups was higher than that of the non-prophylactic group (P 0 group). Specifically, most of test groups embodied grade II-III myelosuppression, while the minimum value of the no-prevention group appeared grade IV myelosuppression. In addition, both doses of PEG-rhG-CSF could shorten the recovery time of patients with ≥ grade 3 leukopenia/neutropenia and reduce the risk of serious complications resulting from leukopenia/neutropenia, significantly shorten the duration of radiotherapy interruption, ensure the continuity of radiotherapy, reduce the risk of serious complications due to leukopenia/neutropenia, and ensure the maximum therapeutic effect of radiotherapy. After all, the conclusion that frequent or prolonged interruption of radiotherapy would impair the efficacy of radiotherapy has been drawn by several studies [28, 29, 40, 41].PEG-rhG-CSF facilitated a more rapid recovery of the patient’s white blood cell/neutrophils count to normal levels, enabling uninterrupted treatment. The statistically significant difference between the test groups (P 50 group and P 100 group ) and the control group was documented. Although the therapeutic effect of the P 100 group (100 μg/kg) was more pronounced than that of the P50 group (50 μg/kg), there was no statistical difference in efficacy between these two prophylactic doses. In the past, it was believed that during radiotherapy, due to the continuous myelosuppression effect, the prophylactic application of drugs that raise white blood cells would not only be ineffective but also aggravate the injury of bone marrow function. On account of the lack of effective research data, PEG-rhG-CSF was not recommended to be utilized for radiotherapy or concurrent chemoradiotherapy when initially developed. As the research moves along, some researchers have attempted to use PEG-rhG-CSF for the treatment of bone marrow suppression during concurrent chemoradiotherapy. It is heartening to note that PEG-rhG-CSF displayed a degree of certain effect, even though it is not clear whether it could be used for the prevention of bone marrow suppression. Through analysis of prospective large sample data, this study confirmed that PEG-rhG-CSF held promise as a preventive measure against leukopenia/neutropenia during concurrent chemoradiotherapy for cervical cancer patients. Simultaneously, it is noteworthy that the efficacy of 100 μg/kg PEG-rhG-CSF was equivalent to that of 50 μg/kg.

Secondly, this study did not show that PEG-rhG-CSF had a preventive effect on FN. Compared with the no-prevention group (P 0 group), the incidence of FN in the test groups (P 50 group and P 100 group) saw a moderately dropping trend, but the difference between groups was not statistically significant. In this study, there were few patients with ≥ grade 3 leukopenia/neutrophilia accompanied by fever, most of whom had a low fever. No severe high fever or even death cases were observed. The incidence of FN in this study was lower than that documented in existing literature, which may be related to the fact that patients received radiotherapy on an outpatient basis, who were extremely nervous and intervened prematurely in case of abnormal body temperature (injection of rhG-CSF, application of prophylactic antibiotics, application of antipyretic drugs, etc.). It cannot be ruled out that the patient's condition was concealed for fear of treatment interruption and the relevant information was not reported in time. Future research endeavors should prioritize more stringent management protocols and comprehensive observations.

Thirdly, patients exhibited tolerability towards the adverse effects of PEG-rhG-CSF used in preventing leukopenia/neutrophilia during concurrent chemoradiotherapy for cervical cancer. All patients in the three groups were given short-action rhG-CSF symptomatic treatment after they suffered from grade 3 or greater leukopenia/neutrophilia. Therefore, adverse reactions occurred in all patients in the three groups, including fatigue, osteoarthromyalgia, fever, skin mucosal reaction, nausea, and vomiting. Even though it was challenging to differentiate between adverse reactions caused by rhG-CSF and PEG-rhG-CSF administration, the incidence of bone pain in the PEG-rhG-CSF prevention group (P 50 group and P 100 group) was lower than that in the control group (P 0 group), and the difference was statistically significant. Although the incidence of bone pain in the 100 μg/kg group was lower than that in the 50 μg/kg group, the difference was not statistically significant. The reasons for this result may be as follows. PEG-rhG-CSF caused less pain and the prophylactic use of PEG-rhG-CSF could decrease the use frequency of rhG-CSF, thus reducing the occurrence of bone pain. In terms of the low incidence of drug-induced fever, there was no statistical difference between the three groups. These fevers were transient and mild-to-moderate in nature which could mostly be alleviated by patients themselves without significant impact on their mental state.

In addition, PEG-rhG-CSF used for the prevention of leukopenia/neutrophilia during concurrent chemoradiotherapy for cervical cancer did not result in an increase in medical costs.. It is universally acknowledged that the economic benefit ratio of treatment is an important factor affecting the choice of treatment by patients and hospitals. PEG-rhG-CSF has shown a prevailing preventive effect in concurrent chemoradiotherapy of cervical cancer. Nevertheless, due to its relatively high cost, many many patients have refrained from using it. In the previous retrospective study, the clinical use of PEG-rhG-CSF has not been extensively promoted, resulting in poor patient acceptance and limited usage of preventive drugs. As treatment experience accumulated and efficacy became apparent, along with improved patient understanding of the medication, there was a certain degree of improvement in accepting PEG-rhG-CSF. In this study, the dropout rate of the P 100 group was as high as 10.95%, which was significantly higher than that of the P 50 group (1.57%). Therefore, this study compared the total medical expenses of the three groups in the premise of confirming that the P 50 group and the P 100 group had similar preventive effects. The results showed that although the medical expenses of the P 50 group and the P 100 group were slightly higher than those of the P 0 group, the difference was not statistically significant. Therefore, the prophylactic application of PEG-rhG-CSF could promote the therapeutic efficacy and compliance of patients without escalating medical costs, thus patients benefiting from cost-effectiveness, which is consistent with literature reports [42].

Moreover, PEG-rhG-CSF with a high dose of 100 μg/kg or a low dose of 50 μg/kg for the prevention of leukopenia/neutrophilia during concurrent chemoradiotherapy for cervical cancer exhibited similar efficacy. The results of binary logsitic regression analysis in this study showed that compared with the P 0 group, both the P 50 group and the P 100 group could significantly cut down the risk of grade 3-4 leukopenia/neutropenia, and compared with the P 100 group, the P 50 group had similar preventive effect, OR=1.192 (0.761,1.868), P=0.443. It is suggested that PEG-rhG-CSF with a dose of 50 μg/Kg could sufficiently achieve the efficacy of preventing leukopenia/neutrophilia of cervical cancer with concurrent chemoradiotherapy, which can actually decline the medical cost, improve the treatment compliance and satisfaction of patients, and be used safely. Moreover, it may be feasible to initially administer a low dose of PEG-rhG-CSF for prevention before considering an overall increase in dosage after grade 3-4 leukopenia/neutrophilia occurs.

It cannot be denied that there were some limitations in this study. In the first place, due to the limitations of research conditions, this study was conducted as a single-center clinical trial and could not be designed as a double-blind trial, potentially leading to selection bias. Therefore, further multi-center, double-blind trials are anticipated to yield more robust results. In addition, the analysis of efficacy and safety regarding prophylactic use of PEG-rhG-CSF did not include further stratification based on different radiotherapy methods (such as pelvic irradiation field or pelvic irradiation field and extended field etc.). Moreover, future data should be collected and analyzed in order to summarize the observed differences in thrombocytopenia between the PEG-rhG-CSF prophylaxis group and the non-prophylaxis group. Furthermore, the effect of the other two types of bone marrow suppression (thrombocytopenia and hemoglobin reduction) on treatment outcomes was not included in the analysis, which may have influenced the study results. Besides, one of the limitations of this study is that the baseline values of white blood cells and neutrophils were not recorded, neglecting their potential influence on bias. This aspect will receive greater attention and supplementation in future studies. Finally, it should be noted that this study exclusively focused on cervical cancer patients undergoing concurrent chemoradiotherapy; therefore, its applicability to all patients receiving concurrent chemoradiotherapy cannot be confirmed.

In conclusion, the prophylactic application of PEG-rhG-CSF in the course of concurrent chemoradiotherapy for cervical cancer is safe and effective. PEG-rhG-CSF could remarkably reduce the incidence of ≥ grade 3 leukopenia/neutrophilia, shorten the recovery time of leukopenia/neutrophilia, and reduce the occurrence of interruption of radiotherapy without increasing treatment costs. A low dose (50 μg/kg) of PEG-rhG-CSF was equipped with the potential to achieve similar preventive effects as a high dose (100 μg/kg), reducing medical costs while increasing patient adherence to treatment, although further studies are essential for the use of low doses to screen more suitable populations.