|Year : 2017 | Volume
| Issue : 5 | Page : 790-795
A clinical study of polyethylene glycol recombinant human granulocyte colony-stimulating factor prevention neutropenia syndrome in patients with esophageal carcinoma and lung cancer after concurrent chemoradiotherapy
Fang Liu1, Yu Du2, Boning Cai1, Maohui Yan1, Wei Yang1, Qianqian Wang1
1 Department of Radiation Oncology, Chinese PLA General Hospital, Beijing 100853, China
2 Department of Radiation Oncology, Chinese PLA General Hospital, Beijing 100853; Department of Radiation Oncology, First Affiliated Hospital of Chinese PLA General Hospital, Beijing 100048, China
|Date of Web Publication||13-Dec-2017|
Department of Radiation Oncology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853
Source of Support: None, Conflict of Interest: None
Objective: To compare the efficacy and safety of PEG-rhG-CSF and recombinant human G-CSF (rhG-CSF) for the prevention and delayed application in febrile neutropenia, hospitalization rate in concurrent chemoradiotherapy of tumors.
Methods: A total of 163 patients, who received concurrent chemoradiotherapy for solid tumors. There were 75 patients in the PEG-rhG-CSF group (PEG group), who received 146 cycles of concurrent chemoradiotherapy, of which 132 cycles (90.42%) were prophylactic therapy, while 9 cycles (6.16%) were delayed therapy. There were 88 patients in the rhG-CSF group (rhG group), who received 164 cycles of concurrent chemoradiotherapy, of which 48 cycles (29.3%) were prophylactic, while 116 cycles (70.7%) were delayed therapy. G-CSF was used for prophylaxis in 180 cycles of chemotherapy, with delayed use in 130 cycles.
Results: Comparison between the prevention group and the delayed group showed that the incidence of neutropenia-related hospitalization was 4.44% and 14.62%, respectively (OR = 0.272, 95% CI, 0.115-0.642) (P = 0.002). Intravenous antibiotics usage was 2.78% vs. 11.54%, (OR = 0.004, 95% CI, 0.077-0.619) (P = 0.004). Dose reduction of chemotherapy or delay was 5% vs. 17.69% (OR = 0.245, 95% CI, 0.109-0.549) (P = 0.001). The prevention group had protective effects from all factors as compared to the delayed group (all P < 0.05, and all OR < 1). Moreover, the protective role of intravenous antibiotics was the strongest in the prevention group.
Conclusion: Prophylactic use of GSF reduced hospitalization rate and the rate of intravenous application of antibiotics.
Keywords: Esophageal carcinoma and lung cancer, pegylated recombinant human granulocyte colony-stimulating factor, neutropenia
|How to cite this article:|
Liu F, Du Y, Cai B, Yan M, Yang W, Wang Q. A clinical study of polyethylene glycol recombinant human granulocyte colony-stimulating factor prevention neutropenia syndrome in patients with esophageal carcinoma and lung cancer after concurrent chemoradiotherapy. J Can Res Ther 2017;13:790-5
|How to cite this URL:|
Liu F, Du Y, Cai B, Yan M, Yang W, Wang Q. A clinical study of polyethylene glycol recombinant human granulocyte colony-stimulating factor prevention neutropenia syndrome in patients with esophageal carcinoma and lung cancer after concurrent chemoradiotherapy. J Can Res Ther [serial online] 2017 [cited 2019 Nov 17];13:790-5. Available from: http://www.cancerjournal.net/text.asp?2017/13/5/790/220469
| > Introduction|| |
Concurrent chemoradiotherapy can reduce the volume of the tumor, improve blood supply of the tumor, and have the synergistic effect of sensitization, which has become a standard therapeutic mode for advanced solid tumors such as lung cancer and esophageal carcinoma., However, about only 14%–57% of patients develop Grade III–IV myelosuppression during concurrent chemoradiotherapy, whereas only 55% of patients are able to complete a predetermined chemotherapy cycle on time, whereas most of the patients are at the expenses of delayed concurrent chemoradiotherapy or reduced-dose chemotherapy, affecting the patients' prognosis. NCCN guidelines of concurrent chemoradiotherapy do not recommend to perform prophylactic use of granulocyte colony-stimulating factor (G-CSF) for concurrent chemoradiotherapy, but ordinary radiotherapy technology is often used in literature, which has larger radiotherapy field and significant involvement of the hematopoietic tissue. However, in our study, patients with bone and bone marrow metastases were excluded, and three-dimensional conformal or intensity-modulated radiotherapy was used, which reduced the exposure dose of adjacent flat bones and irregular bones, thus reducing the impact of radiotherapy on the proliferation of bone marrow. G-CSF has become one of the important supportive means for tumor therapy. However, half-life of the recombinant human (rhG) G-CSF is short, requiring daily administration, and the compliance of the patients is low.,, PEG- rhG-CSF is a long-acting and self-regulating stimulating factor with long half-life. Moreover, only one time of administration is needed in one chemoradiotherapy cycle.,, The effectiveness of the two drugs has been confirmed by clinical studies, but there are few studies about the clinical practice of concurrent chemoradiotherapy.
The patients with esophageal and pulmonary tumors who received concurrent chemoradiotherapy were admitted and treated in our department, and then the patients were conducted to PEG-rhG-CSF and rhG-CSF therapies. We compared the differences of and hospitalization rates due to neutropenia, fever, and all reasons, as well as the differences of the use of G-CSF at different starting times together with the preventive and delayed administrations.
| > Materials and Methods|| |
A total of 163 patients with solid tumors were selected from our hospital from January 2013 to August 2016. Inclusion criteria were (1) patients with locally advanced esophageal carcinoma who cannot receive surgery and/or patients with lung cancer who were subjected to induction + concurrent chemoradiotherapy; (2) patients without serious complications who aged ≥18 years but ≤65 years; and (3) patients with Karnofsky Performance Status (KPS) scores ≥90 points, the absolute neutrophil count (ANC) ≥1.5 × 109/L, and platelet count ≥100 × 109/L. Exclusion criteria were (1) patients with aspartate transaminase and/or alanine transaminase level ≥1.5 times of the upper limits of normal (ULN), and who were combined with alkaline phosphatase >2.5 times of ULN, or bilirubin level >2 times of ULN, or creatinine level >1.5 times of ULN; (2) patients with previous histories of systemic chemoradiotherapy or radiotherapy; and (3) patients with unmanageable infection or the tumor developed bone metastasis and bone marrow metastasis.
Program of concurrent chemoradiotherapy
It was planned that all the patients underwent four cycles of chemotherapy. The first and second cycles were inducting chemotherapy, and the third and fourth cycles were concurrent chemoradiotherapy. The dose during concurrent chemoradiotherapy was reduced according to 75% of the dose in the chemotherapy regimen. Lung cancer: the chemotherapy regimen was DC (docetaxel of 75 mg/m2 on d1 + cisplatin of 75 mg/m2 on d1-3), VP (etoposide of 350 mg/m2 on d1-3 + cisplatin of 75 mg/m2 on d1-3), and the radiotherapy regimen was conformal/intensive radiotherapy; moreover, the dose was DT: GTV60-66Gy/30Gy/30 fractions, five fractions, W-1, 1fractions.d-1. Esophageal carcinoma: TP (paclitaxel of 175 mg/m2 g on d1 + cisplatin of 75 mg/m2 g on d1-3) regimen. The radiotherapy regimen was conformal/intensive radiotherapy, and the dose was DT: GTV60-66Gy/30Gy/30 fractions, five fractions, W-1, 1fractions.d-1.
Application regimen of granulocyte-stimulating factor during concurrent chemoradiotherapy
Prophylactic application: G-CSF was used at 24 h after the completion of chemotherapy, and 100 μg/mg PEG-rhG-CSF was subcutaneously injected, whereas 150 μg of rhG-CSF was subcutaneously injected; the injection was performed once daily until leukocytes >10 × 109. Delayed application: G-CSF was used 5 days after the completion of chemotherapy.
SPSS 22.0 (IBM) software was used to perform statistical analysis for the data, and the inspection level was α = 0.05.
| > Results|| |
General data of the patients
A total of 163 patients were included in our study, and the general data were shown in [Table 1]. There was no statistical significance in age, gender, median KPS, and ANC baseline between PEG group and rhG group (All P > 0.05), which were comparable.
|Table 1: Comparison of the general data of patients between polyethylene glycol group and recombinant human granulocyte group|
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The PEG group planned to perform 150 cycles of concurrent chemoradiotherapy. Due to neutropenia and/or serious mucosal response in four cycles, the fourth cycle of concurrent chemoradiotherapy was not performed, so there were actually 146 cycles. The rhG group planned to perform 176 cycles of concurrent chemoradiotherapy, but the chemotherapy was disabled in 12 cycles due to adverse reaction. Therefore, there were actually 164 cycles.
The patients were then divided into the prevention group and the delayed group according to the application modes of G-CSF. The prevention group performed a total of 180 cycles of concurrent chemoradiotherapy; among them, PEG was applied in 132 cycles (accounting for 90.42% of the PEG group), and rhG was applied in 48 cycles (accounting for 28.3% of the rhG group). The delayed group performed a total of 130 cycles of chemotherapy; among them, PEG was applied in 14 cycles (accounting for 9.58% of the PEG group), and rhG was applied in 116 cycles (accounting for 70.4% of the rhG group).
The time for the first dose of prophylactic PEG-rhG-CSF was on d4 in the process of chemotherapy, whereas the time for the first dose of rhG-CSF was on d9. There were significant differences in the usage between PEG and rhG in clinical practice.
Related clinical factors
Comparison was performed based on the application modes of G-CSF. Comparison between the prevention group and the delayed group showed that the incidence of febrile neutropenia (FN) was 5.56% and 18.46%, respectively (odds ratio [OR] =0.260, 95% confidence interval [CI]: 0.120–0.565), and there was statistical significance in the prevention of neutropenia between the prevention group and the delayed group (P = 0.001) [Figure 1]. The neutropenia-related hospitalization rate was 4.44% and 14.62% (OR = 0.272, 95% CI: 0.115–0.642) in the prevention group and the delayed group, respectively, with statistical significance in neutropenia-induced hospitalization rate (P = 0.002). The incidence of antibiotic use due to various reasons was 6.11% and 15.38% in the prevention group and the delayed group (OR = 0.380, 95% CI: 0.174–0.830), respectively, with statistical significance (P = 0.018). The incidence of intravenous antibiotic use was 2.78% and 11.54% in the prevention group and the delayed group (OR = 0.004, 95% CI: 0.077–0.619), respectively, with statistical significance (P = 0.004). That chemotherapy delayed more than 3 days was defined as delay. In all predetermined chemotherapy cycles, dose-reduction or delayed chemotherapy was performed due to mucosal and myelosuppressive responses. The incidence in the prevention group and the delayed group was 5% and 17.69% (OR = 0.245, 95% CI: 0.109–0.549), respectively, and there was statistical significance between the two groups (P = 0.001).
|Figure 1: The protective effects of the prevention group on each factor compared to the delayed group. Note: The prevention group had protective effects in the five factors compared to the delayed group (all P < 0.05 and all odds ratios < 1); moreover, odds ratio values were 0.260, 0.272, 0.380, 0.219, and 0.245. Thus, the prevention group had the strongest protective effects on “the number of cycles of intravenous antibiotic use” compared to the delayed group, and “the number of cycles of intravenous antibiotic use” in the prevention group was 21.9% of that in the delayed group|
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Forest map was plotted in Stata 12.0 (StataCorp., College Station, Texas) using SPSS 22.0 and OR as well as its 95% CI. The inspection level was α = 0.05. The prevention group had protective effects on the five factors compared to the delayed group (all P < 0.05, all ORs <1). Moreover, the protective effects of the prevention group were the strongest regarding intravenous antibiotic use, and the cycles of intravenous antibiotic use in the prevention group were 21.9% of that in the delayed group [Figure 1]. However, in the prevention group and the delayed group, there was no statistical significance in drugs between PEG group and rhG group whether in FN and related hospitalization rate or in antibiotic use, as well as delay and dose reduction of chemotherapy drugs [Table 2].
|Table 2: Comparison of the therapeutic statuses of patients between the prevention group and the delayed group|
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Treatment-related complication was mainly bone pain, and there was no statistical significance in the incidence rate of bone pain. Regarding mucosal pain in radiotherapy, there were more patients in PEG group with 85.3% of patients of Grade I/II response, and only 14.7% of patients of Grade III/IV response, whereas 25% of patients in rhG group showed Grade III/IV response, without clear statistical difference between the two groups (P = 0.084) [Table 3].
|Table 3: Toxic side effects and radiotherapy mucosal reactions of the two drugs|
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Classification based on diseases [Figure 2]
It can be seen from the comparison of hospitalization rate during concurrent chemoradiotherapy and neutropenia-related hospitalization rate between esophageal carcinoma and lung cancer patients that the proportion of patients with esophageal carcinoma was relatively high (P = 0.359 and P = 0.651), and there was no statistical significance.
|Figure 2: Classification of mucosal responses of patients in polyethylene glycol and recombinant human granulocyte groups|
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| > Discussion|| |
Studies have shown that prophylactic use of G-CSF can reduce neutropenia-related hospitalization rate compared to that of delay application, and prophylactic PEG-G-CSF reduces 62% of neutropenia-related hospitalization rate compared to that of prophylactic use of rhG-CSF. In clinical practice, long-acting leukocyte elevation needle is usually prophylactically used, whereas short-acting leukocyte elevation needle often applies when bone marrow suppression occurs. In the patients of our study, 90.42% of chemotherapy cycles in PEG group were prophylactic use, whereas only a small number of patients were the prophylactic use of rhG-CSF at concurrent chemoradiotherapy due to the occurrence of Grade III–IV bone marrow suppression at induction therapy. Prophylactic use of G-CSF had clear protective effects in reducing FN and hospitalization rate as well as antibiotic use compared to the delayed application of G-CSF. Moreover, there were few patients with intravenous antibiotic use, which was only 21.9% of the delayed group, greatly reducing medical cost of the patients. Meanwhile, prophylactic use clearly reduced delay and dose reduction of chemoradiotherapy and improved the completion rate of concurrent chemoradiotherapy, which was consistent with those reported in literature. In our study, there was no difference in the efficacies of prophylactic use of the two drugs, which was considered to be related to the small number of cases. However, due to repeated injection-induced reduction of the degree of tolerance, adverse reactions such as bone pain were aggravated, and the tolerance of the patients was reduced.
Although Wu et al. reported the feasibility of rescue treatment by delayed application of PEG-rhG-CSF, FN and the hospitalization rate were observed to be relatively high in the delayed application of PEG-rhG-CSF in our study, which was inconsistent with the reports; thus, it was considered to be related to the few cases. However, in view of its pharmacological effects, the author did not recommend the delayed application, especially during the period of concurrent chemoradiotherapy, to avoid delay of chemoradiotherapy or dose reduction.
Neutropenia is the most common complication of concurrent chemoradiotherapy, and the gastrointestinal mucosal response occurs in the process of esophageal and pulmonary radiotherapy is also an important cause leading to delayed chemoradiotherapy or dose reduction for some patients, which then affects the efficacy of chemoradiotherapy., In our study, it can be seen that there were relatively more hospitalized patients due to neutropenia during the concurrent chemoradiotherapy of esophageal neoplasms, which may be because patients with esophageal neoplasms were more prone to radiation-induced mucosal inflammation, so it needed to be further verified clinically [Figure 3]. However, PEG-rhG-CSF can stimulate the production and maturation of neutrophils; moreover, during the period of ANC reduction, plasma concentration maintained at a higher level, which enhanced neutrophil functions and phagocytosis, as well as chemotaxis and anti-infection abilities, thus reducing the occurrence of systemic and local mucosal infection. Furthermore, it may improve the treatment tolerance of concurrent chemoradiotherapy. Meanwhile, our study also found that III and IV mucosal response in PEG group was milder than that in rhG-CSF group, which was more obvious in the concurrent chemoradiotherapy for tumors of head and neck. Although no statistical significance was found, it still needed to be further confirmed by large-scale clinical experiments.
|Figure 3: Analysis of the proportion of patients classified by diseases. The comparison of hospitalization rate during concurrent chemoradiotherapy and neutropenia-related hospitalization rate between esophageal carcinoma and lung cancer patients|
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In summary, results of our study showed that prophylactic use of G-CSF in the concurrent chemoradiotherapy of esophageal carcinoma and lung cancer can clearly decrease FN and hospitalization rate compared to the delayed application, especially that prophylactic use of PEG-rhG-CSF was a long-acting, more stable, and safer method, which reduced the workload of the medical staff, improved the compliance of the patients to the treatment, and was conductive to the implementation of the therapeutic plan. Therefore, it was perspective in clinical application.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Bedenne L, Michel P, Bouché O, Milan C, Mariette C, Conroy T, et al.
Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102. J Clin Oncol 2007;25:1160-8.
Pritchard RS, Anthony SP. Chemotherapy plus radiotherapy compared with radiotherapy alone in the treatment of locally advanced, unresectable, non-small-cell lung cancer. A meta-analysis. Ann Intern Med 1996;125:723-9.
Chan AT, Teo PM, Ngan RK, Leung TW, Lau WH, Zee B, et al.
Concurrent chemotherapy-radiotherapy compared with radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: Progression-free survival analysis of a phase III randomized trial. J Clin Oncol 2002;20:2038-44.
Wetten S, Li X, Haas J, Worth G, Jacob C, Braun S, et al.
Comparative effectiveness of granulocyte colony-stimulating factors (G-CSF) for reducing incidence of Febrile Neutropenia (FN) – Related hospitalization: A retrospective cohort study using German claims data. Value Health 2015;18:A434.
Tan H, Tomic K, Hurley D, Daniel G, Barron R, Malin J. Comparative effectiveness of colony-stimulating factors for febrile neutropenia: A retrospective study. Curr Med Res Opin 2011;27:79-86.
Fortner BV, Houts AC, Schwartzberg LS. A prospective investigation of chemotherapy-induced neutropenia and quality of life. J Support Oncol 2006;4:472-8.
Gabrilove JL. An analysis of current neutropenia therapies, including pegfilgrastim. Clin Cornerstone 2006;8 Suppl 5:S19-28.
Zhai Y, Zhao Y, Lei J, Su Z, Ma G. Enhanced circulation half-life of site-specific PEGylated rhG-CSF: Optimization of PEG molecular weight. J Biotechnol 2009;142:259-66.
Ozer H, Mirtsching B, Rader M, Luedke S, Noga SJ, Ding B, et al.
Neutropenic events in community practices reduced by first and subsequent cycle pegfilgrastim use. Oncologist 2007;12:484-9.
Wu F, Wang H, Li N, Guo Y, Cheng Y, Liu Q, et al.
Clinical observation of the salvage therapy using pegylated recombinant human granulocyte colony stimulating factor for grade IV neutropenia induced by concurrent chemoradiotherapy. Zhonghua Zhong Liu Za Zhi 2014;36:708-12.
Weycker D, Malin J, Kim J, Barron R, Edelsberg J, Kartashov A, et al.
Risk of hospitalization for neutropenic complications of chemotherapy in patients with primary solid tumors receiving pegfilgrastim or filgrastim prophylaxis: A retrospective cohort study. Clin Ther 2009;31:1069-81.
Allison RR, Ambrad AA, Arshoun Y, Carmel RJ, Ciuba DF, Feldman E, et al.
Multi-institutional, randomized, double-blind, placebo-controlled trial to assess the efficacy of a mucoadhesive hydrogel (MuGard) in mitigating oral mucositis symptoms in patients being treated with chemoradiation therapy for cancers of the head and neck. Cancer 2014;120:1433-40.
Bacher U, Zander AR. Long-term safety of filgrastim (rhG-CSF) administration: Application of haematopoietic growth factors in healthy individuals. Br J Haematol 2007;137:78-9.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]