2Department of Acupuncture & Moxibustion, Kyung Hee University College of Korean Medicine, Kyung Hee University Hospital at Gangdong
3Department of Acupuncture and Moxibustion, College of Korean Medicine, Kyung Hee University
4Soram Korean Medicine Hospital
5Division of Pharmacology, School of Korean Medicine, Pusan National University
Correspondence to: Wonnam Kim, Division of Pharmacology, School of Korean Medicine, Pusan National University, Yangsan 50612, Republic of Korea, Tel: +82-51-510-8460, E-mail: eb75lab@pusan.ac.kr
Received October 10, 2024 Revised November 4, 2024 Accepted November 12, 2024
Abstract
Objectives
Neutropenia is a complication due to chemotherapy or radiotherapy that can limit clinical outcomes. Previous systematic reviews and meta-analysis have suggested that traditional Asian medicine may relieve neutropenia. This study investigated the effect of the combination therapy of Korean Medicine (KM) and filgrastim on neutropenia.
Methods
A total of 336 subjects were included, with 167 in the only filgrastim treatment group and 169 in the filgrastim with KM treatment group. Absolute neutrophil count (ANC) was calculated by multiplying the white blood cell count by the total percentage of neutrophils. ANC was observed on the day of filgrastim and up to 6 days with hospital medical records.
Results
The clinical characteristics of the participants in the filgrastim with KM treatment group tended to have higher age. Comparing the two groups, by the linear mixed-effects model, ANC mean was significantly different on the 3rd day. A linear mixed effect model was performed to estimate difference in slope of ANC over time after treatment between the two groups. The slope difference was significant in neutropenia grade 3 patients. The mean of ANC increment after initial treatment tends to increase with the number of days of KM treatment but not statistically significant. During the follow-up period, the average blood levels of patients in the filgrastim with KM treatment group were within the normal range.
Conclusions
The combination treatment with filgrastim and KM can be effective for patients with neutropenia.
Many myelosuppressive drugs currently used to treat cancer involve toxicity to the rapidly dividing cells of the hematopoietic system. Therefore, some of the most common side effects of chemotherapy include damage to the hematopoietic system is neutropenia.1–8) Radiotherapy is also known to be associated with neutropenia.9) Neutropenia increases the risk of infection, often present with fever, leading to hospitalization and high follow-up costs.7,8,10,11) Filgrastim, a granulocyte colony stimulating factor, significantly expanded treatment options for cancer patients with myelosuppression. Filgrastim has been proven effective in reducing the incidence, duration, and severity of chemotherapy-induced neutropenia and related complications by promoting hematopoietic recovery after chemotherapy.12–17)
Korean medicine (KM) is one of the traditional medical systems in east Asia that has been used to treat various diseases including cancer for more than 2,000 years.18) Systematic review and meta-analysis have been performed to elucidate the effect of KM on chemotherapy-related adverse events.19–21) Recent studies suggest that KM may contribute to the treatment of chemotherapy-induced neutropenia. Findings from 26 studies (1867 participants) revealed that herbal medicine reduced the risk of leukopenia induced by chemotherapy, as well as the grade 3/4 leukopenia.22) Meta-analysis showed that Diyushengbai tablet significantly improved the patients’ white blood cell counts and neutrophils, against the efficacy of conventional leukocyte-enhancing drugs.23) However, there were no studies focusing on the effect of combination therapy of KM and filgrastim on neutropenia. Therefore, this study was conducted to investigate the synergistic effect of combination with KM and filgrastim on neutropenia, by comparing with filgrastim monotherapy.
Methods
1. Study Population
This single-center, retrospective study was conducted at Soram Korean Medicine Hospital, Seoul, Korea. The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in the approval by Korean Public Institutional Review Board (No. P01-202110-21-002). All patients who received treatment with filgrastim between 1 June 2019 and 31 May 2021 were enrolled. Among them, the following exclusion criteria were applied: (1) patients whose absolute neutrophil count (ANC) was not measured; (2) patients who were not grade 3 or 4 neutropenia according to the criteria defined by the National Cancer Institute; (3) patients who did not undergo cancer; (4) patients were treated with KM within 6 days of filgrastim monotherapy. Finally, a total of 336 subjects were included, with 167 in the only filgrastim treatment group and 169 in the filgrastim with KM treatment group (Figure 1). ANC was calculated by multiplying the white blood cell count by the total percentage of neutrophils. ANC was observed on the day of filgrastim and up to 6 days with hospital medical records.
2. Korean Medicine Treatment
Four types of KM that were first taken together with filgrastim (Table 1). SSR50 and SVH50 were prescribed to immunocompromised patients undergoing cancer treatment. SGY50 and DBT were prescribed to symptoms related to Qi deficiency that leads to lack of blood. The prescription was based on the doctor’s medical decision.
3. Statistical Analysis
The patients’ characteristics and number of events are presented as the mean (standard deviation) or numbers (%). And continuous variables were compared using t test, categorical variables were compared using χ2 test and Fisher’s exact test as appropriate. The trend of ANC was estimated with linear mixed effect models adjusted for baseline values, a time effect, and an interaction effect between time and treatment. Least-squares mean and standard error for each time point were estimated with a mixed model including age and gender at baseline and compared between two treatment groups. For Subgroup analysis, the means of ANC increment were compared using ANOVA in the three groups, classified by the number of prescription days with KM. The renal and hepatic functions of the two treatment groups were compared at baseline and after treatment, respectively. Statistical significance was defined as p-value under 0.05 in this study. All statistical analyses were performed using R statistical software package (version 4.1.0; R Foundation for Statistical Computing, Vienna, Austria).
Results
1. Characteristics of Study Participants
Table 2 shows the clinical characteristics of the participants according to the treatment group when filgrastim was first treated. A total of 336 patients were enrolled: 167 (49.7%) with only filgrastim treatment and 169 (50.3%) with filgrastim with KM treatment. The average age at the time participants received filgrastim was 54.3 ± 11.4 years. We found that participants in the filgrastim with KM treatment group tended to have higher age. Sex, diabetes mellitus, hypertension, hemoglobin, albumin, white blood cell, lymphocyte, ANC, neutropenia grade, cancer type and filgrastim initial dose were not significantly different between the two groups.
2. Trend of ANC by treatment group
We compared the least-squares means of ANC, by the linear mixed-effects model, between the two groups at each time point up to 6 days post-treatment (Table 3). As a result of comparison, the estimated ANC mean in the only filgrastim treatment group was higher than filgrastim with KM treatment group at baseline, but was lower at all subsequent time points. Among them, it was statistically significant on the 3rd day (P=0.033). The same results were also found in the analysis that adjusted for age and sex. On the 3rd day, the age and sex adjusted least squares ANC mean of the only filgrastim treatment group was 4169.9 and the standard error was 383.7, and the adjusted mean and standard error of the filgrastim with KM treatment group were 5418.4 and 409.2, respectively. The difference between the two groups on 3rd day was statistically significant (P=0.026). There was no statistically significant difference in the other time points, the adjusted ANC mean was estimated to be greater than the only filgrastim treatment group, but except for the baseline.
A linear mixed effect model was performed to estimate difference in slope of ANC over time after treatment between the two groups (Figure 2). The slope difference was significant in neutropenia grade 3 patients, and there was no statistically significant difference in total patient and grade 4 patients (Total: P=0.179, neutropenia grade 3: P=0.016, neutropenia grade 4: P=0.605). In all situations, the slope of ANC in filgrastim with KM group tends to be larger than in only filgrastim treatment group.
3. Subgroup analysis
The patients in the filgrastim and KM treatment group were divided into 3 groups based on the number of KM prescription days, and the criteria were 1 day, 2–3 days, and more than 4 days. There were 23 patients in the 1 day group, 69 patients in the 2–3 days group, and 77 patients in the more than 4 days. The mean of ANC increment after initial treatment tends to increase with the number of days of KM treatment (Figure 3). But it was not statistically significant (P=0.389).
4. Safety analysis
A blood urea nitrogen (BUN) test is most often interpreted together with creatinine to help assess how well the kidneys are working. Also, aspartate (AST) and alanine (ALT) aminotransferase can be used to evaluate liver function or liver damage. So, these results were followed up to 10 days from the initial treatment to confirm renal and hepatic function (Figure 4). During the follow-up period, the average blood levels of patients in the filgrastim with KM treatment group were within the normal range. And the number of patients outside the normal range for all values was the same or less than that of the only filgrastim treatment group (Table 4).
Discussion
Several case reports showed that combination of filgrastim and traditional medicine, including herbal medicine, acupuncture, moxibustion, is effective for neutropenia.24,25) To our knowledge, this is the first comparative study of interactive effect based on filgrastim and KM treatment for neutropenia. Although our results should be interpreted with caution, due to a retrospective study and other limitations discussed below, we found that filgrastim with KM treatment contributed to the ANC increment in patients with neutropenia.
Previous clinical studies have shown that some herbal medicine could modulate immune effector cells, reduce the side effects of chemotherapy, and alleviate myelosuppression.26–29) The main component of Panax Ginseng C.A. Meyer contains tetracyclic triterpenoid saponins (ginsenosides) including Rb1, Rg1, Rc, and Rg3.30,31) A study showed that Korean Panax ginseng (KG) and Rg1 ameliorated 5-flurouracil (5-FU) induced myelotoxicity by cytokine mediated hematopoietic recovery.32) In cyclophosphamide treated mice, Rg1 relieved myelosuppression by inducing hematopoietic stem and progenitor cells (HSPCs) proliferation in the spleen and migration to the bone marrow.33) Interestingly, ginseng extract protected the hematopoietic function of cyclophosphamide induced immunosuppressed mice more than total ginsenosides suggesting the multicomponent synergistic effect.34)Angelica gigas Nakai Extract enhanced the recovery of hematopoiesis-related genes in the spleen and blood marrow in a myelosuppression model.35) The upregulated reactive oxygen species and senescence associated proteins, by cyclophosphamide, were ameliorated with Astragalus polysaccharides treatment via Wnt/β-catenin pathway.36) The combination of Astragalus membranaceus Bunge and Angelica sinensis (OLIV.) DIELS upregulated the production and secretion of hematopoietic growth factor and proliferation of hematopoietic progenitor cells in cyclophosphamide injected mice.37)
Age, sex, comorbidities, hemoglobin, albumin, white blood cell, and lymphocytes are known as various risk factors for neutropenia.38–41) In our data, only age among these risk factors differed between the two groups. The filgrastim with KM treatment group showed a larger increase in ANC despite the older age, and the same results were also indicated when age and gender were adjusted. In randomized clinical trials confirming the effectiveness of filgrastim, the ANC peaked 3 days after dosing.16,42–44) In this study, ANC peaked 3 days after treatment in only filgrastim group and filgrastim with KM group, consistent with the results of previous studies. Overall, the ANC value tended to be large in the combination group, which was seem to be a result of the effects of the previously mentioned ingredients such as ginseng, angelica, ginger and astragalus. Granulopoiesis involves different growth factors, especially granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF).45) Interestingly, KG ameliorated hematopoietic recovery in 5-FU-induced mice by increasing IL-3 and GM-CSF.32) This may suggest that both G-CSF and GM-CSF mediated granulocytes production in the combination group. However, further research is needed to fully understand the mechanism. There have been studies that KM and KM with Western medicines are safe from side effects on liver and kidney function.46–48) The liver and kidney function of the patients appeared to be well maintained in the filgrastim with KM treatment group.
Because our study is a retrospective study design, it is possible that various confounding variables were included in the patients. An additional randomized, controlled study is necessary to confirm our results.
Conclusion
Neutropenia contributes to significant morbidity, increased mortality and increased costs for cancer patients. Treatment option is needed to accelerate neutrophil recovery for patients receiving chemotherapy. This study showed that the combination treatment of filgrastim and KM can be effective in patients with neutropenia.
Fig. 1
Flow chart of study population in the retrospective study. KM: Korean medicine, ANC: absolute neutrophil count.
Fig. 2
Trends of ANC over time. The straight lines represent the best-fitting lines in the linear mixed effects model. And solid and dotted lines indicate the filgrastim with KM treatment group and the only filgrastim treatment group, respectively.
Fig. 3
Boxplot of ANC increment. The dot-line represents the normal range.
Fig. 4
Mean profile plots of renal and hepatic function.
Table 1
Types and compositions of Korean Medicine treatment.
a Adjusted variables included age; sex. Values are presented as the least squares mean ± standard error
Table 4
Number of patients with abnormal range
AST
ALT
BUN
Creatinine
Only filgrastim
36
32
31
25
Filgrastim with KM
23
19
22
25
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