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. 2021 May 4;12:573500. doi: 10.3389/fphar.2021.573500

Chinese Herbal Medicine for Chemotherapy-Induced Leukopenia: A Systematic Review and Meta-Analysis of High-Quality Randomized Controlled Trials

Qing Wang 1, Hui Ye 1,†, Qiu-qin Wang †, Wei-tong Li 1, Bei-bei Yu 2, Ya-mei Bai 1,*, Gui-hua Xu 1,*
PMCID: PMC8129503  PMID: 34017246

Abstract

Aim: We conducted a systematic review of high-quality randomized controlled trials (RCTs) to assess the efficacy and safety of Chinese herbal medicine (CHM) for the treatment of chemotherapy-induced leukopenia (CIL).

Methods: Eight electronic databases were searched from the date of inception to November 4, 2020 for high-quality RCTs that met the requirements of at least four key domains of the Cochrane risk of bias (RoB) tool. RevMan 5.3 was applied for the meta-analysis.

Results: Fourteen RCTs involving 1,053 patients were included. The pooled results showed that CHM + chemotherapy exerted greater beneficial effects on white blood cell (WBC), neutrophil (NEU), hemoglobin (Hb), and platelet (PLT) counts in addition to the Karnofsky performance scale (KPS) score, but showed no significant difference on granulocyte colony-stimulating factor (G-CSF) dosage compared with chemotherapy alone. Placebo (PBO) + chemotherapy and CHM + chemotherapy groups showed no significant differences in terms of reduction of the incidence of neutropenia. CHM + chemotherapy was superior to Western medicine (WM) + chemotherapy in improving the WBC count, KPS, infection amount, G-CSF use rate, and incidence of leukopenia. In addition, no severe adverse events were observed in the 14 RCTs.

Conclusion: CHM in combination with chemotherapy could effectively improve the clinical symptoms of CIL when compared with chemotherapy alone or Western medicine + chemotherapy, except when comparing with PBO + chemotherapy. While CHMs were generally safe for clinical use and exerted no severe side effects in the 14 RCTs, high-quality RCTs with larger sample sizes are essential to reduce study heterogeneity.

Keywords: traditional Chinese medicine, systematic review, meta-analysis, Chinese herbal medicine, chemotherapy-induced leukopenia

Introduction

Chemotherapy is widely applied for treatment of multiple cancer types, with one or more anticancer drugs generally used as part of a standardized chemotherapy regimen in the clinic (Johnstone et al., 2002). However, chemotherapy drugs often have poor targeting problems, and combined application of several drugs inevitably results in a series of adverse events (Sarah, 2013), such as bone marrow dysfunction, peripheral neuropathy, chronic pain, sleep disorders, nausea and vomiting, fatigue, and flushes, which not only negatively affect curative effects but also lead to severe patients’ discomfort and poor quality of life (QOL) posttreatment (Torre et al., 2015; Kato et al., 2019; Makary et al., 2019). Bone marrow suppression remains a major toxic effect (Yeshurun et al., 2014), which is characterized by a decrease in three critical cell types: leukocytes, erythrocytes, and platelets. Leukopenia is one of the most prominent effects of bone marrow suppression (Park et al., 2015) and often accompanied by severe infection and bleeding. Long-term usage of cytotoxic drugs is clearly associated with chemotherapy-induced leukopenia (CIL) (Merryman et al., 2012). To increase the white blood cell (WBC) counts within a short time frame for the maintenance of therapeutic efficacy and continue subsequent courses of treatment, granulocyte colony-stimulating factor (G-CSF) is commonly used to treat CIL (Winkler et al., 2016). However, while the effects of G-CSF are rapid, side effects, such as myalgia and fever, are also commonly reported (Yamauchi et al., 2014), making its usage less acceptable in the clinic. Moreover, for patients with severe myelosuppression, repeated treatment is required to maintain the curative effects of chemotherapy. Once medication is stopped, patients are prone to recurrent episodes of illness (Yang et al., 2015). Therefore, treatments that can facilitate effective and stable relief of CIL and promote patients’ QOL by consolidating the clinical value of previous chemotherapeutic regimens and ensuring continuation of therapy are currently a hot topic of research.

Recent studies have shown that traditional Chinese medicine (TCM) aiming to provide personalized treatment plans with multi-targeted and long-lasting effects together with fewer side effects (Zhang et al., 2015) can alleviate the adverse events of conventional chemotherapy (Li et al., 2019). Based on the key treatment concept of syndrome differentiation, TCM has been popularized and widely applied for patients on chemotherapy, including Chinese herbal medicine (CHM), Chinese patent drug, acupuncture, cupping, and other treatments (Li ta al., 2018). Accumulating reports have confirmed beneficial effects of TCM on adverse conditions resulting from bone marrow suppression after chemotherapy. In earlier pharmacological studies, administration of CHM as an adjuvant treatment significantly improved WBC counts in patients with CIL (Liu and Bi, 2015), relieved tumor-related fatigue and dizziness (Han and Jiang, 2018), elevated patients’ QOL (Li et al., 2019), and reduced toxic side effects (Jia et al., 2014). Data from previous meta-analyses clearly suggested that CHM is more effective than conventional oral Western medicine (WM) for the treatment of CIL induced by specific tumors (Li et al., 2015; Zhang et al., 2019), which we find enlightening, but limiting due to different CHM methods and tumor types. Two other systematic reviews and meta-analyses were not limited by the CHM method or tumor type (Li et al., 2016; Niu et al., 2018), but their clinical application and conclusive reliability were unfortunately affected by the low methodological quality of the included literature. Accordingly, we conducted a comprehensive advanced systematic review and meta-analysis of the effects of CHM on CIL, focusing on high-quality RCTs.

Materials and Methods

Our study was conducted according to the guidelines provided by the Preferred Reporting Item for Systematic Reviews and Meta-Analyses (PRISMA) statement (Moher et al., 2009) and Cochrane Handbook (Higgins et al., 2011).

Search Strategy

We performed a comprehensive search of 4 English electronic databases (PubMed, Web of Science, Cochrane Library, and Elsevier) from the date of inception to November 4, 2020 and 4 Chinese electronic databases (China National Knowledge Infrastructure, Chinese Biomedical Database, Chinese VIP Information Database, and Wanfang Med Database). The following medical subject heading (MeSH) terms and free text words were used for the search: “Chinese Medicine,” “Chinese Herbal Medicine,” “Chinese patent medicine,” “leukopenia,” “hypoleucocytosis,” “hypolekocytosis,” “neutropenia,” and “bone marrow suppression.” In the Chinese electronic databases, keywords were searched in Chinese characters and Pinyin. There was no limitation on language used.

Inclusion and Exclusion Criteria

Inclusion Criteria

Inclusion criteria were based on the following:

  • (1) Type of participant: diagnosis of cancer with chemotherapy-induced leukopenia.

  • (2) Type of study: only high-quality randomized controlled trials (RCTs) related to Chinese herbal medicine in the treatment of CIL, which met the requirements of at least four key domains of the Cochrane risk of bias (RoB) tool, along with trials published in the form of dissertations were selected as eligible studies.

  • (3) Type of intervention: participants in the intervention groups were treated with CHM in combination with chemotherapeutic drugs. There was no limitation with regard to the form of CHM used (e.g., decoction, capsule, and granule), dosage, or treatment duration. The control groups used chemotherapy alone, chemotherapeutic drugs plus placebo, or chemotherapeutic drugs plus Western medicine, which used to raise leukocytes. All participants were treated via oral administration.

  • (4) Type of outcome measure: primary outcome measures were white blood cell (WBC), neutrophil (NEU), hemoglobin (Hb), and platelet (PLT) counts in addition to the incidence of leukopenia and neutropenia. Secondary outcome measures were the Karnofsky performance scale (KPS) score and improvement, infection amount, granulocyte colony-stimulating factor (G-CSF) dosage and use rate, and adverse events.

Exclusion Criteria

Exclusion criteria were as follows:

  • (1) Patients with leukopenia not caused by chemotherapy.

  • (2) Duplicate studies, review, animal experiments, and conference abstracts.

  • (3) Nonoral TCM methods, such as acupuncture, moxibustion, massage, and acupoint injection, in the intervention group or use of CHM drugs in the control group.

Data Extraction

Two reviewers (QW and HY) independently extracted the relevant data according to the predetermined inclusion and exclusion criteria. The following information was obtained using a standard data extraction form: 1) general information: publication year, language, and first author; 2) characteristics of participants: sample size, age, and gender; 3) intervention information: intervention method, medication dose, and course of treatment; and 4) outcome measures. To resolve any disagreements, the two reviewers discussed the issue or consulted the corresponding author (G-HX).

Risk of Bias Assessment

The RoB tool was used to assess the methodological quality of included studies (Higgins et al., 2011). Seven aspects were evaluated: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias. RCTs that met the requirements of at least 4 of the above parameters were selected for the final analysis.

Statistical Analysis

RevMan 5.3 was used for statistical analysis. Chi-square test and I 2 statistic were employed to assess the heterogeneity between intervention and control results. In cases where I 2 was < 50% or chi-square p value was > 0.1, a fixed-effects model was used. Otherwise, a random-effects model was applied. p values <0.05 were considered statistically significant. The risk ratio (RR) with 95% confidence interval (CI) was used to calculate the dichotomous data, while the mean difference (MD) or standardized mean difference (SMD) was used to express the continuous data.

Assessment of Evidence Quality

The overall quality of the evidence for each outcome was assessed by two reviewers (QW and HY) in accordance with the methodology recommended by the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) criteria (Schunemann et al., 2008). In the system, quality of the evidence varies in four levels: very low quality, low quality, moderate quality, and high quality. Risk of bias, inconsistency, indirectness, imprecision, and other factors (e.g., publication bias) are factors relating to lowering the level of evidence. According to specific criteria such as large I 2 indicating inconsistency, the level of evidence from RCTs can be downgraded by one or two levels. Summary of findings table for outcomes was performed using GRADEpro GDT.

Results

Study Selection

A total of 6,197 studies were identified after searching eight databases, from which 1,494 duplicates were removed. Among the remaining 4,703 records, 4,274 were excluded for various reasons after screening according to titles and abstracts. Specifically, 3,264 studies were irrelevant, 437 used other TCM methods, 372 were animal experiments, and 201 were reviews. Comprehensive reading of the full text of the remaining 429 articles resulted in exclusion of 415 studies due to the following reasons: 257 articles did not meet the inclusion criteria, two had no available data, and 156 had low methodological quality. Finally, 14 RCTs with RoB scores ≥4 were included (Mok et al., 2007; Wang, 2011; Liu, 2013; Qian and Li, 2013; Liu and Yao, 2014; Ren and Wu, 2015; Zou, 2015; Wang et al., 2016; Yuan and Zhang, 2016; Zhao and Lu, 2016; Wang and Li, 2017; Li and Liu, 2019; Huang and Zhang, 2020; Li et al., 2020). A flowchart of the screening process is presented in Figure 1.

FIGURE 1.

FIGURE 1

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Flowchart of screening process.

Characteristics of Included Studies

A total of 14 studies involving 1,053 patients were included. Only one study was published in English (Mok et al., 2007) and the remaining in Chinese (Wang, 2011; Liu, 2013; Qian and Li, 2013; Liu and Yao, 2014; Ren and Wu, 2015; Zou, 2015; Wang et al., 2016; Yuan and Zhang, 2016; Zhao and Lu, 2016; Wang and Li, 2017; Li and Liu, 2019; Huang and Zhang, 2020; Li et al., 2020). Sample sizes of studies published from 2007 to 2020 ranged from 30 to 120, which included a total of 530 patients in the treatment and 523 in the control groups. Six studies compared CHM + chemotherapy with chemotherapy alone (n = 391) (Liu, 2013; Qian and Li, 2013; Liu and Yao, 2014; Zhao and Lu, 2016; Li and Liu, 2019; Huang and Zhang, 2020), and two compared CHM + chemotherapy with placebo (PBO)+ chemotherapy (n = 164) (Mok et al., 2007; Yuan and Zhang, 2016). Six studies compared CHM + chemotherapy with WM + chemotherapy (n = 498) (Wang, 2011; Ren and Wu, 2015; Zou, 2015; Wang et al., 2016; Wang and Li, 2017; Li et al., 2020). The treatment courses lasted from 14 to 60 days. The preparations used for treatment in the intervention groups of the 14 RCTs were administered orally in the form of decoction (nine comparative analyses), granules (three comparative analyses), capsules, and gel (one comparative analysis separately). The characteristics of the 14 trials are presented in Table 1, and the components are described in Table 2.

TABLE 1.

Characteristics of the included trials.

First author and publication year Publication language Sample size and characteristics (M/F), age (years) Course of disease Intervention and dose Course of treatment (days) Main outcomes
Experimental Control Intervention Control
Liu (2013) Chinese 28 (20/8) 28 (21/7) 0.1∼7.8 years Fuzheng Guben decoction, 1 dose, bid + chemotherapy Chemotherapy 60 WBC count, G-CSF dosage, adverse events
53.8 ± 3.6 54.2 ± 5.8
Qian and Li (2013) Chinese 62 (32/30) 58 (31/27) NA Hua Liao Jian du decoction + chemotherapy Chemotherapy 21 WBC count, Hb count, PLT count, KPS, adverse events
60.20 ± 7.79 60.40 ± 8.86
Liu and Yao (2014) Chinese 38 (20/18) 38 (22/16) NA Husui decoction 1 dose, tid + chemotherapy Chemotherapy 14 WBC count, NEU count, G-CSF dosage, adverse events
34–64 28–67
Zhao and Lu (2016) Chinese 15 (0/15) 15 (0/15) NA Fuzheng Shengbai decoction, 1 dose, bid + chemotherapy Chemotherapy 21 WBC count, NEU count, Hb count, PLT count, KPS, adverse events
53.07 ± 7.72 48.00 ± 9.80
Li and Liu (2019) Chinese 26 (12/14) 26 (11/15) NA Jianpi Shengsui gel, 15–20 g, tid + chemotherapy Chemotherapy 42 WBC count, NEU count, Hb count, PLT count, KPS, adverse events
53.78 ± 5.95 54.13 ± 6.37
Huang and Zhang (2020) Chinese 29 (18/11) 28 (16/12) NA Yisui Shengxue capsules 1.8 g, tid + chemotherapy Chemotherapy 21 WBC count, NEU count, Hb count, PLT count, KPS, adverse events
62.00 ± 6.35 63.97 ± 6.33
Mok et al. (2007) English 55 (5/50) 56 (6/50) NA CHM granules, 3–10 g, qd + chemotherapy Placebo, 3–10 g, qd + chemotherapy 28 Incidence of neutropenia, adverse events
32–75 39–72
Yuan and Zhang (2016) Chinese 27 (15/12) 26 (13/13) 1˜21 month Qijing Shengbai granules, 12 g, bid + chemotherapy Placebo 12 g, bid + chemotherapy 42 ± 7 Incidence of neutropenia, adverse events
59.37 ± 5.869 59.67 ± 6.449
Ren and Wu (2015) Chinese 20 (12/8) 20 (13/7) 10˜24 months Fuzheng Shengbai decoction, 1 dose, bid + chemotherapy Leukogen tablets 20 mg, tid + chemotherapy 21 WBC count, adverse events
58.19 ± 8.67 55.5 ± 5.6
Wang and Li (2017) Chinese 45 (23/22) 45 (24/21) NA Modified Liu Wei Di Huang decoction 1 dose, tid + chemotherapy Leukogen tablets 20 mg, tid + chemotherapy 21 WBC count, KPS improvement, G-CSF use rate, adverse events
54.87 ± 8.137 54.73 ± 7.347
Wang (2011) Chinese 45 (24/21) 44 (23/21) NA Modified Sancai Fengsui decoction, 1 dose, bid + chemotherapy Leucogen 20 mg and Batyl alcohol 100 mg, tid + chemotherapy 14 WBC count, KPS improvement, infection amount
35–74 34–75
Zou (2015) Chinese 47 (20/27) 48 (21/27) NA Sanhuang Sanxian decoction, 1 dose, bid + chemotherapy Leucogen 20 mg, Batyl alcohol 50 mg, tid + chemotherapy 30 Incidence of leukopenia, infection amount, adverse events
55.7 ± 16.3 55.5 ± 16.7
Wang et al. (2016) Chinese 60 (38/22) 58 (36/22) NA Shuanghuang Shengbai granules, 30 g, bid + chemotherapy Leucogen 40 mg, tid + chemotherapy 14 Incidence of leukopenia, G-CSF use rate, adverse events
66.17 ± 5.23 66.82 ± 4.96
Li et al. (2020) Chinese 33 (12/21) 33 (13/20) 7.64 weeks Bazhen decoction 400 ml/d + chemotherapy Leucogen 20 mg, Batyl alcohol 100 mg, tid + chemotherapy 28 WBC count, adverse events
58.41 ± 8.12 58.35 ± 8.13
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M/F, male/female; NA, not available; WBC, white blood cell; NEU, neutrophil; Hb, hemoglobin; PLT, platelet; KPS, Karnofsky performance scale; G-CSF, granulocyte colony-stimulating factor.

TABLE 2.

Components of Chinese herbal medicine used in the included trials.

First author and publication year Chinese herbal medicine Ingredients of herb prescription
Latin name English name Chinese name
Liu (2013) Fuzheng Guben decoction Processed product of Glycyrrhiza uralensis Fisch Glycyrrhizae Radix et Rhizoma Praeparata Cum Melle Zhigancao
Horn processed product of Cervus nippon Temminck Cervi Cornus Colla Lujiaojiao
Rehmannia glutinosa Libosch Rehmanniae Radix Praeparata Shudihuang
Psoralea corylifolia L. Psoraleae Fructus Buguzhi
Dipsacus asper Wall. ex Henry Dipsaci Radix Xuduan
Poria cocos (Schw.) Wolf Poria Fuling
Atractylodes macrocephala Koidz Atractylodis Macrocephalae Rhizoma Baizhu
Pseudostellaria heterophylla (Miq.) Pax ex pax et Hoffm Pseudostellariae Radix Taizisheng
Angelica sinensis (Oliv.) Diels Angelicae Sinensis Radix Danggui
Processed product of Astragalus membranaceus (Fisch.) Bge. Astragali Radix Praeparata Cum Melle Zhihuangqi
Qian and Li (2013) Hua Liao Jian du decoction Panax ginseng C. A. Mey Ginseng Radix et Rhizoma Rubra Hongshen
Astragalus membranaceus (Fisch.) Bge. Astragali Radix Huangqi
Atractylodes macrocephala Koidz. Atractylodis Macrocephalae Rhizoma Baizhu
Angelica sinensis (Oliv.) Diels Angelicae Sinensis Radix Danggui
Equus asinus L. Asini Corii Colla Ejiao
Horn processed product of Cervus nippon Temminck Cervi Cornus Colla Lujiaojiao
Processed product of Carapax et Plastrum Testudinis Testudinis Carapacis et Plastri Colla Guibanjiao
Citrμs reticμlata Blanco Citri Reticulatae Pericarpium Chenpi
Glycyrrhiza uralensis Fisch Glycyrrhizae Radix et Rhizoma Gancao
Liu and Yao (2014) Husui decoction Panax ginseng C. A. Mey Ginseng Radix et Rhizoma Renshen
Astragalus membranaceus (Fisch.) Bge Astragali Radix Huangqi
Lycium barbarum L. Lycii Fructus Gouqizi
Atractylodes macrocephala Koidz Atractylodis Macrocephalae Rhizoma Baizhu
Rehmannia glutinosa Libosch Rehmanniae Radix Praeparata Shudihuang
Angelica sinensis (Oliv.) Diels Angelicae Sinensis Radix Danggui
Spatholobus suberectus Dunn Spatholobi Caulis Jixueteng
Equus asinus L. Asini Corii Colla Ejiao
Horn processed product of Cervus nippon Temminck Cervi Cornus Colla Lujiaojiao
Cuscuta australis R. Br. Cuscutae Semen Tusizi
Oryza sativa L. Oryzae Fructus Germinatus Daoya
Hordeum vulgare L. Hordei Fructus Germinatus Chaomaiya
Aucklandia lappa Decne Aucklandiae Radix Muxiang
Glycyrrhiza uralensis Fisch Glycyrrhizae Radix et Rhizoma Gancao
Zhao and Lu (2016) Fuzheng Shengbai decoction Curculigo orchioides Gaertn Curculiginis Rhizoma Xianmao
Morinda officinalis How Morindae Officinalis Radix Bajitian
Ligustrum lucidum Ait. Ligustri Lucidi Fructus Nvzhenzi
Eclipta prostrata L. Ecliptae Herba Mohanlian
Sanguisorba officinalis L. Sanguisorbae Radix Diyu
Pyrrosia lingua (Bak.) Ching Pyrrosiae Folium Shiwei
Codonopsis pilosula (Franch.) Nannf. Codonopsis Radix Dangshen
Atractylodes macrocephala Koidz Atractylodis Macrocephalae Rhizoma Baizhu
Li and Liu (2019) Jianpi Shengsui plaster Chinemys reevesii (Gray) Testudinis Carapax et Plastrum Guijia
Trionyx sinensis Wiegmann Trionycis Carapax Biejia
Horn of Cervus nippon Temminck after extraction Cervi Cornu Degelatinatum Lujiaoshuang
Codonopsis pilosula (Franch.) Nannf. Codonopsis Radix Dangshen
Lycium barbarum L. Lycii Fructus Gouqizi
Polygonatum kingianum Coll. et Hemsl. Polygonati Rhizoma Huangjing
Ligustrum lucidum Ait. Ligustri Lucidi Fructus Nvzhenzi
Eclipta prostrata L. Ecliptae Herba Mohanlian
Stomach of Gallus domesticus Brisson Galli Gigerii endothelium corneum Jineijin
Hordeum vulgare L. Hordei Fructus Germinatus Maiya
Crataegus pinnatifida Bge Crataegi Fructus Shanzha
Cyperus rotundus L. Cyperi Rhizoma Xiangfu
Glucidtemns Yuanzhen Sugar Yuanzhentang
Equus asinus L. Asini corii colla Ejiao
Polygonatum odoratum (Mill.) Druce Polygonati Odorati Rhizoma Yuzhu
Ophiopogon japonicus (L.f) Ker-Gawl Ophiopogonis Radix Maidong
Huang and Zhang (2020) Yisui Shengxue capsule Cervus nippon Temminck Cervi Cornu Pantotrichum Lurong
Epimedium brevicomu Maxim Epimedii Folium Yinyanghuo
Zingiber officinale Rosc Zingiberis Rhizoma Ganjiang
Panax ginseng C. A. Mey Ginseng Radix et Rhizoma Renshen
Atractylodes macrocephala Koidz Atractylodis Macrocephalae Rhizoma Baizhu
Astragalus membranaceus (Fisch.) Bge Astragali Radix Huangqi
Amomum villosum Lour Amomi Fructus Sharen
Magnetium magnetite Magnetitum Cishi
Cornus officinalis Sieb. et Zucc Corni Fructus Jiuyurou
Processed product of polygonum multiflorum Thunb Polygoni Multiflori Radix Praeparata Zhiheshouwu
Equus asinus L Asini corii colla Ejiao
Rheum palmatum L Rhei Radix et Rhizoma Dahuang
Processed product of Glycyrrhiza uralensis Fisch Glycyrrhizae Radix et Rhizoma Praeparata Cum Melle Zhigancao
Mok et al. (2007) CHM granules A combination of single-itemized herbs from the stocking 225 different types of commonly used herbs
(see Appendix for details)
Yuan and Zhang (2016) QijingShengbai granules Panax quinquefolium L Panacis Quinquefolii Radix Xiyangshen
Astragalus membranaceus (Fisch.) Bge Astragali Radix Huangqi
Angelica sinensis (Oliv.) Diels Angelicae Sinensis Radix Danggui
Eclipta prostrata L Ecliptae Herba Mohanlian
Polygonatum kingianum Coll. et Hemsl Polygonati Rhizoma Huangjing
Lycium barbarum L Lycii Fructus Gouqizi
Horn processed product of Cervus nippon Temminck Cervi Cornus Colla Lujiaojiao
Epimedium brevicomu Maxim Epimedii Folium Yinyanghuo
Psoralea corylifolia L Psoraleae Fructus Buguzhi
Spatholobus suberectus Dunn Spatholobi Caulis Jixueteng
Ren and Wu (2015) Fuzhengshengbai decoction Codonopsis pilosula (Franch.) Nannf Codonopsis Radix Dangshen
Astragalus membranaceus (Fisch.) Bge Astragali Radix Huangqi
Gastrodia elata Bl Gastrodiae Rhizoma Tianma
Angelica sinensis (Oliv.) Diels Angelicae Sinensis Radix Danggui
Rehmannia glutinosa Libosch Rehmanniae Radix Praeparata Shudihuang
Alisma orientate (Sam.) Juzep Alismatis Rhizoma Zexie
Cassia obtusifolia L Cassiae Semen Juemingzi
Cuscuta australis R. Br Cuscutae Semen Tusizi
Lycium barbarum L Lycii Fructus Gouqizi
Eucommia ulmoides Oliv Eucommiae Cortex Duzhong
Atractylodes macrocephala Koidz Atractylodis Macrocephalae Rhizoma Baizhu
Paeonia lactiflora Pall Paeoniae Radix Alba Baishao
Glycyrrhiza uralensis Fisch Glycyrrhizae Radix et Rhizoma Gancao
Wang and Li (2017) Modified Liu wei di Huang decoction Rehmannia glutinosa Libosch Rehmanniae Radix Praeparata Shudihuang
Cornus officinalis Sieb. et Zucc Corni Fructus Shanzhuyu
Dioscorea opposita Thunb Dioscoreae Rhizoma Shanyao
Epimedium brevicomu Maxim Epimedii Folium Yinyanghuo
Achyranthes bidentata Bl Achyranthis Bidentatae Radix Niuxi
Eucommia ulmoides Oliv Eucommiae Cortex Duzhong
Poria cocos (Schw.) Wolf Poria Fuling
Alisma orientate (Sam.) Juzep Alismatis Rhizoma Zexie
Paeonia suffruticosa Andr Moutan Cortex Danpi
Panax ginseng C. A. Mey Ginseng Radix et Rhizoma Renshen
Atractylodes macrocephala Koidz Atractylodis Macrocephalae Rhizoma Baizhu
Astragalus membranaceus (Fisch.) Bge Astragali Radix Huangqi
Crataegus pinnatifida Bge Crataegi Fructus Shanzha
Aucklandia lappa Decne Aucklandiae Radix Muxiang
Massa Medicata Fermentata Medicated Leaven Jianqu
Wang (2011) Modified Sancai Fengsui decoction Panax ginseng C. A. Mey Ginseng radix et Rhizoma Renshen
Asparagus cochinchinensis (Lour.) Merr Asparagi Radix Tiandong
Rehmannia glutinosa Libosch Rehmanniae Radix Praeparata Shudihuang
Phellodendron chinense Schneid Phellodendri Chinensis Cortex Huangbo
Amomum villosum Lour Amomi Fructus Sharen
Astragalus membranaceus (Fisch.) Bge Astragali Radix Huangqi
Glehnia littoralis Fr. Schmidtex Miq Glehniae Radix Beishashen
Cistanche deserticola Y. C. Ma Cistanches Herba Roucongrong
Angelica sinensis (Oliv.) Diels Angelicae Sinensis Radix Danggui
Spatholobus suberectus Dunn Spatholobi Caulis Jixueteng
Schisandra chinensis (Turcz.) Baill Schisandrae Chinensis Fructus Wuweizi
Glycyrrhiza uralensis Fisch Glycyrrhizae Radix et Rhizoma Gancao
Zou (2015) Sanhuang Sanxian decoction Astragalus membranaceus (Fisch.) Bge Astragali Radix Huangqi
Polygonatum kingianum Coll. et Hemsl Polygonati Rhizoma Huangjing
Scutellaria baicalensis Georgi Scutellariae Radix Huangqin
Agrimonia pilosa Ledeb Agrimoniae Herba Xianhecao
Epimedium brevicomu Maxim Epimedii Folium Yinyanghuo
Curculigo orchioides Gaertn Curculiginis Rhizoma Xianmao
Angelica sinensis (Oliv.) Diels Angelicae Sinensis Radix Danggui
Paeonia lactiflora Pall Paeoniae Radix Alba Baishao
Lycium barbarum L. Lycii Fructus Gouqizi
Ligustrum lucidum Ait Ligustri Lucidi Fructus Nvzhenzi
Spatholobus suberectus Dunn Spatholobi Caulis Jixueteng
Ziziphus jujuba Mill Jujubae Fructus Dazao
Wang et al. (2016) Shuanghuang Shengbai granules Astragalus membranaceus (Fisch.) Bge Astragali Radix Huangqi
Astragalus membranaceus (Fisch.) Bge Polygonati Rhizoma Huangjing
Drynaria fortune (Kunze) J. Sm Drynariae Rhizoma Gusuibu
Ligustrum lucidum Ait Ligustri Lucidi Fructus Nvzhenzi
Epimedium brevicomu Maxim Epimedii Folium Yinyanghuo
Trichosanthes kirilowii Maxim Trichosanthis Radix Tianhuafen
Li et al. (2020) Bazhen decoction Codonopsis pilosula (Franch.) Nannf Codonopsis Radix Dangshen
Astragalus membranaceus (Fisch.) Bge Astragali Radix Huangqi
Rehmannia glutinosa Libosch Rehmanniae Radix Praeparata Shudihuang
Paeonia lactiflora pall Paeoniae Radix Alba Baishao
Ligusticum chuanxiong Hort Chuanxiong Rhizoma Chuanxiong
Poria cocos (Schw.) Wolf Poria Fuling
Atractylodes macrocephala Koidz Atractylodis Macrocephalae Rhizoma Baizhu
Angelica sinensis (Oliv.) Diels Angelicae Sinensis Radix Danggui
Dioscorea opposita Thunb Dioscoreae Rhizoma Shanyao
Spatholobus suberectus Dunn Spatholobi Caulis Jixueteng
Cuscuta australis R. Br Cuscutae Semen Tusizi
Glycyrrhiza uralensis Fisch Glycyrrhizae Radix et Rhizoma Gancao
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Risk of Bias Assessment

Risk of bias (ROB) data are shown in Table 3. All 14 RCTs specified the methods of random sequence generation. Only one study reported the allocation concealment method (Wang and Li, 2017). Two studies blinded both participants and personnel (Mok et al., 2007; Yuan and Zhang, 2016), and one blinded outcome assessment (Mok et al., 2007). As shown in the table, one article scored six points (Mok et al., 2007), two scored five points (Yuan and Zhang, 2016; Wang and Li, 2017), and eleven scored four points (Wang, 2011; Liu, 2013; Qian and Li, 2013; Liu and Yao, 2014; Ren and Wu, 2015; Zou, 2015; Wang et al., 2016; Zhao and Lu, 2016; Li and Liu, 2019; Huang and Zhang, 2020; Li et al., 2020).

TABLE 3.

Risk of bias assessment of all included studies.

Studies A B C D E F G Total
Liu (2013) + − − − + + + 4+
Qian and Li (2013) + − − − + + + 4+
Liu and Yao (2014) + − − − + + + 4+
Zhao and Lu (2016) + − − − + + + 4+
Li and Liu (2019) + − − − + + + 4+
Huang and Zhang (2020) + − − − + + + 4+
Mok et al. (2007) + ? + + + + + 6+
Yuan and Zhang (2016) + − + ? + + + 5+
Ren and Wu (2015) + − − − + + + 4+
Wang and Li (2017) + + − − + + + 5+
Wang (2011) + − − − + + + 4+
Zou (2015) + − − − + + + 4+
Wang et al. (2016) + − − − + + + 4+
Li et al. (2020) + − − − + + + 4+
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A, random sequence generation; B, allocation concealment; C, blinding of participants and personnel; D, blinding of outcome assessment; E, incomplete outcome data; F, Selective reporting; G, Other bias. “+” = low risk of bias, “−” = high risk of bias, “?” = unclear risk of bias.

Assessment of Efficacy

Chinese Herbal Medicine Plus Chemotherapy Versus Chemotherapy Alone

Six comparative studies (Liu, 2013; Qian and Li, 2013; Liu and Yao, 2014; Zhao and Lu, 2016; Li and Liu, 2019; Huang and Zhang, 2020) were included for analysis. The results of the meta-analysis disclosed a significant increase in WBC counts with CHM + chemotherapy, compared with chemotherapy alone (n = 391, MD = 0.52, 95% CI: 0.37 to 0.66, I 2 = 64%, p < 0.00001). Data from pooled studies additionally showed that combined treatment with CHM and chemotherapy induced a significant increase in NEU, Hb, and PLT counts and KPS (p < 0.00001; p = 0.02; p = 0.0007; p = 0.006), aside from G-CSF dosage (p = 0.17; Figure 2).

FIGURE 2.

FIGURE 2

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Forest plots of CHM + chemotherpy vs. chemotherapy.

Chinese Herbal Medicine Plus Chemotherapy Versus Placebo Plus Chemotherapy

Two studies (Mok et al., 2007; Yuan and Zhang, 2016) were included for analysis. The pooled results showed no significant differences in reducing the incidence of neutropenia (n = 164, RR 0.95, 95% CI: 0.69 to 1.33, I 2 = 74%, p = 0.78; Figure 3).

FIGURE 3.

FIGURE 3

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Forest plots of CHM + chemotherapy vs. PBO + chemotherapy.

Chinese Herbal Medicine Plus Chemotherapy Versus Western medicine Plus Chemotherapy

Six studies compared CHM + chemotherapy with WM + chemotherapy (Wang, 2011; Ren and Wu, 2015; Zou, 2015; Wang et al., 2016; Wang and Li, 2017; Li et al., 2020). The pooled results revealed significant differences in WBC counts, KPS improvement, infection amount, G-CSF use rate, and incidence of leukopenia (p < 0.05) between the groups (Figure 4).

FIGURE 4.

FIGURE 4

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Forest plots of CHM + chemotherapy vs. WM + chemotherapy.

Adverse Events

One study (Liu, 2013) reported vomiting and nausea in one case from the experimental group and nine cases from the control group. Both symptoms disappeared after reduction of the treatment dose. Another study (Mok et al., 2007) described occurrence of nausea, vomiting, and anorexia in both the experimental and control groups. In particular, CHM had a significant impact on control of nausea. Two studies (Wang and Li, 2017; Huang and Zhang, 2020) also reported nausea and vomiting in both experimental and control groups, with no significant differences in the two groups. Zou (2015) reported adverse events, such as slight muscle aches, fatigue, low-grade fever, nausea, and vomiting, which were relieved after symptomatic treatment, while Wang et al. (2016) noted one case of mild diarrhea in the intervention group and remission after dosage reduction. No severe adverse events were reported in three studies (Wang, 2011; Ren and Wu, 2015; Yuan and Zhang, 2016). Li et al. (2020) reported rash, dizziness, nausea, and vomiting in the experimental group, which indicated no significant difference compared with the control group. Five other studies (Qian and Li, 2013; Liu and Yao, 2014; Zhao and Lu, 2016; Li and Liu, 2019; Huang and Zhang, 2020) showed no significant differences in liver and kidney functions of patients from both experimental and control groups. The collective results from the 14 RCTs indicate that CHM exerts no severe side effects and is generally safe for human use.

Assessment of Evidence Quality

Comparing CHM + chemotherapy with chemotherapy alone or PBO + chemotherapy or WM + chemotherapy, the overall quality of evidence according to each outcome measures was moderate or low. The results of GRADE assessments are presented in Table 4.

TABLE 4.

Assessment of evidence quality.

Outcomes Anticipated absolute effects Relative effect (95% CI) No of Participants (studies) Quality of the evidence (GRADE)
Risk with controls Risk difference with CHM (95% CI)
CHM+ chemotherapy vs. chemotherapy
WBC counts — 0.52 MD higher (0.37 to 0.66 higher) — 391 (6 RCTs) ⊕⊕⊕○ Moderate due to risk of bias
NEU counts — 0.41 MD higher (0.26 to 0.55 higher) — 215 (4 RCTs) ⊕⊕⊕○ Moderate due to risk of bias
Hb counts — 0.46 SMD higher (0.07 to 0.85 higher) — 259 (4 RCTs) ⊕⊕○○ Low due to risk of bias, inconsistency
PLT counts — 10.15 MD higher (4.3 to 16.0 higher) — 259 (4 RCTs) ⊕⊕⊕○ Moderate due to risk of bias
KPS — 7.21 MD higher (2.1 to 12.32 higher) — 259 (4 RCTs) ⊕⊕○○ Low due to risk of bias, inconsistency
G-CSF dosage — 2.5 SMD lower (6.07 lower to 1.07 higher) — 132 (2 RCTs) ⊕⊕○○ Low due to risk of bias, inconsistency
CHM+ chemotherapy vs. PBO+ chemotherapy
Incidence of neutropenia — — RR 0.95 (0.69 to 1.33) 160 (2 RCTs) ⊕⊕○○ Low due to inconsistency, imprecision
CHM+ Chemotherapy vs. WM+ Chemotherapy
WBC counts — 0.80 MD higher (0.20 to 1.40 higher) — 280 (4 RCTs) ⊕⊕○○ Low due to risk of bias, inconsistency
KPS improvement — — RR 1.73 (1.26 to 2.39) 174 (2 RCTs) ⊕⊕⊕○ Moderate due to risk of bias
Infection amount — — RR 0.25 (0.12 to 0.51) 184 (2 RCTs) ⊕⊕⊕○ Moderate due to risk of bias
G-CSF use rate — — RR 0.35 (0.13 to 0.92) 203 (2 RCTs) ⊕⊕⊕○ Moderate due to risk of bias
Incidence of leukopenia — — RR 0.25 (0.08 to 0.79) 213 (2 RCTs) ⊕⊕⊕○ Moderate due to risk of bias
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RCT, randomized clinical trial; SMD, standardized mean difference; MD, mean difference; CI: confidence interval. High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

Discussion

Cancer remains a severe public health problem with rapidly increasing incidence and mortality rates and is the leading cause of death worldwide (Bray et al., 2018; Siegel et al., 2020). Chemotherapy is currently the main treatment modality for cancer. However, CIL is the most common adverse effect of chemotherapy, which is directly associated with survival rates (Liu et al., 2013; Campos et al., 2015; Wyatt et al., 2015; Varughese et al., 2020). G-CSF is commonly used to relieve side effects and improve the QOL of patients with CIL (Disis, 2005; Ohnaka et al., 2013; Cornes et al., 2018). However, despite rapid effects, the drug is not suitable for long-term use in all patients owing to its high cost and secondary malignancy risk (Lyman et al., 2013; Lyman, et al., 2018). Thus, increasing number of patients have turned to complementary and alternative medicines to control symptoms and improve the QOL (Kuo et al., 2018; Knecht et al., 2020). CHM has received considerable research attention over the past few years and is widely applied following chemotherapy for various cancer types. Compared with G-CSF, the long-lasting effects and affordability of CHM have made it the preferred treatment of choice for many patients in China. Based on continued evaluation of clinical efficacy from meta-analyses together with accumulating experimental and pharmacological insights into their mechanisms of action, CHM drugs could increasingly benefit patients with chemotherapy-induced leukopenia (CIL) worldwide (Jia et al., 2015; Yang et al., 2017; Chen et al., 2018).

Trials included in previous meta-analyses (Li et al., 2016; Niu et al., 2018) had low methodological quality, with no information on blinding and allocation concealment. This updated systematic review included 14 high-quality studies that were divided into three subgroups to reduce heterogeneity, with a total of 1,053 selected patients. Earlier studies by Li et al. (2016) and Niu et al. (2018) had few evaluation indicators, and both showed superiority of CHM in improving the clinical efficacy rate. Niu and coworkers (2018) additionally demonstrated that CHM could enhance the KPS score.

In the current meta-analysis, the methodological quality was adjusted, the latest literature was included, and more specific indicators were evaluated, with the aim of providing a comprehensive and reliable reference for subsequent research. Pooled data on comparative analyses of CHM + chemotherapy and chemotherapy alone revealed that CHM had greater beneficial effects on several indicators, including WBC, NEU, Hb, and PLT counts, as well as KPS, but not G-CSF dosage. The CHM + chemotherapy group was non-inferior to the PBO + chemotherapy group for the incidence of neutropenia, supporting the findings of Liew et al. (2019) and Mok et al. (2007); CHM did not reduce hematologic toxicity associated with chemotherapy. The CHM + chemotherapy group was superior to the WM + chemotherapy group in terms of improvement of the WBC counts, KPS score, infection amount, G-CSF use rate, and incidence of leukopenia. In addition, CHM drugs were generally safe and induced no severe adverse events.

Our study has several limitations that should be taken into consideration. First, the methodological quality of the included studies was generally low. Although we searched both English and Chinese databases, potential selection bias may have been introduced since most of the included records retrieved were Chinese. Second, although all the trials met the requirements of at least four parameters of the Cochrane RoB tool, some methodological restrictions existed in primary studies. Only one study reported the method of allocation concealment that could lead to selection bias. Only two described blinding of participants and personnel, and one described blinding of outcome assessment. Missing blinding may cause detection bias. It is difficult to conduct adequate blinding in CHM RCTs due to different smells and tastes of CHM decoctions. Third, different components, doses, and duration of CHM interventions may have caused potential heterogeneity. Fourth, some indicators appeared less frequently, only in two studies. Finally, the small sample of subgroup and the quality of the evidence lead the conclusion to be more objective and explicit, giving us inspiration to design related clinical intervention.

Conclusion

CHM in combination with chemotherapy could improve clinical symptoms of CIL when compared with chemotherapy alone or Western medicine + chemotherapy, except when comparing with PBO + chemotherapy. While CHMs were generally safe and exerted no severe side effects in all 14 RCTs, larger sample sizes and high-quality RCTs are required to reduce study heterogeneity.

Appendix

Radix Scrophulariae, Polyporus, Coix Lacrymajobi, Semen Plantaginis, Herba Lysimachiae, Spora Lygodii, Herba Artemisiae Scopariae, Fructus Kochiae, Herba Dianthi, Herba Plantaginis, Pericarpium Arecae, Rhizoma Smilacis Glabrae, processed Radix Aconiti, Rhizoma Zingiberis, Cinnamomun cassia, Herba Asari, Fructus Evodiae, Radix Aconiti Kusnezoffii, Citrus Reticulata, Fructus Auranti Immaturus, Citrus medica, Cyperus Rotundus,Wuyao, Fructus Toosendan, Caulis Perillae, Massa Medicata Fermentata, Fructus Hordei Germinatus, Fructus Crataegi, Semen Raphani, Herba seu Radix Cirsii Japonici, Herba Cephalanoploris, Radix Sanguisorbae, Sophora Japonica, Thuja orientalis, Herba, Agrimoniae, Radizoma Bletillae, Pollen Typhae, Radix Notoginseng, Radix Sangyisorbae, Rhizoma Chuanxiong, Olibanum, Myrrha, Rhizoma Corydelis, Radix Curcumae, Rhizoma Curcumae, Rhizoma Sparganii, Radix Salviae Miltiorrhizae, Herba Leonuri, Semen Persicae, Flos CArthami, Faeces Trogopterori, Achyranthes Bidentata Blume, Cyathula Officinalis Kuan, Squama Manitia, Lignum Dalbergiae Odoriferae, Fructus Liquidambaris, processed Rhizoma Pinelliae, Rhizoma Pinelliae, Rhizoma Arisaematis, Rhizoma Typhonii, Radix Aconiti Coreani, Radix Platycodi, Flos Inulae, Bulbus Fritillariae Thunbergii, Rhizoma Cynanchi Stauntonii, Fructus Trichosanthis, Bulbus Fritillariae Cirrhosae, Caulis Bambusae in Taeniam, Bitter Apricot Kernel, Sargassum Fusiforme, Radix Stemonae, Radix Stemonae, Loquat leaf, Radix Scutellariae, Sangbaipi, Semen Lepidii, Stir-baked Flos Farfarae, Radix Peucedani, Ferrosoferric Oxide, Os Draconis Fossilia, Semen Ziziphi Spinosae, Semen Biotae, Radix Polygalae, Cortex Albiziae, Radix Codonopsis, Radix Pseudostellariae, Radix Astragali, Rhizoma Atractylodis Macrocephalae, Rhizoma Dioscoreae, Glycyrrhiza Uralensis, Radix Panacis Quinquefolii, Ziziphus Jujuba, Radix Morindae Officinalis, Herba Cistanches, Rhizoma Curculiginis, Herba Epimedii, Cortex Eucommiae, Radix Dipsaci, Rhizoma Cibotii, Rhizoma Drynariae, Fructus Psoraleae, Frucyus Alpiniae Oxyphyllae, Cuscuia Japonica, Herba Cynomorii, Radix Angelicae Sinensis, Rehmannia glutinosa, Radix Polygoni Multiflori, Radix Paeoniae Alba, Radix Ophiopogonis, Herba Dendrobii, Bulbus lilii, Fructus Lycii, Herba Ecliptae, Ligustrum Lucidum, Radix Glehniae, Rhizoma Atractylodis Macrocephalae, Fructus Schisandrae, Fructus Tritici Levis, Radix Oryzae Glutinosae, Radix Ephedrae, Fructus Corni, Fructus Rosae Laevigatae, Fructus Rubi, Concha Arcae, Folium Ginseng, Radix Adenophorae.

Author Contributions

QW designed the study and wrote the article. HY and QW performed the literature database search, data collection, extraction, and assessment of evidence quality. Q-qW and W-tL performed data analysis and rationalization of the results. B-bY helped with improving the writing of the manuscript. Y-mB and G-hX supervised all aspects of the study.

Funding

This study was supported by the Nursing Advantageous Discipline Construction Project in Nanjing University of Chinese medicine, Jiangsu Province (2019YSHL017).

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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