Nowadays, cancer imposes a major threat to human lives with high incidence and mortality. There were about 24.5 million cancer incident cases and 9.6 million deaths around the world in 2017 [
As an integral component of traditional Chinese medicine (TCM), acupuncture-moxibustion therapy is one of the most popular methods for complementing medicines in China and other East Asian countries. It is an external therapy to prevent and treat disease by stimulating particular acupoints on the human body with special needles or burning moxa [
This systematic review and meta‐analysis was performed in line with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) schema and was registered at PROSPERO under registration number CRD42020152517 [
A comprehensive search was carried out in PubMed, Embase, Scopus, Web of Sciences, the Cochrane Library (CENTRAL), and four Chinese databases (Chinese Biomedical Database, Chongqing VIP Information, China National Knowledge Infrastructure, and WanFang Data) from their inception up to September 19, 2020 without language limitation. The search strategy consisted of Medical Subject Heading (Mesh) terms and free-text terms with logical operators. We performed an initial search of PubMed as follows: “Neoplasms” (Mesh) AND “Drug Therapy” (Mesh) AND “Leukopenia” (Mesh) AND “Acupuncture Therapy” (Mesh) AND “Moxibustion” (Mesh). The exploration of grey literature and hand-checking of key journals were completed to identify potentially relevant trials [
Studies were eligible in this meta-analysis, which met the following criteria. Study participant: the patient undergoing chemotherapy and diagnosed with leukopenia under clear criteria: (i) the total number of leukocytes remained below 4.0 or (ii) WHO grading standards. Study intervention: the patient in the experimental group was treated with acupuncture-moxibustion therapy. There were no restrictions on the selection of acupuncture points and the course of treatment. Comparison treatment: (i) conventional leukocyte-enhancing drugs (e.g., leucogen tablets, berbamine hydrochloride tablets, and rhG-CSF injection) or (ii) no comparator treatment. Study outcome: (i) primary measures: leukocyte count and total effective rate. Total effective rate = markedly effective + effective. Markedly effective: the count of leukocyte recovers to a normal value of 4.0 × 109/L; effective: although the leukocyte count did not return normal, it increased (0.5∼1.0) × 109/L; and invalid: no significant change in leukocyte count. (ii) Secondary measures: Karnofsky’s index of performance status. Study design: randomized controlled trial. Additionally, the exclusion criteria included the following: (i) full-text not be obtained; (ii) incomplete data and the unclear outcome effect; (iii) duplicate publication; and (iv) case report, expert experience, review article, and other nonrandomized control trials.
After deleting the duplications, two reviewers (HMJ and YTZ) independently screened the title and abstract of studies according to the inclusion and exclusion criteria. Then, a full-text screening was performed by the same two reviewers. Any disagreement during study selection was resolved by consulting a third senior reviewer (YYX).
We designed a data extraction sheet to record related characteristics from the included articles, including diagnostic criteria, sample size, outcome measures, and treatment details. This was performed and proofread after completion by two authors (HMJ and YTZ) independently to ensure the accuracy of the extracted data. And then, they continued to assess the quality of included studies. The methodological quality was evaluated using the Cochrane risk of bias tool to assess the risk of bias in each included trial. The contents include six domains: random sequence generation, allocation concealment, blinding, integrity of outcome data, selective reporting, and other bias. Each item was rated three levels as low risk, high risk, and uncertain risk for insufficient information. Any disagreement in the assessment process was resolved through the third reviewer (YQF).
All statistical analyses were performed using Review Manager software (version 5.3, Cochrane Collaboration, 2014, Copenhagen, Denmark). The risk ratios (RR) along with the corresponding 95% confidence intervals (95% CI) were calculated for dichotomous data, and mean differences (MD) with 95% CIs were calculated for continuous data. Statistical heterogeneity between studies was assessed by the
The database and manual searches yielded 3435 potentially relevant records, of which 849 were duplicates. Following two rounds of screening, 17 publications were identified in quantitative synthesis [
PRISMA flow diagram for literature search and study selection.
A total of 17 trials with 1206 participants were selected and varied widely in sample size (32–160 participants). All the included studies were conducted in China and published from 2010 to 2019. All patients fulfilled the diagnostic criteria of chemotherapy-induced leukopenia, with one study only confirmed in the title and abstract. Twelve studies adopted acupuncture therapy, while five studies relied on moxibustion therapy as the treatment of CIL. The primary outcome measures, i.e., the leukocyte count or clinical efficacy, could be obtained in all studies. The main characteristics and the specific interventions of each identified study are presented in Table
Characteristics of included studies.
No. | Study ID | Diagnostic criteria | Number (T/C) | Age, years (T/C) | Interventions | Outcomes | |||
---|---|---|---|---|---|---|---|---|---|
Control group | Treatment group | Duration | Adverse events | ||||||
1 | Lin et al. [ | The total number of leukocytes remained below 4.0 | 20/19 | 52.1 ± 7.65/53.7 ± 6.14 | Oral medicine (leucogen tablets) | Acupoint injection at ST36 with Shenmai injection | 1× per day for 21 days (21 total) | Not mentioned | TER |
2 | Wang [ | The total number of leukocytes remained below 4.0 | 20/18 | 55.35 ± 9.73/54.80 ± 8.15 | Oral medicine (blood increasing pill) | Moxibustion at ST36, CV4, and CV6 | 1× per day for 7 days (7 total) | No local scalds and no allergies or discomfort caused by other treatments during and after treatment | LC, TER, and KI |
3 | Fan [ | The total number of leukocytes remained below 4.0 | 30/30 | 57.72 ± 12.09/61.59 ± 12.78 | Intravenous drip of Shenqi Fuzheng injection | Ginger moxibustion at GV14, BL20, BL23, BL17, CV12, CV14, and CV4 for 4 moxa cone | 1× per day for 10 days (10 total) | A total of 4 cases of adverse events occurred (two were intolerable to moxa smoke, one had blisters from moxibustion, and one treated middle back pruritus). | LC |
4 | Lu et al. [ | WHO grading standards | 30/30 | 30–76/40–75 | Intravenous drip of granisetron hydrochloride injection | Intravenous drip of granisetron hydrochloride injection + acupoint injection at ST36 with Aidi injection | ND | Not mentioned | LC |
5 | Yang [ | The total number of leukocytes remained below 4.0 | 27/30 | 56.04 ± 10.98/54.10 ± 11.02 | rhG-CSF injection | rhG-CSF injection + moxibustion with warming needle at ST36, BL17, CV4, and CV6 | 1× per day for 7 days (7 total) | No signs of infection | LC and TER |
6 | Fu et al. [ | The total number of leukocytes remained below 4.0 | 38/38 | 55–79; mean: 61.5 ± 8.9 | Oral medicine (leucogen tablets and batilol tablets) | Moxibustion with warming needle at ST36, SP6, SP9, SP10, GV14, BL20, PC6, CV4, and CV6 | 1× per day for 14 days (14 total) | Not mentioned | TER |
7 | Wang et al. [ | WHO grading standards | 37/35 | 54.24 ± 7.89/51.25 ± 8.97 | Oral medicine (leucogen tablets and batilol tablets) | Moxibustion at ST36, SP6, SP10, CV4, and CV8 for 4 moxa cone | (1× per day for 14 days, rest 7 days) | Not mentioned | LC and TER |
8 | Zhang [ | The total number of leukocytes remained below 4.0 | 16/16 | 60.06 ± 7.54/61.38 ± 8.40 | rhG-CSF injection | Moxibustion with seed-sized moxa cone at ST36 and GV14 for 9 moxa cone | 1× per day | ND | LC and TER |
9 | Tian [ | WHO grading standards | 34/34 | 32–76; mean: 51.6 ± 4.3 | Oral medicine (leucogen tablets and batilol tablets) | Moxibustion at ST36, CV4 and CV6 for 15 minutes | 1× per day for 14 days (14 total) | Not mentioned | LC |
10 | Hu [ | The total number of leukocytes remained below 4.0 | 30/30 | 1.30 ± 9.64/52.03 ± 8.87 | Oral medicine (batilol tablets) or subcutaneous injection of rhG-CSF injection | Oral medicine (batilol tablets) or subcutaneous injection of rhG-CSF injection + acupuncture at ST36, SP6, SP10 and BL23 for 30 minutes | 1× per day for 5 days (5 total) | Not mentioned | LC and TER |
11 | Zhu [ | The total number of leukocytes remained below 4.0 | 40/38 | 47 ± 16/46 ± 14 | Oral medicine (batilol tablets) or subcutaneous injection of rhG-CSF injection | Oral medicine (batilol tablets) or subcutaneous injection of rhG-CSF injection + acupuncture at ST36, SP6, BL18, BL23, CV4, and SP10 | 1× per day for 5 days (5 total) | ND | LC and TER |
12 | Chen and Xu [ | Definitive diagnosis without basis | 52/50 | 38–72/37–70 | Oral medicine (leucogen tablets and berbamine hydrochloride tablets) | Oral medicine (leucogen tablets and berbamine hydrochloride tablets) + moxibustion at ST36 for 15 minutes | 1× per day for 7 days (7 total) | No adverse events found | LC and TER |
13 | Mo et al. [ | WHO grading standards | 41/41 | 55 ± 10/56 ± 10 | Oral medicine (leucogen tablets and batilol tablets) | Moxibustion at ST36, CV4, CV6, and CV8 for 20 minutes | 6× per week for 3 weeks (18 total) | Not mentioned | LC, TER, and KI |
14 | Nie [ | The total number of leukocytes remained below 4.0 | 24/24 | 49.09 ± 8.01/51.2 ± 6.04 | rhGM-CSF Injection | Moxibustion at GV14, CV4, CV8, BL17, BL20, and BL23 | 1× per day for 10 days (10 total) | Not mentioned | LC and TER |
15 | Wang [ | The total number of leukocytes remained below 4.0 | 36/36 | 57.21 ± 7.37/57.30 ± 8.37 | Oral medicine (Shenqi tablets) | Acupoint injection at ST36 with Shenfu injection | 1× per day for 7 days (7 total) | No obvious adverse events such as skin rashes and allergies during the study | LC and KI |
16 | Gong et al. [ | WHO grading standards | 50/50 | 4.17 ± 5.71/51.49 ± 6.27 | Oral medicine (batilol tablets and vitamin B4 tablets) | Ginger moxibustion at CV4, CV6, and CV8 | 1× per day for 10 days (10 total) | Not mentioned | LC, TER, and KI |
17 | Li et al. [ | The total number of leukocytes remained below 4.0 | 80/80 | 8.35 ± 9.27/66.70 ± 12.13 | Subcutaneous injection of rhG-CSF injection | Subcutaneous injection of rhG-CSF injection + moxibustion at ST36, CV4, CV6, BL23, and GV4 | 1× per day for 14 days (14 total) | Not mentioned | LC |
WHO, World Health Organization; T, treatment group; C, control group; rhG-CSF, recombinant human granulocyte colony-stimulating factor injection; rhGM-CSF, recombinant human granulocyte/macrophage colony-stimulating factor injection; ND, not determined; LC, leukocyte count; TER, total effective rate; KI, Karnofsky’s index.
Figure
Risk of bias graph.
Thirteen studies involving 873 participants reported the total effective rate [
Forest plot of dichotomous data outcomes: total effective rate.
Subgroup analysis was performed based on different AMT types.
The leukocyte count was recorded in 15 studies [
Forest plot of dichotomous data outcomes: leukocyte count.
Subgroup analysis was performed based on the different duration of treatment.
Four studies [
Forest plot comparing living quality between the AMT group and the control group.
Safety outcome refers to the adverse events, such as allergic reaction, local responses (rash and scald), liver, and kidney injury, during the study. Among the conducted trials, safety outcomes were mentioned in five studies [
To evaluate the robustness of pooled results, we performed the sensitivity analysis by omitting each study sequentially. Under the leave-one-out approach analysis, our results did not change noticeably.
Publication bias was observed visually using funnel plot analyses. In this meta-analysis, the funnel plot for the total effective rate shaped with bilateral symmetry, indicating a lack of publication bias (Figure
Funnel plot for assessing publication bias.
As the meta-analysis reveals, acupuncture-moxibustion therapy could be an alternative treatment for chemotherapy-related leukopenia. From the clinical perspective, AMT could indeed increase the number of leukocyte and improve health status. Furthermore, there were almost no serious adverse events and treatment-related safety issues. We conducted subgroup analyses for each primary outcome, and the results suggested that different choices of AMT types and duration of treatment might be sources of heterogeneity. Based on our summaries about specific interventions of included studies, the most commonly used acupoints in treating CIL were Zusanli (ST36) and Guanyuan (CV4).
Chemotherapy-induced leukopenia is regarded as a potential serious adverse event, defined as white blood cell (WBC) count less than 4.0 × 109/L during the course of chemotherapy. Patients with CIL typically present symptoms of loss of appetite, fatigue, insomnia, and dizziness. Based on the theory of traditional Chinese medicine (TCM), CIL belongs to the category of consumptive disease, owing to the exhaustion of genuine qi in the zang-fu viscera and the insufficiency of kidney essence and qi-blood. Researchers believe that there is an intimate association between the occurrence of malignant tumors and the deficiency of genuine qi. During attacking the cancer cells, chemotherapeutics also damaged the function of zang-fu viscera and qi-blood, leading to CIL. According to the theory of TCM and meridian, acupuncture-moxibustion is an ancient therapeutic modality that may be traced back more than 3500 years in China. Through meridian conduction, acupuncture-moxibustion therapy stimulates acupoints to strengthen the condition of zang-fu viscera and immune function, supporting genuine qi to improve symptoms of consumption. At the same time, some studies have attempted to further explore the molecular biological mechanism of acupuncture-moxibustion for relieving chemotherapy-induced leukopenia. By increasing the level of serum GM-CSF and G-CSF, acupuncture-moxibustion could prompt the proliferation and maturation of marrow hematopoietic cells, which favor the recovery of hematopoiesis function and reduce myelosuppression from chemotherapeutic agents [
To the best of our knowledge, the present systematic review and meta-analysis is the first study on the effect and safety of AMT in treating CIL. Distinguished from the previous study [
First, even though comprehensive literature search was performed, we only identified studies published in Chinese. So, the potential language bias might be caused. Second, there were no uniform standards for the selection of acupoints of patients with leukopenia after chemotherapy. By combining experience in clinical practice, clinicians might have preferences for different acupoints regimens. Finally, the methodological quality of included trials was deemed weak to moderate. Hence, interpretations of our findings should be taken with caution.
With the above limitations, more multicenter randomized clinical trials with rigorous design should be conducted to clarify the efficiency and safety of acupuncture-moxibustion therapy in CIL. Meanwhile, the most optimal regimen of acupoint selection for CIL treatment needs to be investigated in future research. Besides, further studies with extended follow-up periods are required to determine the long-term efficacy and benefits of AMT in CIL.
In summary, this is an updated systematic review and meta-analysis, revealing that the AMT, as a nonpharmaceutical intervention, could be an effective and safe alternative for patients undergoing CIL. Despite limitations, the study provides the direction and basis for future research. High-quality randomized controlled trials are warranted to further validate current results, offering more confident conclusions for clinical practices.
All articles retained for this review were made available to the public through PubMed, Embase, the Cochrane Library, Scopus, Web of Sciences, Chinese BioMedical Database, Chongqing VIP Information, China National Knowledge Infrastructure, and WanFang Data. All data analysed in this study are included in the published articles.
The funding organizations played no role in the design of the study and data collection, analysis, or interpretation. They also were not involved in the writing of the manuscript.
The authors declare that they have no conflicts of interest.
This work was supported by the National Natural Science Foundation of China (No. 81573902) and Zhejiang Provincial Project for the Key Discipline of Traditional Chinese Medicine (Yong Guo, No. 2017-XK-A09,