Comparative efficacy of moxibustion in chemotherapy-induced leukopenia: A Bayesian network meta-analysis.

Introduction

According to the Global Cancer Statistics Report 2020, cancer ranks as the first or second leading cause of death in 112 countries. 1 Chemotherapy is among the most effective therapeutic approaches for treating cancer, but it is associated with adverse reaction that can lead to dose reductions, delays, and other treatment interruptions, 2 as well as weakness and inappetence in patients. For example, chemotherapy-induced leukopenia is a common side effect that can trigger neutropenia and febrile neutropenia in 10 %–20 % of those undergoing standard chemotherapy regimens. 3 In an extensive study of adjuvant chemotherapy for breast cancer, leukopenia-neutropenia led to a mean relative dose reduction of <85 % in the majority (58 %) of patients. 4 Timely treatment or prevention of leukopenia thus is essential for ensuring proper chemotherapy dosage and completion.

Many treatments that are effective for neutropenia and febrile neutropenia often have significant side effects or prohibitive costs. For example, primary prophylaxis using granulocyte colony-stimulating factor (G-CSF) can reduce the duration and severity of neutropenia and the risk of febrile neutropenia. 5 However, G-CSF has many adverse effects, including joint pain, flu-like symptoms, aortitis, and splenic rupture, 6 , 7 , 8 , 9 and its high cost increases the financial burden on patients. 10 Additionally, G-CSF should be used cautiously in therapies relying on activating T cells, as T cells are often inhibited by G-CSF-mobilized myeloid cells. 11 Cost-effectiveness analyses suggest that primary prophylaxis with G-CSF can reduce management costs by lowering FN occurrences. Long-acting G-CSF therapies may be more effective than short-acting ones, but the high cost limits their feasibility in countries with less developed economies. 12

Moxibustion has been used in China and other East Asian countries for thousands of years. The technique involves burning moxa to act on acupuncture points and produce effects through warm stimulation. It has been shown to improve the quality of life of cancer patients by reducing cancer-related pain and fatigue, 13 , 14 , 15 as well as gastrointestinal issues and other adverse reactions to chemotherapuy. 16 In a rat model, moxibustion has been shown to increase peripheral blood leukocytes in subjects treated with cyclophosphamide and to enhance macrophages' ability to induce granulocyte-macrophage colony-stimulating factor (GM-CSF), promoting rapid proliferation of hematopoietic stem/progenitor cells. 17 As a low-cost and easy-to-use alternative, moxibustion is a viable supplementary therapy that warrants further research.

Numerous clinical trials have explored the effects of moxibustion techniques, such as suspended moxibustion, ginger moxibustion, and grain-sized moxibustion, on chemotherapy-induced leukopenia. A meta-analysis by Choi et al. confirmed its therapeutic benefits in this setting. 18 However, the analysis lacks direct comparisons of clinical efficacy across different techniques, relying instead on single studies or limited evidence. To address this gap and clarify guidance for practitioners, a systematic evaluation of various moxibustion methods is needed to determine the relative effectiveness rates and provide robust evidence for clinical decision-making. Network meta-analysis is a powerful tool that can synthesize direct and indirect evidence and rank interventions based on comparative efficacy rates. Given the wide range of moxibustion techniques and the critical need for effective treatments for chemotherapy-induced leukopenia, applying this type of meta-analysis in this context has both theoretical and practical significance. This study systematically compared the efficacy of various moxibustion methods (suspended, ginger, and grain-sized) in treating chemotherapy-induced leukopenia. The results offer high-quality, evidence-based insights to inform and enhance clinical treatment strategies.

Methods

This network meta-analysis was conducted according to a prospectively registered protocol (PROSPERO CRD42023402588). This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension statement for reporting network meta-analyses. 19 See Supplement 1 for details of the PRISMA Network Meta-analysis Checklist of Items.

Data sources and search

Data sources included PubMed, Medline, Embase, Web of Science, Cochrane Central, China National Knowledge Infrastructure, SinoMed, Wanfang Database, and China Science and Technology Journal Database, as well as the Chinese Clinical Trial Registry. The search period for each database spanned from its inception until January 1, 2024. No restrictions were placed on date, year, or publication status. See Supplement 2 for a detailed description of the comprehensive search strategy.

Eligibility criteria

All randomized controlled trials (RCTs) involving moxibustion for patients with chemotherapy-induced leukopenia were included. Intervention types included suspended, herb-separated, direct, ginger, grain-sized, heat-sensitive, thunder-fire, and other moxibustion therapies, either alone or in combination with Western medication. No restrictions were placed on the selection of acupoints or duration of treatment. For the control group, eligible studies included those involving sham moxibustion, conventional treatment, comparisons of different moxibustion methods, or simple medication. Studies on moxibustion combined with any other traditional Chinese medicines (either related to chemotherapy or external) or with other acupuncture-related interventions (e.g., acupoint injection, electroacupuncture) were excluded.

Outcomes

The primary outcome was white blood cell (WBC) count, which was objectively evaluated by the degree of leukopenia and then used to assess the biological side effects of chemotherapy. The secondary outcome was the Karnofsky performance status (KPS) score, developed by the Eastern Cooperative Oncology Group to assess patients' quality of life by measuring their physical capacity in terms of movement, self-care ability, and disease condition. 20 The KPS score ranges from 0 to 100 points (10 points per level), with higher scores indicating better health, tolerance of treatment side effects, and likelihood of completing therapy. A score below 60 indicates that many prospective anti-cancer measures would be more challenging to implement.

Study selection and data extraction

Two independent investigators (Chunlan Chen and Wenge Huo) used EndNoteX9 to screen titles, abstracts, and full texts and to exclude ineligible studies. Data extraction was conducted independently by the same authors using a structured form. Study characteristics (publication year, country, and number of participants enrolled) were extracted, as well as participant characteristics (age, sex, and other baseline characteristics), intervention characteristics (acupoints for therapy, duration, and co-interventions), and outcomes. Any disagreements in judgment regarding trial inclusion or data collection were resolved through discussion with a third investigator (Xiaoyan Li).

Quality assessment

The quality of the included trials was evaluated using the Cochrane risk-of-bias tool (RoB 2.0) to assess bias in RCTs arising from 1) the randomization process; 2) deviations from intended interventions; 3) missing outcome data; 4) measurement of the outcome; and 5) selection of the reported result. Two investigators (Zunyuan Li and Zhidan Liu) independently conducted the assessment, and disagreements were discussed and resolved through consensus. Only trials with a low risk of bias in all five domains above were classified as having an overall low risk. Trials for which one or more domains had some or high risk were classified as high risk.

Statistical analysis

Bayesian network analyses were performed using the gemtc package (version 1.0–0), netmeta, ggplot2, and other tools from R (version 4.3.1) and JAGS (version 4.3.1). The network plot command of Stata (version 17.1) was used to create the network plots, with nodes representing the compared interventions and edges representing the available direct comparisons. 21

A Bayesian random effect network meta-analysis was performed to compare the relative effectiveness of different moxibustion therapies. 22 To do so, 50,000 stimulation iterations were performed using four Markov chains with one thinning interval and 20,000 tuning iterations. A final convergence diagnostic diagram showed the scatter plot of posterior sample values generated by the Markov chain against the number of iterations. If these scatter plots became stable and overlapped after several iterations, the algorithm was assumed to be converged. A league table was simultaneously generated to quantify the network meta-analysis results.

Ranking probabilities were calculated for all treatment options using ggplot2 in R Studio to create a line graph of the surface under the cumulative ranking (SUCRA) and perform probability ranking, making the data easier to visualize. SUCRA values closer to 0 indicated poor therapeutic effect and those closer to 1 indicated a better therapeutic effect.

Funnel plots were constructed, and the Egger test was performed to detect risk of publication bias. Asymmetry in the funnel plots was associated with an increased risk of publication bias. Ideally, each study should be uniformly distributed on both sides of the vertical line, with larger-sample studies clustered at the top and smaller-sample studies scattered at the bottom. Truncation in the funnel plot could indicate publication bias, whereas circles falling outside the funnel plot's slant line (the 95 % confidence interval) implied potential heterogeneity.

Results

Study characteristics

This meta-analysis involved an extensive database search that initially identified 1639 potentially relevant articles in the data imported into EndNote X9 software. After meticulous screening, 749 duplicate studies were removed. Another 750 (436 non-RCTs, 105 with an incongruent population, 164 with incompatible interventions, 19 with incongruent controls, 11 with inconsistent outcome indicators, and 15 on unrelated topics) were excluded during the title and abstract screening phase. Of the remaining 140 articles, 30 were included for quantitative synthesis meta-analysis after reading the full text. Fig. 1 illustrates t he literature screening process. Table 1 summarizes the aggregated characteristics of the included 30 RCTs 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 comprising 2282 total participants.

All studies identified for the outcome indicators were two-arm studies. Of the 15 included RCTs, 12 involved moxibustion-related therapies such as suspended (SMo), herb-separated (HMo), direct (DMo), ginger (GMo), grain-sized (GSMo), heat-sensitive (HSMo), thunder-fire (TFMo), suspended combined with medication (SMo+ M ), ginger combined with medication (GMo+ M ), grain-sized combined with medication (GSMo+ M ), heat-sensitive combined with medication (HSMo+ M ), and thunder-fire combined with medication (TFMo+ M ). Three control studies involved medication (M), sham moxibustion (ShMo), and conventional (Conv) treatments. See the Box 1 for a summary.

Risk of bias

A bias assessment of 30 articles was conducted using the Cochrane Collaboration risk of bias tool, ROB version 2.0, which revealed seven trials (23.3 %) at high risk of bias and only one at low risk. One reason for the bias identified could be a lack of blinding of either the participants and the people delivering the interventions, which could lead to deviations from the intended interventions. 53 Fig. 2 and Supplement 3 show the results.

Of the 19 articles mentioning a specific randomization, 24 , 27 , 30 , 32 , 33 , 34 , 35 , 36 , 39 , 40 , 41 , 42 , 43 , 45 , 46 , 47 , 49 , 51 , 52 only four mentioned allocation sequence concealment. 24 , 32 , 36 , 47 As it is difficult to achieve blindness in RCTs related to moxibustion treatment, participants and intervention implementers in most of the studies analyzed were aware of participants’ assigned interventions. Given the objectivity of hematologic measures, assessors of studies using WBC count as an outcome indicator were considered to be blind. Supplement 3 provides more detailed information on the risk of bias assessment.

Network meta-analysis

The convergence evaluation showed that the potential scale reduction factor (PSRF) value was close to 1, indicating stable and consistent results. Therefore, the Markov chain-Monte Carlo (MCMC) fitting consistency model was used for analysis. All analyses were run using four Markov chains with 50,000 iterations after an initial burn-in of 20,000 and a thinning interval of 1. Convergence was monitored using trace plots (see Supplement 4).

Primary outcome

Fig. 3 A shows the network plots of various moxibustion therapies. Nodes reflect various intervention measures, node sizes represent sample capacity, and line thickness denotes the number of studies. Lines connecting two treatments represent direct comparisons between two interventions, with thicker lines representing a larger number of studies for the two treatments and larger nodes representing a larger sample size. Twenty-seven RCTs (2,074 total participants and 11 moxibustion therapies) were associated with the primary outcome. Among the primary outcome indicators, the most common comparison was between suspended moxibustion and conventional treatment, 24 , 29 , 32 , 49 followed by ginger moxibustion and medication. 39 , 41 , 48

According to the SUCRA values, thunder-fire moxibustion combined with medication (SUCRA: 95.9 %) ranked first as the optimal treatment for chemotherapy-induced leukopenia, followed by grain-sized moxibustion combined with medication (76.2 %) and herb-separated moxibustion (76.0 %). Fig. 4 A and Supplement 5 summarize the results.

As shown in Table 2 A , compared to therapies involving medication alone, most moxibustion therapies showed better efficacy, including thunder-fire combined with medication (MD = 2.79, 95 % CI: 1.27∼4.31), grain-sized combined with medication (MD = 1.68, 95 % CI: 0.11∼3.24), herb-separated (MD = 1.53, 95 % CI: 0.51∼2.55), suspended (MD = 0.97, 95 % CI: 0.19∼1.76), heat-sensitive (MD = 1.26, 95 % CI: 0.32∼2.24), and ginger (MD = 0.87, 95 % CI: 0.12∼1.64), all of which demonstrated statistically significant improvements in WBC levels. Compared to conventional treatment, thunder-fire combined with medication (MD = 2.78, 95 % CI: 1.05∼4.49), herb-separated (MD = 1.52, 95 % CI: 0.59∼2.43), direct (MD = 1.51, 95 % CI: 0∼3.03), suspended (MD = 0.95, 95 % CI: 0.26∼1.64), and ginger (MD = 0.86, 95 % CI: 0.03∼1.69) moxibustion therapies revealed statistically significant differences. The intervention comparison showed that thunder-fire moxibustion combined with medication was better than ginger moxibustion combined with medication, grain-sized moxibustion, ginger moxibustion, and suspended moxibustion. There was no statistically significant difference between the other therapies.

Secondary outcome

Eight RCTs involving seven total moxibustion therapies reported data on KPS scores for 662 total participants with chemotherapy-induced leukopenia (see Fig. 3 B). For the secondary outcome measure, most comparisons were between conventional treatment and thunder-fire moxibustion. 45 , 46 No significant difference in KPS score was observed between those receiving different moxibustion treatments, as shown in Table 2B Regarding SUCRA values, grain-sized moxibustion combined with medication (76.5 %) ranked first as the optimal treatment for improving KPS scores of patients with chemotherapy-induced leukopenia, followed by thunder-fire (71.1 %) and heat-sensitive (67.7 %) moxibustion, as shown in Fig. 4 B and Supplement 5.

Adverse events

Nine articles mentioned adverse reactions, 25 , 31 , 32 , 34 , 36 , 44 , 45 , 46 , 47 , 50 , 51 , 52 including skin allergy, but no serious reactions (e.g., scalds, blisters, local skin infections) were observed.

Network heterogeneity and publication bias

A random-effects model was used for the network meta-analysis of all outcome indicators. The heterogeneity assessment found I² = 90.61 %, indicating high global heterogeneity in the direct comparisons. However, the limited number of studies and lack of detailed descriptions made it difficult to investigate heterogeneity in the source subgroup analysis. Supplement 6 shows the results. The inconsistency assessment between direct and indirect comparisons using a node-splitting model showed no significant inconsistencies among most studies ( P > 0.05; see Supplement 7). Publication bias was assessed using a funnel plot ( Fig. 5 ); Egger's tests indicated no potential publication bias ( P > 0.05).

Discussion

Main findings

This meta-analysis identified three moxibustion-based therapies that have been found to improve chemotherapy-induced leukopenia in patients undergoing cancer treatment: thunder-fire moxibustion combined with medication, grain-sized moxibustion combined with medication, and herb-separated moxibustion. It also identified three potentially effective interventions for improving KPS scores: grain-sized moxibustion combined with medication, thunder-fire moxibustion, and heat-sensitive moxibustion.

Thunder-fire moxibustion showed positive effects on both leukopenia and KPS scores. This moxibustion therapy differs from typical moxibustion treatment in that the moxa sticks are made by mixing aromatic herbal powders, such as musk and Chinese eaglewood with moxa floss. 54 Researchers for the cited study hypothesized that thunder-fire moxibustion stimulated local nerve terminals after acting on acupoints, thereby regulating the physiological activities of viscera through reflexes and nervous system conduction and enhancing the body's immunity. 34 Other research has shown that grain-sized moxibustion may repair damaged bone marrow in mice after cyclophosphamide-based chemotherapy. 55 This finding is consistent with results of this meta-analysis showing that grain-sized moxibustion could improve leukopenia, KPS scores, and quality of life for patients. The reported adverse events primarily included minor and short-lived skin allergy, and no serious adverse reactions were reported.

Heterogeneity

Our findings revealed significant overall heterogeneity among the direct comparisons, aligning with initial observations about methodological differences among the included studies. This heterogeneity stemmed primarily from inconsistencies in how studies implemented blinding and concealed participant allocation. Despite this methodological variation, the consistency analysis across direct and indirect comparisons indicated reliable overall findings.

Strengths and limitations

Moxibustion can be a long-term adjuvant of chemotherapy to improve the quality of life of those undergoing cancer treatment. Due to their various action modalities, different moxibustion techniques have different efficacy and therapeutic mechanisms. 56 , 57 The results of this network meta-analysis showed that most moxibustion treatments outperformed conventional treatments for chemotherapy-induced leukopenia, consistent with findings from previous meta-analyses. 13 , 58 This study contributes important insights into the potential role of moxibustion as a supportive treatment for chemotherapy-induced leukopenia, particularly highlighting differences among various moxibustion techniques. It addresses a gap in existing literature by systematically comparing these therapies, identifying thunder-fire moxibustion as particularly promising. This fills a knowledge gap left by earlier studies that did not compare multiple moxibustion techniques directly.

However, this study has several limitations. Firstly, methodological issues such as inadequate blinding and unclear allocation concealment were common among included studies, potentially introducing bias. Only four trials 24 , 32 , 36 , 47 clearly reported adequate allocation concealment, suggesting the possibility of selection bias. Secondly, the secondary outcome measure—quality of life (KPS score)—is subjective and thus vulnerable to measurement bias, limiting the strength of conclusions regarding moxibustion’s impact on quality of life.

Third, despite extensive searches across multiple databases, all the included trials were conducted in China, limiting the diversity and possibly affecting the generalizability of findings internationally. Additionally, significant variability was noted in the types of cancers treated, chemotherapy regimens, acupoints, duration, and intensity of moxibustion therapies across studies. This clinical heterogeneity may influence the reliability and applicability of the results. Finally, although the analysis indicated no obvious publication bias, the small number of studies meeting the inclusion criteria could have increased the risk of bias.

Future researchers should adhere to CONSORT reporting guidelines and eliminate implementation and measurement bias to improve reporting quality and reliability. Future research also should address this study's limitations by improving their study designs, particularly regarding aspects of randomization, allocation concealment, and blinding, to reduce bias and enhance reliability. Expanding to multicenter studies in diverse international contexts is essential to confirm the generalizability and effectiveness of moxibustion therapies. Standardizing intervention protocols, including acupoint selection, treatment duration, and moxibustion techniques, also can improve consistency and comparability across studies. Investigating the biological mechanisms underlying different moxibustion methods could clarify how each alleviates leukopenia and improves KPS scores, providing a stronger foundation for clinical application. Finally, future studies should evaluate a wider range of secondary outcomes and include longer follow-up periods to better understand the long-term safety and efficacy of moxibustion and ensure its potential benefits are thoroughly documented.

Conclusion

The results suggest that compared to conventional treatment, various moxibustion therapies offer more benefits in treating chemotherapy-induced leukopenia. Thunder-fire moxibustion combined with medication, grain-sized moxibustion combined with medication, and herb-separated moxibustion showed the highest efficacy rates for treating leukopenia. In terms of enhancing KPS scores, grain-sized moxibustion combined with medication may have the strongest therapeutic effect. However, no significant difference between the various moxibustion methods was observed due to the small number of included studies. Well-designed and large-scale studies should be conducted to confirm our conclusions.

Author contributions

Zun-Yuan Li : Conceptualization, Data curation, Formal analysis, Methodology, Software, Validation, Writing – Original Draft. Chun-Lan Chen : Data curation, Investigation, Software, Visualization. Xiao-Yan Li : Data curation, Validation. Wen-Ge Huo : Data curation, Investigation. Yan Yang : Writing – Review & Editing. Yu-Hong Guo : Writing – Review & Editing. Zhi-Dan Liu : Conceptualization, Data curation, Funding acquisition, Validation, Supervision, Writing – Review & Editing.

Declaration of competing interest

The authors declare that they have no conflicts of interest.

Funding

This research was supported by the National Natural Science Foundation of China (Grant number 82174481) and Baoshan District Health Commission Talents (Excellent Academic Leaders) Program(BSWSYX-2024–02) and Cultivation Project Class B in Keynote Medical Disciplines and Characteristic Brands, Health Commission of Baoshan District, Shanghai (BSZK-2023-BP07) and 2024 Science and Technology Development Project of Shanghai University of Traditional Chinese Medicine (24KFL039).

Ethical statement

No ethical approval was required as this study did not involve human participants or laboratory animals.

Data availability

The data that support the findings of this study are included in the article.

Footnotes

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.imr.2025.101145 .

Supplementary materials

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Supplementary Materials

Data Availability Statement

The data that support the findings of this study are included in the article.