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Abstract

Introduction: Inflammation is associated with tumor initiation, and existing tumors are associated with immune suppression locally and systemically. Cancer treatment is also associated with immune suppression. This review evaluates evidence related to the use of acupuncture for modulation of inflammation and the immune system in cancer patients. Methods: Nine databases were searched for prospective, randomized, controlled trials evaluating the use of acupuncture for modulation of the immune system in cancer patients through March 2024. Only studies involving needle insertion into acupuncture points were included. No language limitations were applied. Studies were assessed for risk of bias (ROB) according to Cochrane criteria. The primary outcomes were levels of immune and inflammatory markers. Results: Of 3607 articles identified, 1526 duplicates were omitted, and 2261 articles were screened. Sixty-four (58 Chinese, 6 English) publications met all inclusion criteria and were evaluated for ROB. Forty-seven studies were rated as unclear ROB, and nine studies were rated as high ROB. However, when the blinding and allocation concealment criteria were removed, 12 studies had low ROB. Fifty-six studies were included in the meta-analysis, which found that acupuncture significantly increased interferon gamma (IFN-γ; P < .01), natural killer (NK) cells (P < .01), immunoglobulin G (IgG; P = .04), immunoglobulin M (IgM; P = .04), CD3 cells (P < .01), CD4 cells (P < .01), and the CD4/CD8 cell ratio (P < .01), and significantly lowered interleukin (IL)-1 (P = .01), IL-4 (P < .01), IL-6 (P < .01), and C-reactive protein (P < .01). Yet except for IFN-γ, there was high heterogeneity of results between studies. No significant differences were found in white blood cells, CD-8, neutrophil levels, IL-2, IL-10, or tumor necrosis factor alpha (TNF-α). Conclusion: The current evidence is insufficient to either support or refute the immunomodulatory effects of acupuncture in cancer patients due to no studies fully meeting the low ROB criterion. The preliminary data, however, are promising. Future studies that are higher powered, with low ROB designs, are warranted.

Keywords

acupuncture immunity inflammation cancer systematic review meta-analysis integrative medicine traditional Chinese medicine

Introduction

The immune system plays a critical role in cancer. While inflammation promotes tumor initiation and growth,¹ cell-mediated immunity can help identify and eliminate tumor cells in a process known as immune surveillance.² Tumors work to suppress the immune response, both systemically and in the tissue microenvironment.³ Cancer treatments may also impact the immune system. Immunotherapies work to increase the anti-tumor immune response, either through stimulation of the immune response or by blocking tumor-induced suppression of the immune system. Cytotoxic chemotherapy targets rapidly dividing cells, among other mechanisms, and commonly causes leukopenia and neutropenia owing to the off-target killing of immune cells. Additionally, chemotherapy-induced leukopenia/neutropenia results in treatment delays, can lead to infectious complications, and is a major cause of treatment-related morbidity and mortality.

The current standard treatment for chemotherapy-induced neutropenia includes hematopoietic colony-stimulating factors (CSF), such as granulocyte colony-stimulating factor (G-CSF), and granulocyte macrophage colony stimulating factor (GM-CSF). These treatments are expensive, and patients frequently report significant adverse effects, such as musculoskeletal pain, fever, or development of myelodysplasia or acute myeloid leukemia.^4
-7 Therefore, finding a non-pharmacological approach to decrease chemotherapy-induced neutropenia is desirable.

Prior meta-analyses on acupuncture for chemotherapy induced leukopenia or bone marrow suppression found significant improvements in white blood cell (WBC) counts,^8
-11 neutrophil levels,^8,9 natural killer (NK) cell counts.⁸ Previous animal studies suggest that acupuncture may increase serum CSF and promote the maturation of granulocytes.^12,13 One meta-analysis¹¹ suggested that acupuncture could increase WBC by an average of 1221 cells/mL (95% confidence interval: 636-1807 cells/mL). In preclinical models, acupuncture led to increased NK cell activity and shift T cell populations.^14,15 In an effort to identify effective, safe, and cost-effective treatment approaches to maintain the integrity of the immune system during cancer treatment, the current systematic review and meta-analyses explored the effects of acupuncture on immune and inflammatory markers in cancer patients.

Methods

Literature Search

The Ovid Medline, Ovid Embase, EBSCO CINAHL, EBSCO Alt HealthWatch, Wiley Cochrane Library, Elsevier Scopus, PubMed, Wanfang Data, and China National Knowledge Infrastructure (CNKI) China Academic Journals databases were searched from inception through March 2024 for prospective randomized clinical trials (RCTs) related to acupuncture modulation of the immune system in cancer patients in Chinese/English languages. Key search topics were acupuncture, cancer, randomized controlled trial, and immunity; see Supplemental 2 for detailed search strategy.

Study Selection

See study selection PRISMA diagram in Figure 1. Seven authors (WL, KG, JM, LC, AC, BZ, and RWW) independently screened articles for inclusion. Inclusion criteria were prospective RCTs, involved needle insertion into acupuncture points, and evaluated the use of acupuncture for modulation of the immune system in cancer patients. Unpublished reports, letters to the editor, retrospective chart reviews, studies for which only interim data analyses were available, studies for which only an abstract was available, and studies that did not evaluate acupuncture for modulation of the immune system were excluded. If contact information was available from an interim analysis or abstract only, the first author was contacted via email and asked if the results had been published. Studies that did not involve needle insertion (ie, acupressure, laser acupuncture, and electrostimulation without needles) or studies that only compared 2 types of active acupuncture, without a no-acupuncture or sham-acupuncture control group, or that evaluated acupuncture in combination with herbal treatments were excluded.

Figure 1.

Flow chart for selection of studies.

Data Abstraction and Rating of Articles for Risk of Bias

For articles published in English, two independent reviewers (KG, JM, LC, BZ, WL, RW, and AC) abstracted data and rated articles using the Cochrane Risk of Bias (ROB) criteria (Table 1).¹⁶ Articles written in Chinese were evaluated by two independent reviewers fluent in Mandarin (JM and WH or BZ and WL). For a study to be rated as having a low ROB, the low ROB criteria were required in all domains (sequence generation/randomization, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, and other sources of bias). Secondarily, we also reported the ROB after excluding the allocation concealment and blinding domains, as the outcome measures studied are objective in nature and blood-based outcomes are less likely to be influenced by expectation and a placebo response. Discussion to consensus settled differences in ROB ratings.

Table 1.

Risk of Bias (ROB) Criteria.¹⁶†

Domain	Criteria	Examples
Sequence generation	Allocation sequence was adequately generated.	Random number table
		Computerized random assignment
		Coin tossing
		Shuffled cards
Allocation concealment	Allocation of group assignment could not be foreseen prior to randomization.	Centralized allocation (telephone or web-based randomization)
Allocation concealment		Sequentially numbered, opaque, sealed envelopes
Blinding of participants, personnel, and outcome assessors	Knowledge of the allocated intervention was adequately prevented during the study.	Blinding ensured (and unlikely to have been broken) for participants and key study personnel
Blinding of participants, personnel, and outcome assessors		No blinding, but outcome not likely influenced
Incomplete outcome data	Incomplete outcome data were adequately addressed.	No missing outcome data
		Missing outcome data unlikely related to true outcome
		Similar reasons for missing data across groups
		Missing outcome data balanced across groups
Selective outcome reporting	The study was free of apparent selective outcome reporting.	Study protocol available
		All pre-specified outcomes of interest reported
		Study protocol not available but reported all expected pre-specified outcomes
Other sources of bias	The study was free of other problems that could introduce bias.	Small sample size (<30/group randomized)
		One acupuncturist gave all treatments to active and inactive acupuncture groups
		Baseline group differences
		Inconsistent or unclear recruitment strategies or treatment methods
		Study stopped early
		Vague/unclear outcome measures
		Short wash-out period in a crossover design

†

Complete criteria for judgment of high, low, or unclear risk of bias may be accessed at: www.cochrane-handbook.org/ [Part 2, Chapter 8, Section 8.5, Table 8.5.d Criteria for judging risk of bias in the “Risk of bias” assessment tool]. Found here: https://handbook-5-1.cochrane.org/chapter_8/table_8_5_d_criteria_for_judging_risk_of_bias_in_the_risk_of.htm

After determining ROB, the reviewers also independently evaluated each study to determine whether the findings for the primary outcomes were positive, negative, or unclear. Although some studies reported statistical analyses for within-group changes in immune markers from baseline, between-group pre-post differences were emphasized in evaluating study outcomes.

For inclusion in the meta-analyses, studies needed to report sample size per group at baseline and follow-up time points, raw means, and standard deviations for each variable at baseline and at least 1 follow-up time point, and ideally details on any missing data. Pre-post (baseline to post-treatment), between-group differences for acupuncture treatment versus controls were compared. In most studies the control group was a non-attention standard-of-care treatment. The pre-post difference scores from the combined meta-analyses per outcome variable are presented.

Statistical Analysis

We plotted the effect measure and the 95% confidence intervals (CIs) using forest plots and assessed the studies’ heterogeneity using the I² statistic, which measures the percentage of total variation due to heterogeneity rather than chance.¹⁷ I² values of less than 25% represent low heterogeneity, whereas I² values between 25% and 50% represent moderate heterogeneity. If a statistically significant percentage of the total variation was found to be due to heterogeneity, the combined effect measure from the studies in our meta-analysis was estimated using a random effects model in which each study was weighted relatively more equally (than a fixed-effect analysis). We included 2 forest plots for each analysis, with 2 including the I² statistic and the other including the Q statistic (Cochran’s heterogeneity statistic used to calculate I²; I² = 100% × [(Q − df)/Q]). For the pre- and post-treatment difference outcomes, a correlation of .3 was assumed as a moderate yet realistic association between pre- and post-treatment biomarker levels, as needed. This assumption was necessary because no study except one¹⁸ reported the standard deviations of the pre-post differences. If the correlation was greater than .3, the corresponding effect size estimates would be larger than those presented below. We also estimated potential publication bias (ie, tendency to publish either positive or negative results) using funnel plots.¹⁹ We used the inverse variance-weighted average method when performing the meta-analysis.

Results

Of 3787 items identified, 1526 duplicates were omitted, and 2261 articles were screened. Sixty-four publications, 58 in Chinese and 6 in English, met all inclusion criteria and were evaluated for ROB according to the Cochrane criteria. Twenty-five studies examined participants with gastrointestinal cancers, 13 with unspecified cancers, 8 with lung cancer, 7 with breast cancer, 5 with gynecological cancers, and 5 with multiple cancers. Fifty-two trials used a two-group design that compared acupuncture to a heterogeneous variety of control groups. Nine studies compared 3 groups, with 5 of the studies comparing 2 different acupuncture treatments to a control group. Of the 3 four-group comparison studies, 1 study examined 2 different usual care control groups with and without acupuncture,²⁰ while the other 2 compared 3 different acupuncture treatments to a control group.^21,22 One study used a delayed-effects group in the comparison.²³

The 64 studies examined 14 different channels (12 regular and 5 classified as “extra”) employing more than 80 unique acupuncture points. The most common channels examined were the Stomach (ST; 56 studies), Spleen (SP; 39 studies), Pericardium (PC; 26 studies), Large Intestine (LI; 17 studies), Kidney (KI; 14 studies), Dū mài/Governor Vessel (GV; 15 studies), Bladder (BL; 14 studies), Heart (HT; 11 studies), and Liver (LR; 10 studies). Among the most common acupoints used were ST36 (51 studies), ST37 (14 studies), ST39 (11 studies), SP6 (24 studies), PC6 (22 studies), and LI4 (20 studies).

Risk of Bias

Of the 64 included studies, 53 were rated unclear ROB, 11 were rated high ROB, and 0 were rated low ROB (see Tables 2 and 3 for design and treatment parameters for all included studies). Two studies used a placebo control group, and although they were rated as having a high²⁴ or unclear²⁵ ROB, both studies found acupuncture effective at supporting the immune system.^24,25

Table 2.

Risk of Bias (ROB) for Included Studies.

Study	Sequence generation	Allocation concealment	Blinding	Incomplete outcome data	Selective outcome reporting	Other sources of bias	Level of risk	Study	Sequence generation	Allocation concealment	Blinding	Incomplete outcome data	Selective outcome reporting	Other sources of bias	Level of risk
Unclear ROB due to allocation concealment and/or blinding (would receive an L instead of U)
Hu et al 2016²⁶	+	0	-	+	+	+	U	Sun and Zhou N 2019²⁷	+	0	-	+	+	+	U
Qian et al 2017²⁸	+	0	-	+	+	+	U	Wang, Y et al 2019²⁹	+	0	-	+	+	+	U
Gao et al 2018³⁰	+	0	-	+	+	+	U	Bai et al 2020³¹	+	0	-	+	+	+	U
Liu M et al 2018³²	+	0	-	+	+	+	U	Qing et al 2020³³	+	0	-	+	+	+	U
Ni et al 2018³⁴	+	0	-	+	+	+	U	Quan et al 2020²²	+	0	-	+	+	+	U
Lin, G et al 2019³⁵	+	+	-	+	+	+	U	Lian JL et al 2021³⁶	+	0	-	+	+	+	U
Unclear ROB
Yuan and Zhou 1993¹⁸	0	0	-	+	+	0	U	Zhao, L et al 2019³⁷	0	0	-	+	+	+	U
Wu, B et al 1994³⁸	0	0	-	+	+	0	U	Song W et al 2020³⁹	-	0	-	+	+	+	U
Wu B 1995⁴⁰	0	0	-	+	+	0	U	Tao et al 2020⁴¹	+	0	-	+	+	0	U
Gu et al 2004²⁰	0	0	-	+	+	0	U	Zhang Y et al 2020⁴²	-	0	-	+	+	+	U
Lu et al 2009²⁵	+	+	+	+	+	0	U	Gong C et al 2021⁴³	0	-	-	+	+	0	U
Han et al 2010⁴⁴	+	+	-	+	0	0	U	Li W et al 2021⁴⁵	+	0	-	+	+	0	U
Zhang and Du S 2011⁴⁶	0	0	-	+	0	+	U	Lian et al 2021⁴⁷	+	0	-	+	+	0	U
Lin S et al 2014⁴⁸	0	0	-	+	+	0	U	Ren et al 2021⁴⁹	+	0	-	+	+	0	U
Ning et al 2014⁵⁰	0	0	-	+	+	0	U	Sun H et al 2021⁵¹	0	0	-	+	+	0	U
Li G et al 2015⁵²	0	0	-	+	+	+	U	Wu X 2021⁵³	+	0	-	+	+	0	U
Wang X et al 2016⁵⁴	0	0	-	+	+	0	U	Zhang X 2021⁵⁵	0	0	-	+	+	0	U
Liu and Teng Z 2017⁵⁶	+	0	-	+	+	0	U	Zeng K 2021⁵⁷	0	0	-	+	+	0	U
Mai et al 2017⁵⁸	+	0	-	+	+	0	U	Zhou M 2021⁵⁹	0	0	-	+	+	0	U
Peng et al 2017⁶⁰	0	0	-	+	+	0	U	Chen G et al 2022⁶¹	+	0	-	+	+	0	U
Chen M et al 2018⁶²	+	0	-	+	+	0	U	Xia Y et al 2022⁶³	+	0	-	+	+	0	U
Liu Y 2018⁶⁴	+	0	-	+	+	0	U	Xiang T 2022⁶⁵	+	0	-	+	+	0	U
Ma et al 2018²¹	0	0	-	+	+	0	U	Xuan et al 2022⁶⁶	+	0	-	+	+	0	U
Tu 2018⁶⁷	0	0	-	+	+	+	U	Zhao X et al 2022⁶⁸	0	0	-	+	+	0	U
Wang H 2018⁶⁹	0	0	-	+	+	0	U	Zheng et al 2022⁷⁰	+	0	-	+	0	0	U
Wang N et al 2018²³	+	+	-	0	+	0	U	Fan G et al 2024⁷¹	+	+	-	+	+	0	U
Saraswati et al 2019⁷²	+	+	-	+	+	0	U
High ROB
Li H et al 1997⁷³	0	0	-	0	0	-	H	Li R et al 2017⁷⁴	-	0	-	+	+	-	H
He et al 2005⁷⁵	0	0	-	0	-	0	H	Zhu et al 2018⁷⁶	-	0	-	+	+	0	H
Crew et al 2007⁷⁷	0	0	-	+	-	-	H	Gong J et al 2019⁷⁸	-	0	-	+	+	0	H
Xie et al 2007⁷⁹	0	0	-	0	-	0	H	Lin Z et al 2022⁸⁰	-	-	-	+	+	-	H
Li and Cao 2014⁸¹	0	0	-	0	0	0	H	Xu J et al 2022⁸²	0	-	-	0	+	0	H
Pei et al 2016²⁴	+	0	+	+	+	-	H

Abbreviations: ROB, risk of bias; -, high ROB; 0, unclear ROB; +, low ROB; H, high ROB for one or more domains; U, unclear ROB for one or more domains; L, low ROB for all domains.

Table 3.

Study Design and Treatment Parameters by ROB Rating.

Unclear ROB due to allocation concealment and/or blinding
Author	Cancer type	Cancer treatment setting	Trial design/type of acupuncture	N	Retention, frequency, and duration of acupuncture	Acupoints	Immune & inflammatory parameter(s) measured	Findings
Hu et al 2016²⁶	Breast cancer	Adjuvant chemotherapy	2-armSANA	60	30 min, daily for 5 d	ST36, SP6, SP10, BL23	WBC	WBC and neutrophil counts in the acupuncture group significantly increased compared with the control group.
Qian et al 2017²⁸	Stomach cancer	Surgery	2-armSANA	60	20 min, daily for 7 d	ST36, ST37, ST39	WBC, CRP	Acupuncture group had higher WBC counts, but lower CRP levels compared with control 24 h post-surgery.
Gao et al 2018³⁰	Lung cancer	Not specified	2-armSANA	114	30 min, 6 d/week for 4 wk	Back Shu points or along the lung meridian at the arm, ST36, LI11, CV6	TNF-α, IL-6	TNF-α and IL-6 levels in the acupuncture group were significantly lower than in the control group.
Liu et al 2018³²	Colorectal cancer	Chemotherapy	2-armSANA	63	30 min, daily for 5 d	REN6, REN3, ST36, P6	WBC, neutrophils, platelets	Acupuncture group had higher post-chemotherapy WBC and platelet levels.
Ni et al 2018³⁴	Respiratory and digestive cancers	Chemotherapy	2-armSANA	80	20 min, Daily for 12 d	DU20, Si Shen Chong, REN12, SP6, ST36	WBC, immunoglobulins	Acupuncture group had significantly higher WBC and immunoglobulin levels compared with the control group.
Lin et al 2019³⁵	Non-small cell lung cancer	Chemotherapy	2-armSA-FNA	60	3 Quick punctures, no needle retention, daily for 7 d	ST36, SP6, P6, LV3, KI3 with fire	Il-2, Il-4, Il-10, IFN-γ	Acupuncture significantly increased IL-2 and IFN-γ levels, and significantly decreased IL-4 and IL-10 levels compared with the control.
Sun and Zhou 2019²⁷	Breast cancer	Surgery	2-armEANA	84	30 min, once before anesthesia	Nei Ma Dian (extra), LR2	TNF-α, IL-6, CD3, CD4, CD8, CD4/CD8 ratio	The acupuncture group had lower postoperative TNF-α and IL-6 levels but higher CD3, CD4, and CD4/CD8 ratio than the control.
Wang et al 2019²⁹	Lung cancers	Chemotherapy	3-armSA1SA2NA	150	SA,1: 30 min, before chemotherapy for 3 dSA,2: 30 min, after chemotherapy for 3 d	P6, REN12, ST36	WBC	Post-chemotherapy WBC reduction was not significantly different between the groups.
Bai et al 2020³¹	Advanced cancers	Not specified	2-armSA-FNA	100	Only puncture, no needle retention, every other day for 14 sessions	ST36, SP6 3 to 4 tender points on the disease site, 1 to 2 tender points on the contralateral (mirror) side of the disease	CD3, CD4, CD4/CD8 ratio	CD3, CD4, and CD4/CD8 ratio were significantly higher and CD8 significantly lower in the acupuncture group.
Qing et al 2020³³	Unspecified cancers	Cancer-related fatigue	2-armSANA	80	15 min, daily, 5 d/week, for 4 wk	DU20, REN3, REN6, GB20, ST36, SP6	CRP, IL-6, TNF-α, sTNF-R1	Acupuncture significantly reduced CRP, IL-6, TNF-α, and sTNF-R1, and there were significant post-treatment between group differences in IL-6, CRP, and TNF-α.
Quan et al 2020²²	Rectal cancer	Surgery	4-armEA,BEA,CEA,DNA,A	240	30 min, EA, B: 1 d before surgeryEA, C: 1 d before surgery, and 30 min before anesthesiaEA, D: 1 d before, 30 min before anesthesia, and 1 d after surgery	P6, LI4, LI11, St37, St39,	WBC, neutrophils, CRP, HSP70, IL-6, IL-4, IFN-γ, CD4, CD8	More frequent perioperative acupuncture (Group D) produced the strongest effects in reducing postoperative inflammatory response (lower WBC, neutrophils, CRP, SP70 (heat shock protein), IL-6, IL-4, and IFN-γ, and higher CD4 count and CD4/CD8 ratio.
Lian, Wu et al 2021³⁶	Unspecified cancers	Cancer-related depression	2-armSANA	120	20-40 min, daily, 5 d/week for 6 wk	REN12, DU20, DU24, UB15, UB18, UB20, HT7, LV3, KI3	IL-2, IL-4, IL-10, IFN-γ, TGF-β	The acupuncture group had a significantly bigger reduction in IL-4, IL-10, and bigger increase in IL-2 and IFN-γ, than the control group.
UNCLEAR ROB
Author	Cancer type	Cancer treatment setting	Trial design/type of acupuncture	N	Retention, frequency, and duration of acupuncture	Acupoints	Immune & inflammatory parameter(s) measured	Findings
Yuan and Zhou 1993¹⁸	Lung and esophageal cancer	None	3-armSANAHealthy control	99	30 min, daily for 7 d	LI4, ST36, SP6, REN4, P6	CD3, CD4, CD8, CD4/CD8 ratio	Acupuncture increased peripheral T cell and subgroup percentages, especially CD4.
Wu et al 1994³⁸	Lung and esophageal cancer	Preoperative	3-armSANAHealthy control	65	30 min, daily for 10 d	ST36, LI11, CV6	IL-2, NK cell activity	Acupuncture increased IL-2 levels and NK cell activity and IL-2 levels and NK cell activity was higher in the acupuncture group compared to the control group.
Wu 1995⁴⁰	Lung and esophageal cancer	Preoperative, but not clear about treatment history	3-armSANAHealthy control	60	30 min, daily for 10 d	CV4, LI4, ST36, P6	CD3, CD4, CD8, CD4/CD8 ratio, IL-2, beta endorphin	Acupuncture increased T cell subgroup CD3 and CD4% and CD4/CD8 ratio and increased beta endorphin levels, but decreased IL-2 levels.
Gu et al 2004²⁰	GI cancers	Surgery	4-armGAGA + SAEGAEGA + SA	44	15 to 30 min prior to anesthesia, continued through surgery completion	ST36, ST37, GB34	CD3, CD4, CD8, CD4/CD8 ratio	Decrease in CD4 and CD4/CD8 ratio was less in acupuncture and general anesthesia than general anesthesia arms alone. These benefits were not significant with acupuncture applied alongside epidural anesthesia.
Lu et al 2009¹¹	Ovarian cancer	Myelosuppressive chemotherapy	2-armEASA	21	30 min, 2 to 3 times/week for 10 sessions starting week 1 before second chemotherapy cycle and ending at beginning of third cycle	LV3, KI3, SP6, ST 36, SP10, LI4, P6, LI11, DU 20	WBC, ANC, G-CSF	Higher WBC values during one cycle of chemotherapy, which suggests a potential myeloprotective effect of acupuncture. But changes were clinically relevant and not statistically significant.
Han et al 2010⁴⁴	Gynecological cancer	Chemotherapy	2-armSANA	86	20 to 30 min, daily for 7 d starting 3 d after chemotherapy	SJ6, LI11, LI4, ST36, SP10, SP9, SP6, KI3, LV3	WBC, neutrophils	Acupuncture increased the therapeutic effect of G-CSF and caused a delayed decrease in WBCs after G-CSF ended.
Zhang and Du 2011⁴⁶	Colorectal cancer	Surgery	3-armSA + MoxibustionNAChinese medicine	105	45 min, daily for 10 d starting 1 d after surgery	ST36, ST37, ST39, SP6, SP9	WBC, neutrophils, lymphocytes, CD3, CD4, CD8, CD4/CD8 ratio, NK cells	Compared with either control group or herbal intervention group, the acupuncture group had higher NK cell activity as well as CD3, CD4 count and CD4/CD8 ratio.
Lin et al 2014⁴⁸	GI tumors	Surgery	2-armEANA	83	30 min before anesthesia till the end of surgery	DU20, P6, ST36	TNF- α, IL-1 beta, IL-6	Acupuncture inhibited postoperative TNF- α, IL-1 beta, and IL-6 release.
Ning et al 2014⁵⁰	Colorectal cancer	Adjuvant chemotherapy	2-armEANA	84	40 min, twice a day for 6 d	ST26, ST44	WBC	Fewer patients had low WBC levels in the acupuncture group than control group.
Li et al 2015⁵²	Supratentorial tumors, not specified	Surgery	3-armEATEASNA	120	Duration of anesthesia	LI4, SJ5, SJ7, UB63, LV3, ST36, GB40, GB20, UB10, UB2, EXHN4	TNF-α, IL-8, IL-10, IgM, IgA, and IgG	Electroacupuncture, but not transcutaneous electrical acupoint stimulation, lessened inhibition of immune function, with IL-8 and IgA higher both 4 h and 1-d post-surgery.
Wang et al 2016⁵⁴	Non-small cell lung cancer	Chemotherapy	2-armEANA	140	30 min, daily on chemotherapy days, number of cycles unclear (until the end of chemotherapy)	ST36, SP6	NK, CD3, CD4, CD8, IL2, neutrophil/lymphocyte ratio	Post-treatment IL2 level and CD3 and CD4 counts were significantly higher and neutrophil/lymphocyte ratio lower in the acupuncture group than the control group.
Liu and Teng 2017⁵⁶	Unspecified cancers	Surgery	2-armSANA	98	30 min before surgery until the completion of surgery	DU20, P6, ST3	TNF-α, IL-1b, IL-6	Lower levels of TNF-α, IL-1b, and IL-6 in the acupuncture group after tumor resection.
UNCLEAR ROB
Author	Cancer type	Cancer treatment setting	Trial design/type of acupuncture	N	Retention, frequency, and duration of acupuncture	Acupoints	Immune & inflammatory parameter(s) measured	Findings
Mai et al 2017⁵⁸	Colorectal cancer	Surgery	3-armEA,1EA,2NA	60	EA,1 30 min, 1 d beforeEA,2 30 min, 1 d before and 30 min before anesthesia	Group B: ST36, ST37, ST39Group C: REN12, ST25, ST36, ST37, ST39	WBC, neutrophil	Post-operative increase of WBC and neutrophils was least prominent in Group C acupuncture points.
Peng et al 2017⁶⁰	Gastric cancer	No active treatment	2-armSA + TCM enemaNA	90	Retention not specified, daily for 1 to 2 wk	ST36, ST37, ST39	WBC, CRP, ESR, TNF-α, IL-1	WBC, C-reactive protein, erythrocyte sedimentation rate, and TNF-α were lower in the acupuncture group.
Chen et al 2018⁶²	Breast cancer	Surgery	2-armSANA	40	30 min, before surgery, 1 h after surgery, and then daily for 3 d	P6, SP6, ST36, LI4	Visual analog scales, T-lymphocytes (CD3, CD4, CD8, CD4/CD8 ratio), NK cells (CD16, CD56)	The acupuncture group had significantly higher CD3, CD4, CD4/CD8 ratio, and NK cell levels.
Liu 2018⁶⁴	Mixed cancers	Chemoradiation	2-armSA + MoxibustionNA	64	30 min, daily for 28 d	REN3, REN6, ST36, REN12, Ki3, SP6, DU14	WBC	Acupuncture group had better recovery of post-treatment low WBC counts than the control group.
Ma et al 2018²¹	GI cancers	Surgery	4-armEA,BEA,CEA,DNA,A	80	30 min, EA,B: 1 d before anesthesia induction;EA,C: 1 d before anesthesia induction, 30 min before surgery; EA,D: 1 d before anesthesia induction, 30 min before surgery, 1 d after surgery	ST36 (right), ST37 (right), ST39 (right), P6, REN12, ST25	WBC, neutrophils	Electroacupuncture attenuated postoperative increases in WBCs and neutrophils; however, increased electroacupuncture frequency did not have a stronger effect.
Tu 2018⁶⁷	Breast cancer	Surgery	2-armEANA	116	30 min before surgery until end of surgery, then 30 min, daily for 3 d	LI4, P6, ST36	CD3, CD4, CD8, CD4/CD8 ratio, NK cells	The acupuncture group had a significantly higher CD4%, CD4/CD8 ratio, and NK cell percentage postoperatively than the control group.
Wang 2018⁶⁹	Lung cancer	Surgery	2-armEANA	100	15 min, daily for 10 d	UB13, ST36	CRP, TNF- α, IL-10	The acupuncture group had a significant increase in IL-10 and a significant decrease in CRP and TNF- α compared with the control group.
Wang et al 2018²³	Gastric cancer	Surgery	2-armEANA	96	15 to 20 min, daily for 10 d starting 1 d after surgery	ST36, P6, LI4, and ST37	CD3, CD4, CD8	Acupuncture group had higher CD3, CD4, and CD4/CD8 ratio.
Saraswati et al 2019⁷²	Cervical squamous-cell carcinoma	Chemotherapy	2-armEANA	53	30 min, 1 d after each chemotherapy, totaling 4 treatments	ST36	NK cells	Electroacupuncture at ST36 significantly increased NK cells.
Zhao et al 2019³⁷	Various cancers	Chemoradiation	2-armSANA	80	30 min, daily for 12 d	ST36, DU14, LI4	WBC	Acupuncture plus rh G-CSF significantly improved post-cancer treatment WBC recovery over rh G-CSF alone.
Song et al 2019³⁹	Rectal cancer	Surgery	2-armEANA	80	15 min before anesthesia to end of anesthesia	ST36, SP6	CD4, CD8, CD4/CD8 ratio	Electroacupuncture was effective in improving hemodynamic stability and lessening immune suppression from surgery/anesthesia.
Tao et al 2020⁴¹	Unspecified cancers	Chemotherapy	2-armSANA	66	30 min, daily for 7 d	REN3, ST36, SP6, GB12, P6, KI3, SP5	WBC, neutrophils	Compared with control, neutrophil percentage were higher in the acupuncture group.
Zhang et al 2020⁴²	Cervical cancers	Chemoradiation	3-armSA + MoxibustionNA + TropisetronNA	96	30 min, daily for 22 d (on the days of radiation treatments)	ST36, P6, SP4, REN12	Lymphocytes (as part of nutritional assessment)	Both Tropisetron and acupuncture groups had significant improvement in lymphocyte count over no treatment group, with even stronger effects in the acupuncture group.
UNCLEA ROB
Author	Cancer type	Cancer treatment setting	Trial design/type of acupuncture	N	Retention, frequency, and duration of acupuncture	Acupoints	Immune & inflammatory parameter(s) measured	Findings
Gong et al 2021⁴³	Colorectal cancer	Chemotherapy	2-arm SA + Moxibustion NA	60	daily for 7 d	BL17, ST36, CV4	WBC, neutrophil	Post treatment WBC and neutrophil levels were higher in the acupuncture group compared with the control group.
Li W et al 2021⁴⁵	Colorectal cancer	Surgery	3-armEA,B(2 Hz)EA,C (100 Hz)NA,A	120	30 min before general anesthesia	SP6, ST36, PC6, GV20	CD4+, CD8+, CRP, IL-2, IL-6	Compared with control, CRP, SAA, and IL-6 were lower, levels of CD4 and CD4/CD8 higher at postop day 1, 3, 5 in the electroacupuncture groups, with 100 HZ stimulation having superior effects over 2 HZ.
Lian Zhang et al 2021⁴⁷	Multiple cancers	Not specified	2-arm SA NA	120	15 to 20 min, 5 d per week for 6 wk.	GV20, GV24, BL18, BL20, BL24, LR3, HT7, KI3, CV12	CD3+, CD4+, CD8+, CD4+/CD8+	Post treatment CD3, CD4, and CD4/CD8 were higher, CD8 lower within each group with greater change in the acupuncture group compared with the control group.
Ren et al 2021⁴⁹	Lung cancer	Chemotherapy	2-armSA + MoxibustionNA	148	15 min, daily, 15 days/cycle for 6 cycles	UB13, ST40, LU1, LU9, LU5, UB15, SI11, REN17, UB43, Ashi. Moxa at REN3	CD3, CD4, CD8, CSF, TNF- α, IL-2	Moxibustion acupuncture was better than control in improving immune function (higher CD4, CD4/CD8 ratio) and reducing inflammation (lower CSF, TNF- α, and IL-2 levels).
Sun et al 2021⁵¹	Colorectal cancer	Surgery	2-arm SA + Moxibustion NA	82	45 min, daily starting postop day 1, 15 days.	ST36, ST37, SP6, SP9, KI6	CD3+, CD4+, CD8+, CD4+/CD8+, IL-6, CRP, TNF-a, WBC	CD3, CD4, and CD4/CD8 were significantly higher, while levels of IL-6, CRP, and TNF-a were significantly lower in both groups, with more favorable response in the acupuncture group compared with the control group.
Wu 2021⁵³	Multiple cancers	Chemotherapy	2-arm SA + Moxibustion NA	82	25-30 min, daily for 14 d	SP6, ST36, SP9, BL20, GV14, CV6	WBC, CD3+, CD4+, CD8+, CD4+/CD8+	WBC, CD3, CD4, and CD4/CD8 were higher in the acupuncture group compared with the control group.
Zhang 2021⁵⁵	Colorectal cancer	Surgery	2-arm SA NA	70	30 min, 6 h post-op then twice daily until bowel sound, flatulence and defecation	ST36, SP6, SP10, GB39	CD3+, CD4+, CD8+, CD4+/CD8+	Post treatment CD3, CD4, and CD4/CD8 were higher, CD8 lower at day 5 in the acupuncture group compared with the control group..
Zeng et al 2021⁵⁷	Breast cancer	Chemotherapy	2-arm SA + Moxibustion NA	93	30 min, daily for 28 d.	ST36, SP6, SP10, GB39	WBC, Neutrophil	WBC and neutrophil were higher in the moxibustion and acupuncture group compared with the control group.
Zhou 2021⁵⁹	Multiple cancers	Not specified	2-arm SA + Massage NA	134	12 h, daily for 1 mo	HT7, HT3, SP6, SP9	IL-6, TNF-a	IL-6, TNF-a, and neutrophils were higher in the moxibustion and acupuncture group compared with the control group.
Chen et al 2022⁶¹	Cervical cancer	Surgery	2-arm EA + Massage NA	98	1 h, every other day for 36 treatments	ilioinguinal and iliohypogastric nerves, pudendal nerve	IgA, IgG, IgM, CD3+, CD4+/CD8+	Compared with control, IgA, IgG, IgM, CD3, and CD4/CD8 were higher in the acupuncture group at 13 wk post-surgery
Xia et al 2022⁶³	Cervical cancer	Surgery	2-arm SA NA	80	30 min, twice daily, for 7 d	ST36, LI4, SP9	IL-6, IL-8, TNF-a	Postoperative day 1 levels of IL-6, IL-8, and TNF-a were significantly lower in the acupuncture group compared with the control group.
Xiang and Wang 2022⁶⁵	Gastrointestinal cancers	Not specified	2-arm SA + Moxibustion NA	68	10 min, daily for 2 wk	ST36, CV6	CD3+, CD4+, CD8+, CD4+/CD8+	Post treatment CD3, CD4, and CD4/CD8 were higher, CD8 lower within each group with greater change in the acupuncture group compared with the control group.
UNCLEAR ROB
Author	Cancer type	Cancer treatment setting	Trial design/type of acupuncture	N	Retention, frequency, and duration of acupuncture	Acupoints	Immune & inflammatory parameter(s) measured	Findings
Xuan et al 2022⁶⁶	Gastrointestinal cancers	Surgery	2-arm SA NA	71	30 min, post op 24, 48, and 72 h	LI4, LI11, ST36, ST37, ST39, SP9	WBC, neutrophil, CRP	Post treatment WBC, neutrophil, and CRP were significant in both groups, and the inflammatory response was more favorable in the acupuncture group.
Zhao et al2022⁶⁸	Lung cancer	Chemotherapy	2-arm SA + Moxibustion NA	68	30 min, daily for 3 wk	LR3, SP10, TE5	IgG, IgM, C3, C4, CD3+, CD4+, CD8+, CD4+/CD8+, NK cells	Post treatment CD3, CD4, CD8, and NK levels were significantly higher in the acupuncture and moxibustion group compared with the control group.
Zheng et al 2022⁷⁰	Colorectal cancer	Chemotherapy	2-arm SA NA	96	30 min, daily for 20 d	BL 31, BL32, BL33, BL34	CRP, TNF-a, IL-8, CD3+, CD4+, CD8+, CD4+/CD8+	Post treatment, CRP, TNF-a, IL-8 were significantly lower, CD4/CD8 significantly higher in the acupuncture group compared with the control group.
Fan et al 2024⁷¹	Lung cancer	Chemotherapy	3-arm SA press-needle SA timing press-needle NA	142	Retention time unclear,48 h, stimulation 3 times a day, for 14 d.	BL17, BL20, BL21, BL23, ST36, SP6, GV14	WBC, neutrophil	WBC and neutrophil counts were higher at day 7 and 14 post chemotherapy in the press-needle and timing press-needle groups compared to the control group. These counts were also higher in the timing press-needle groups than those in the press-needle group compared with the control group.
High ROB
Li H et al 1997⁷³	Multiple cancers	Chemoradiation	2-armSANA	42	30 min, daily for 6 d plus 1 resting day as a cycle, 3 cycles totaling 18 sessions	ST36, SP6, LI4, LI11	WBC, NK cells, IL-2	Acupuncture group had much higher post-treatment WBC count as well as NK cell and IL-2 activities than chemoradiation alone.
He et al 2005⁷⁵	Esophageal cancer	Radical resection	3-armEANAHealthy control	21	20 to 30 min before anesthesia to the end of anesthesia	SJ8, SJ17, P4	CD3, CD4, CD8, CD4/CD8 ratio	CD3 was significantly reduced postoperatively in the general anesthesia alone group, but not in the acupuncture group.
Crew et al 2007⁷⁷	Breast cancer	Hormone therapy	2-armSASA, Delayed	21	20 to 25 min, twice a week for 6 wk;	SJ5, GB41, GB34, LI4, ST41, KD3; Auricular points: shen men, kidney, liver, upper lung, and sympathetic; Shoulder pain add: LI15, SJ14, SI10; Wrists: LI5, SJ4; Fingers: SI5, SI3; Ba Xie, LI3; Lumbar: DU3, DU8, UB23; Hip: GB30, GB39; Knee: SP9, SP10, ST34	IL-1-beta, TNF-α	Levels of IL-1-β and TNF- α were not significantly different before and after acupuncture treatments. (There was no between-group comparison.)
Xie et al 2007⁷⁹	Breast cancer	Adjuvant chemotherapy	2-armEANA	48	30 min, daily for 62 d	ST36, BL17, BL18, BL23	Neutrophil	The acupuncture group had less frequent and less severe neutropenia.
HIGH ROB
Author	Cancer type	Cancer treatment setting	Trial design/type of acupuncture	N	Retention, frequency, and duration of acupuncture	Acupoints	Immune & inflammatory parameter(s) measured	Findings
Li and Cao 2014⁸¹	Non-small cell lung cancer	Chemotherapy	2-armSANA	72	30 min, 30 min before chemotherapy and immediately after completing chemotherapy (2/day), for 10 d	DU14, Bl17, ST36	Neutrophil	The acupuncture group had less severe neutropenia in terms of occurrence rate, severity, and duration.
Pei et al 2016²⁴	Rectal cancer	Surgery	2-armEASA	50	15 min before anesthesia induction and until the completion of surgery	ST36, SP6	IFN-γ, IL-4, IL-6, serum procalcitonin, leukocyte	Electroacupuncture alleviated suppression of immune function and inflammatory reaction. IFN-γ/IL-4 ratio in the acupuncture group did not decrease significantly and was significantly higher compared to the control group. Both IL-4 and IL-6 were significantly lower in the acupuncture group compared to the control group. No significant differences in leukocytes were found.
Li R et al⁷⁴2017	Hepatic cancers	Chemotherapy	2-armSANA	72	30 min, daily for 30 d	DU20, Skulp stomach area, P6, SP6, BL23, BL18, DU4 and Ashi	WBC	The acupuncture group had fewer hematologic side effects with WBC counts significantly higher than the control group after treatment due to a smaller reduction in the control group.
Zhu et al 2018⁷⁶	Gastric cancers	Chemotherapy	2-armSA + MoxibustionNA	200	10 min, daily for 4 sessions (after each chemotherapy cycle)	ST36, REN6	WBC, neutrophils, CD3, CD4, CD8	WBC and neutrophils were significantly higher in the acupuncture group than the control group. The acupuncture group had higher CD3, CD4 and CD4/CD8 ratio, and lower CD8 levels than the control group.
Gong J et al 2019⁷⁸	Digestive cancers	Chemotherapy	2-armSA + MoxibustionNA	70	10 min, daily for 7 d	REN6, ST36	WBC, IgM, IgA, IgG, CD3, CD4, CD8, CD4/CD8 ratio, CRP, IL-2, TNF- α,	IgM, IgA, IgG levels were higher in the acupuncture group.CD3, CD4 and CD4/CD8 ratio were higher with acupuncture, and CD8 was lower in the control group; CRP was lower, and TNF- α, and IL-2 were higher in the acupuncture group; WBC and platelets were higher with in the acupuncture group.
Lin Z et al 2022⁸⁰	Liver cancer	Not specified	2-arm SA NA	118	20 to 30 min, with 2 courses of SA every 3 d for 5 sessions	EX-HN5, C7, C1, T3, S3, L2, L5, S1	CD4+, CD8+, CD4+/CD8+	CD4, CD8, and CD4/CD8 were higher in the acupuncture group compared with the control group.
Xu J et al 2022⁸²	Gastrointestinal cancers	Surgery	2-arm EA NA	118	20 min, 20 min before surgery	GV20, LI4, PC6, HT7, ST36	TNF-α, IL-6, IL-1β, CD3+, CD4+, CD8+, CD4+/CD8+	T Lymphocytes were significantly higher in the electroacupuncture group compared with the control group.

Abbreviations: CRP, C-reactive protein; EA, Electroacupuncture; EGA, combined epidural-general anesthesia; GA, general anesthesia; G-CSF, granulocyte colony-stimulating factor; HSP70, heat shock protein-70; IFN-γ, Interferon-gamma; IgM, IgA, IgG, Immunoglobulins; IL-1, IL-1b, IL-6, Il-2, Il-4, Il-10, IL-8, interleukin; NA, no acupuncture; NK cell, Natural Killer cell; rh G-CSF, Recombinant human granulocyte colony-stimulating factor; SA, Standard acupuncture; SA-F, Standard acupuncture with fire needle stimulation; SOC, Standard of care; sTNF-R1, soluble tumor necrosis factor receptor I; TCM, Traditional Chinese medicine; TEAS, Transcutaneous electrical acupoint stimulation; TGF-β, Transforming growth factor beta; TNF-α, Tumor necrosis factor alpha; WBC, white blood cells.

The placebo-controlled study with the high ROB rating²⁴ had unclear allocation concealment and conclusions that did not match the outcomes shown in tables. The authors compared 25 patients who received electroacupuncture to ST36 and SP6 beginning 15 minutes before rectal cancer surgery and continuing until the surgery’s completion to 25 patients who received sham acupuncture during the same period. Their findings revealed that interleukin (IL)-4 and IL-6 levels slightly increased, while interferon (IFN)-γ/IL-4 ratio went down in the control group.²⁴ IL-4 and IL-6 levels went down in the acupuncture group compared to the control group, and the IFN-γ/IL-4 ratio increased post-surgery in the real acupuncture group but went down significantly in the control group, with between-group differences (P < .05).²⁴ The other placebo-controlled study, a pilot, randomized, two-arm study by Lu et al²⁵ conducted at Dana Farber Cancer Institute, had an unclear ROB rating because of the small sample size (N = 21 patients with gynecological cancers randomized), but was otherwise rated as having a low ROB. The incidence of grade 2-4 leukopenia with chemotherapy was less in the acupuncture arm than in the sham arm (30% versus 90%; p = 0.02).²⁵ The median leukocyte nadir, neutrophil nadir, and recovery absolute neutrophil count (ANC) were all higher in the acupuncture arm, but not statistically significant after adjusting for baseline differences.²⁵ Unfortunately, neither study met the criteria to be included in the meta-analyses.

Review of the Highest-Quality Studies

When the allocation concealment and blinding ROB criteria were removed, 12 studies were rated low ROB. Three of these studies were conducted in the perioperative setting, 6 while patients were undergoing chemotherapy or radiotherapy, and 3 during an unspecified timeframe.

Acupuncture in the perioperative setting

Qian et al²⁸ treated stomach cancer patients post-surgery with 20 minutes of daily acupuncture for 7 days (n = 30) or standard care (n = 30). There were significant increases in WBC counts among all participants, but more so in the control group than the acupuncture group immediately postop.²⁸ However, the acupuncture group’s WBC count was higher than the control group 24 hours postop.²⁸ This study was given a weight of 0% in the meta-analysis because the large variance associated with the effect size estimates from the study when examining WBC counts. C-reactive protein (CRP) was significantly lower in the acupuncture group than the control group at the end of surgery and 24 hours postop.²⁸ Sun and Zhou²⁷ compared 1 electroacupuncture (EA) session (n = 42) before anesthesia for breast cancer surgery to a patient-controlled anesthesia dosing control group (n = 42). After surgery, tumor necrosis factor (TNF)-α and IL-6 increased significantly in the control group, with no changes in the EA group, resulting in significant between-group differences.²⁷ CD3, CD4, and CD4/CD8 ratio levels were significantly higher in the EA group than in the control group, and the EA group remained closer to pre-surgery levels.²⁷ Quan et al²² examined the effects of EA provided 1, 2, or 3 times (n = 60 in each group) versus usual care (n = 60) in the perioperative period among rectal cancer patients. Each EA session was 30 minutes long and provided: (1) 1 day before surgery; (2) 1 day before surgery and 30 minutes before anesthesia; and (3) 1 day before surgery, 30 minutes before anesthesia, and 1 day after surgery.²² The 3-dose acupuncture group had the greatest difference from the control group, resulting in lower levels of CRP, IL-4, IL-6, neutrophils, and WBC counts, and significantly higher IFN-γ/IL-4 ratio, CD4, and CD4/CD8 ratio.²²

Acupuncture during chemotherapy or radiotherapy

Qing et al³³ studied the effects of acupuncture on the immune system during radiotherapy and chemotherapy, comparing a sample that received acupuncture (n = 44) once daily, 5 days a week, over 4 weeks to a usual care group (n = 36). Significant decreases in TNF-α, IL-6, and soluble TNF receptor 1 levels were found after the acupuncture intervention, and there were significant post-intervention group differences in IL-6, CRP, and TNF-α.³³ Hu et al²⁶ examined the effects of daily acupuncture sessions for 5 days during chemotherapy to treat breast cancer (n = 30) compared to usual care (n = 30) and found significantly higher post-treatment WBC and neutrophil counts in the acupuncture group than the control group.²⁶ Ni et al³⁴ compared acupuncture daily for 12 days (n = 40) to standard Western medical care (n = 40) in respiratory and digestive cancer patients getting chemotherapy. They reported significant increases in WBC counts in the acupuncture group, significant differences in immunoglobulin M (IgM) scores between the 2 groups, with increases in the acupuncture group and decreases in the control group, and significant increases in IgG in the acupuncture group and decreases in the control group.³⁴ Liu et al³² compared acupuncture provided daily for 5 days (n = 32) to usual care (n = 31) in patients receiving chemotherapy for colorectal cancer. Both groups had lower WBC and neutrophil counts post chemotherapy, but WBC counts were higher in the acupuncture group, and no between-group differences in neutrophil counts were found.³² Lin et al³⁵ examined the effect of acupuncture (n = 30) provided concurrently with chemotherapy, once daily for 7 consecutive days, compared to usual cancer care (n = 30) in patients with advanced non-small cell lung cancer. The study revealed that IFN-γ and IL-2 levels significantly increased, while IL-4 and IL-10 levels significantly decreased in the acupuncture group relative to the control group.³⁵ Wang et al²⁹ examined WBC counts after 3 separate chemotherapy sessions. Acupuncture was provided 30 minutes before chemotherapy (N = 50) or 30 minutes after chemotherapy (N = 50), or the patients were in a usual care control group (N = 50).²⁹ No statistically significant pairwise differences were found in WBC counts across the 3 groups.²⁹

Acupuncture treatment setting unspecified

Gao et al³⁰ examined the effect of acupuncture delivered for 30 minutes, 6 days a week, for 4 weeks compared to a group that did not receive acupuncture among patients with lung cancer. Findings revealed significantly lower post-treatment TNF-α and IL-6 levels in the acupuncture group than the control group.³⁰ Bai et al³¹ provided acupuncture every other day for 2 weeks (N = 50) compared to usual care (N = 50) in patients with unspecified cancers. They found significantly higher CD3, CD4, and CD4/CD8 ratio, as well as significantly lower CD8 levels in the acupuncture group relative to the control group.³¹ Lian et al³⁶ examined patients with unspecified cancers who were provided acupuncture 5 days a week for 6 weeks (N = 60) or usual care (N = 60). Findings revealed increases in IL-2 and IFN-γ levels in both groups, but they were significantly higher in the acupuncture group than the controls. Similarly, both groups had a decrease in IL-4 and IL-10 levels, which was significantly lower in the acupuncture group than controls.³⁶

Meta-analysis

Fifty-six (83%) of the studies were included in the meta-analysis. The study outcome variables explored were as follows: WBC,^{21,22,26,28,29,32,34,37,41,43,44,46,50,53,57,58,60,62,64,66,76,78,81} CD3,^{18,23,27,31,40,46,47,49,53
-55,61,62,65,67,68,75,76,78} CD4,^{18,22,
23,27,31,
37,38,40,45-47,49,53-55,62,67-
70,75,76,
78,80} CD8,^{18,22,23,27,31,36,38,40,45,49,54,
55,57,62,65,67,68,70,75,76,78,80} CD4/8 ratio,^{18,22,23,27,31,38,40,45-
47,49,53,55,61,62,65,67,70,76,78,80} Neutrophils,^{21,22,41,43,46,57,58,62,64,66,71} NK cells,^{38,46,54,67,68,72,73} IgG,^34,52,78 IgM,^{34,52,61,68,78} IL-1,^48,56,60 IL-2,^{36,38,45,49,54,73,78} IL-4,^22,24,36 IL-6,^{22,24,30,33,45,48,56,59,63} IL-10,^23,36,52 TNF-α,^{23,30,33,48,49,52,56,60,78} IFN-γ,^22,24,36 and CRP.^{22,28,33,45,60,66,69,70,78} Details of the meta-analysis, sample size, and heterogeneity can be found in Table 4 (see Supplemental Tables S1–17 for the meta-analysis forest plots of individual studies and outcomes).

Table 4.

Meta-Analysis Results.^a

Marker	Acupuncture group N	Control group N	Number of studies	I² %, P-value	Standardized mean difference	95% Confidence interval	P-value
WBC,^{21,22,26,28,29,32,34,37,41,43,44,46,50,53,57,58,60,62,64,66,76,78,81}	885	880	23	96.74, <.01	0.17	−0.49 to 0.83	.62
CD3,^{18,23,27,31,40,46,47,49,53-55,61,62,65,67,68,75,76,78}	808	807	19	96.80, <.01	6.14	3.28-9.00	<.01
CD4,^{18,22,23,27,31,37,38,40,45-47,49,53-55,62,65,67-70,75,76, 78,80}	947	946	22	97.89, <.01	5.70	3.30-8.09	<.01
CD8,^{18,22,23,27,31,36,38,40,45,47,49,54,55,62,65,67,68,70,75,76,78,80}	871	870	20	97.00, <.01	−0.78	−2.48 to 0.92	.37
CD4/8 ratio,^{18,22,23,27,31,38,45-47,49,53,55,61,62,65,67,70,76,78,80}	895	896	19	87.76, <.01	0.30	0.20-0.41	<.01
Neutrophils,^{21,22,41,43,46,57,58,62,64,66,71}	390	384	11	95.45, <.01	−0.41	−1.30 to 0.49	.38
NK cells,^{38,46,54,67,68,72,73}	235	223	7	98.93, <.01	10.44	2.80-18.09	.01
IgG,^{34,52,61,68,78}	188	188	5	99.13, <.01	2.51	0.11-4.90	.04
IgM,^{34,52,61,68,78}	188	188	5	99.65, <.01	0.91	0.01-1.79	.04
IL-1,^48,56,60	136	135	3	94.07, <.01	−41.14	−73.64-−8.63	.01
IL-2,^{36,38,45,49,54,73,78}	326	319	7	99.82, <.01	−3.85	−23.41 to 15.71	.70
IL-4,^22,24,36	145	145	3	97.18, <.01	−13.29	−21.01-−5.58	<.01
IL-6,^{22,24,30,33,45,48,56,59,63}	416	411	9	99.78, <.01	−29.27	−46.02-−12.52	<.01
IL-10,^23,36,52	150	150	3	99.07, <.01	1.19	−5.90 to 8.28	.74
TNF-α,^{23,30,33,48,49,52,56,59,60,63,70,78}	583	578	12	100.0, <.01	−20.46	−43.54 to 2.62	.08
IFN-γ,^22,24,36	145	145	3	.0, .92	8.82	6.90-10.74	<.01
CRP,^{22,28,33,45,60,66,69,70,78}	381	373	9	98.06 < .01	−12.63	−19.30-−5.95	<.01

N, sample size; I² % = heterogeneity statistic; WBC, white blood cell; NK, natural killer; IgG, immunoglobulin G; IgM, immunoglobulin M; IL, interleukin; TNF, tumor necrosis factor; IFN-γ, interferon-gamma; CRP c-reactive protein.

Acupuncture was associated with significant increases in CD3 (19 studies), CD4 (23 studies), and the CD4/CD8 ratio (20 studies), with sample sizes of over 1000 participants for each outcome. However, for each outcome there was high heterogeneity in the results. Similarly, acupuncture led to increases in NK cell numbers, but there was a high level of heterogeneity in the results between the 7 studies included in the meta-analysis. Five acupuncture studies included in the meta-analysis led to increases in both IgG and IgM, but there was a high level of heterogeneity in the results. Acupuncture was also found to lower IL-1 (3 studies), IL-4 (3 studies), IL-6 (10 studies), and CRP (9 studies), but there was high heterogeneity in results for each marker included in the meta-analysis. One meta-analysis found acupuncture was associated with increases in IFN-γ, and no concerns with heterogeneity.

Acupuncture was not significantly associated with increases in WBCs, neutrophils, CD8-positive cells, or IL-2. Acupuncture was not associated with decreases in TNF-α or IL-10. In all the studies with negative outcomes, there was a high level of heterogeneity in the results.

Discussion

This systematic review and meta-analysis were conducted to examine the use of acupuncture for immune and inflammatory modulation in cancer patients. Sixty-four publications examining the effect of acupuncture on immune function and inflammation met the inclusion criteria for this review, with 56 studies included in the meta-analysis. More than 80 acupuncture points associated with 14 different channels were used, with the most common point being ST36. All reviewed studies were scored as having unclear or high ROB. The meta-analysis showed that acupuncture resulted in improvements in multiple outcomes, but there was a high level of heterogeneity among all the studies except those showing that acupuncture was associated with increases in IFN-γ.

All studies contained some bias, which raises questions about the veracity of the findings. In general, ROB was worse for the oldest studies, with more recent studies having more domains with low ROB ratings, which is similar to a prior meta-analysis.¹¹ The study by Lu et al²⁵ was blinded and had a low ROB for all of the rating criteria except “other sources of bias” due to a small sample size, which caused an unclear ROB rating. Similarly, the study by Lin et al³⁵ met all the criteria for a low ROB except the acupuncture group participants were not blinded to group assignment. Twelve studies appeared well designed, with low ROB, but had a risk of bias owing to the lack of allocation concealment and blinding.^22,26
-36 The majority of the studies had design or reporting biases resulting in unclear or high ROB ratings.

Findings from the studies included in the meta-analyses suggest that acupuncture may play a role in improving immune outcomes and reducing inflammation during different phases of cancer treatment. Meta-analyses revealed improvements in immune function among the acupuncture treatment groups, with increases in CD3 cells, CD4 cells, and the CD4/CD8 cell ratio, as well as NK cell counts, IgG, and IgM. Acupuncture did not affect WBCs, neutrophils, CD8-positive cells, and IL-2 immune markers. IL-1, IL-4, IL-6, and CRP inflammatory markers all decreased in the acupuncture groups, while no significant reductions were found for TNF-α or IL-10. All immune and inflammatory markers, except for IFN-γ, were found to have significant heterogeneity concerns across studies, as expressed by the I² statistic from the meta-analyses.

Several factors may have contributed to the high heterogeneity of the meta-analyses’ outcomes. There were many differences in the acupuncture designs, including the number of acupuncture sessions, the duration of each individual acupuncture session, the acupuncture techniques used, and the number of points and channels/acupoints used. Other design differences included the type of cancers treated and the timing of the acupuncture treatment (eg, before, during, or after surgery, chemotherapy, or radiotherapy). Despite these differences in the design of the acupuncture interventions and patient populations, the improvements in immune and inflammatory markers seen among individuals undergoing cancer treatment suggest that more studies are needed to increase design homogeneity to determine best practices of acupuncture treatments to improve immune and inflammatory markers.

Our study is the first systematic review/meta-analysis to examine the effects of acupuncture on multiple immune and inflammatory markers among people receiving cancer treatment. However, previous studies do provide support for our findings. In one review of acupuncture and moxibustion that focused on leukopenia,⁸³ all unblinded acupuncture trials were rated as having a high ROB, as we did here. One meta-analysis of acupuncture’s effect on patients with chronic obstructive pulmonary disease found significant improvements in immune function through an increase in the CD4/CD8 ratio, as did our study, but differed in finding a significant reduction in CD8-positive T cells.⁸⁴ Like the current study, another meta-analysis of acupuncture’s effect on cytokines in rodent animal models by Lee and Kim⁸⁵ found significant reductions in IL-1 and IL-6, but unlike the current study, they found a significant reduction in TNF-α, as well as increases in IL-10.⁸⁵ Our findings differed from prior meta-analyses on acupuncture for chemotherapy induced leukopenia and bone marrow suppression where they found that acupuncture improved WBC counts and neutrophils,^8,9,11 while another found no significant differences in neutrophil counts.¹⁰ However, one of the meta-analyses of acupuncture’s effect on leukopenia reported the poor methodological quality of studies included in their analyses.¹¹ Oh and Kim⁸⁶ conducted a literature review of acupuncture at ST36 (the most common acupoint used in the current study) and reported clinical benefits in reducing inflammation.

As with any systematic review, our study had several important limitations. An attempt was made to include databases with the most relevant literature. Other databases and/or search strategies may have produced a different list of RCTs to be screened, and important studies may have been overlooked due to publication bias. Although previous animal and human studies^12,13,83 have shown that the use of moxibustion had a positive effect on immune modulation, cancer centers in the US do not use this technique because of smoke exposure and the associated strong smell. In addition, 61 studies were conducted in China, with only 2 studies conducted in the US and one study conducted in Indonesia. The feasibility of conducting these types of studies outside of China is also at issue. The studies conducted in China included only inpatient populations, and patients were treated daily. Long peri-treatment hospitalizations for cancer patients without complications are standard in China, but not in the US. It is unclear if a less intensive therapy would yield similar outcomes. One study conducted in the US²⁵ screened 587 patients to enroll 21 patients. Over 50% of these patients were excluded based on the treating physician’s decision and 20.7% were not enrolled because of competing protocols. This is a significantly lower rate of enrollment than for other trials of acupuncture reported by Dana Farber as well as other institutions, possibly reflecting skepticism of the utility of acupuncture for this indication. Many of the studies included were underpowered because of small sample sizes. Furthermore, as optimal treatment and dosing parameters are unknown, heterogeneity in study design, outcome measures, and treatment parameters makes comparisons across studies difficult. There was also a high I² heterogeneity statistics for the results for all meta-analyses except IFN-γ. Moreover, no studies used the same interventions, which limited each meta-analysis calculation, and suggests that these findings cannot determine which treatments are best for which immune and inflammatory markers. The study also could not explore subgroup analyses to determine specific factors that could optimize the benefits of acupuncture on immune outcomes. The meta-analyses assumed an arbitrary within-subject correlation of .3 for calculating SDs of the pre-post difference outcomes, as needed, which may have skewed outcomes to certain extent, either downward or upward. Despite this limitation, we believe the moderate correlation assumption is realistic and likely not far off from the truth. Finally, calculations for 6 biomarker meta-analyses employed only 3 studies and should be interpreted with caution.

Although the exact mechanisms of acupuncture are not yet fully understood, leading researchers suggest that acupoints and meridians may function as part of the autonomic nervous system,⁸⁷ helping to explain the broad physiological effects observed. However, to explore acupuncture’s role more effectively as it related to immune regulation, well-designed, adequately powered studies with low risk of bias are necessary to provide meaningful clinical guidance. In our review, most of the 64 studies included were rated as having unclear ROB, with 11 rated as high risk. These challenges in study design and reporting are well-known in acupuncture research,⁸⁸ and our finding was no exception. One key issue is the appropriate selection of controls. Given that the mechanisms of acupuncture are still being explored, we advocate for a research design that mirrors real-world practice as closely as possible, using best standard practices as the control.⁸⁹ This is particularly important because syndrome differentiation is a crucial factor in selecting acupuncture points in real practice, yet sham control points do not account for this, which may make them suboptimal controls. Yet many will see this approach as a challenge to control and still advocate for the sham-controlled design. Immune outcomes being a more objective outcome allays some of the concerns typically associated with the placebo response. Future research should also be designed in a manner to explore demographic or medical factors that can predict better or worse immune response to acupuncture treatment.

This study had several strengths. This is the first to quantify acupuncture’s effects on multiple immune and inflammatory markers among people receiving cancer treatment. Biomarkers are less prone to the influence of allocation concealment and participant blinding than a self-report measure like pain or nausea, and 12 studies were well designed in this regard. The majority (65%) of the meta-analyses for a specific immune or inflammatory outcome used 6 or more studies.

It is important to put the use of acupuncture for immune modulation into its full clinical context. Acupuncture is a safe and cost-effective treatment for many indications. In the case of leukopenia/neutropenia, it would be important to examine the cost-benefit ratio in terms of number of patients needed to treat to prevent febrile neutropenia, the clinically relevant endpoint. The field of cellular immunity has rapidly evolved over the past 10 years. It would be particularly interesting to examine the impact of acupuncture on regulatory T-cell populations and tumor-infiltrating lymphocytes, or to examine the effects of combining acupuncture with the new immune checkpoint inhibitor immunotherapies to “prime” the immune system, as is being done with combined vaccine and checkpoint-inhibitor protocols.

Conclusion

Acupuncture appears to result in significant and meaningful improvements in immune function and reduced inflammatory biomarkers without unwanted side effects. However, the findings from this systematic review and meta-analyses suggests that better-designed, well-powered studies with low ROB designs are needed. More rigorous trials using sham acupuncture groups and/or research design that mirror real-world practice in larger populations are required to validate these findings. Multi-armed research studies comparing interventions focused on specific immune/inflammatory markers could increase acceptance among oncologists that acupuncture may help modulate immune and inflammatory outcomes. Even so, 12 studies would have met low ROB criteria except for allocation concealment and blinding, which is less of an issue for an objective outcome like immune and inflammatory markers relative to subjective outcomes like pain. Acupuncture could be part of an integrative cancer treatment approach for supporting surgery, chemotherapy, and radiotherapy. As a safe and cost-effective treatment, acupuncture could be used to help reduce immune suppression and inflammation in cancer patients.

Supplemental Material

sj-docx-1-ict-10.1177_15347354241302072 – Supplemental material for Systematic Review and Meta-analysis of Acupuncture for Modulation of Immune and Inflammatory Markers in Cancer Patients

Supplemental material, sj-docx-1-ict-10.1177_15347354241302072 for Systematic Review and Meta-analysis of Acupuncture for Modulation of Immune and Inflammatory Markers in Cancer Patients by Wenli Liu, Baisong Zhong, Richard W. Wagner, M. Kay Garcia, Jennifer L. McQuade, Wen Huang, Yisheng Li, Graciela M. Nogueras Gonzalez, Michael R. Spano, Alessandro Cohen, Yimin Geng and Lorenzo Cohen in Integrative Cancer Therapies

Supplemental Material

sj-docx-2-ict-10.1177_15347354241302072 – Supplemental material for Systematic Review and Meta-analysis of Acupuncture for Modulation of Immune and Inflammatory Markers in Cancer Patients

Supplemental material, sj-docx-2-ict-10.1177_15347354241302072 for Systematic Review and Meta-analysis of Acupuncture for Modulation of Immune and Inflammatory Markers in Cancer Patients by Wenli Liu, Baisong Zhong, Richard W. Wagner, M. Kay Garcia, Jennifer L. McQuade, Wen Huang, Yisheng Li, Graciela M. Nogueras Gonzalez, Michael R. Spano, Alessandro Cohen, Yimin Geng and Lorenzo Cohen in Integrative Cancer Therapies

Footnotes

Author Contributions

Conception and design: JM, MKG, WH, YL, MS, LC Collection and assembly of data: WL, BZ, AC, JM, MKG, RWW, YG, LC. Data analysis and interpretation: WL, BZ, JM, MKG, YL, GMNG, AC, YG, LC. Funding acquisition: JM, MKG, LC Writing – original draft: WL, JM, MKG, RWW, LC Writing – review & editing: All authors. Final approval of manuscript: All authors. Accountable for all aspects of the work: All authors.

Data Availability Statement

All data generated or analyzed during this study are included in this published article (and its supplementary information files).

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Support was provided in part by the United States National Cancer Institute (NCI) grants CA148707 and CA160880, and The University of Texas MD Anderson Cancer Center. Partial support for Lorenzo Cohen was also provided by the Richard E. Haynes Distinguished Professorship in Clinical Cancer Prevention. We would especially like to thank Greg Pratt, The University of Texas MD Anderson Cancer Center, for library support and assistance in database searches and strategy, and Dawn Chalaire from the office of Scientific Publications for her editorial support and assistance.

ORCID iD

Richard W. Wagner

Supplemental Material

Supplemental material for this article is available online.

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