The Impact of Acupuncture on Nausea and Vomiting in Cancer Patients: A Systematic Review and Meta-Analysis

doi:10.21203/rs.3.rs-4791691/v1

Background

Nausea and vomiting (NV) are among the most common adverse effects experienced by patients with cancer undergoing treatment worldwide. Because pharmacotherapy is often complicated by medication interactions and causes unwanted side effects, acupuncture may be an optimal candidate for these patients. The objective of this systematic review and meta-analysis was to assess the effectiveness and safety of acupuncture for treating NV in patients with cancer.

Methods

Three electronic databases and two clinical registry platforms were searched from inception to October 11th, 2023. Methodological quality was assessed using the Cochrane risk of bias (ROB).

Results

Fifteen randomized controlled trials (RCTs) were included in the qualitative review, whereas eight RCTs were analyzed for subsequent quantitative meta-analysis. Meta-analysis demonstrated that acupuncture had a significant effect on cancer patients with delayed vomiting (risk ratio (RR): 0.75; 95% confidence intervals (CI): 0.58 to 0.97; p = 0.03; I² = 51%; n = 139). A subgroup analysis con-firmed no significant effect until day 3; however, it became significant on day 5 (RR: 0.56; 95% CI: 0.39 to 0.81; p = 0.002; I² = 0%; n = 92). The most frequently used points were PC6, ST36, CV12, LI4, LR3, and ST25.

Conclusions

In this review, acupuncture showed significant effects on delayed vomiting in cancer patients undergoing various emetogenic cancer-related therapies. These results suggest that clinicians could expect substantial effectiveness with at least five days of acupuncture therapy, with acupuncture points PC6, ST36, CV12, LI4, LR3, and ST25.

Systematic review registration:

the PROSPERO database (registration number: CRD42022333811)

Cancer

Nausea

Vomiting

Acupuncture

Systematic review

Meta-analysis

Nausea and vomiting (NV) are the most common and distressing symptoms experienced by more than 80% of cancer patients (1). These are induced by emetogenic antitumor treatments such as chemotherapy, radiotherapy, or surgery, as well as by the cancer itself. These symptoms can lead to poor compliance with anti-cancer treatments, resulting in metabolic imbalance, malnutrition, dehydration, and an immunodeficient state (2). 5-hydroxytryptamine type 3 receptor antagonists and neurokinin-1 receptor antagonists are commonly recommended as antiemetic prophylaxis in the National Comprehensive Cancer Network (NCCN) guidelines; however, these have comparatively reduced emesis but not nausea (3). Antiemetic agents can produce adverse effects including electrocardiographic changes, sedation, headache, and constipation (4). Considering their weakened conditions due to several overlapping symptoms, patients have sought alternative therapies which were effective, sustainable, and safe.

Acupuncture is a nonpharmacological therapy used to improve NV in patients with cancer. Acupuncture is known to increase the hypophyseal secretion of beta-endorphins and adrenocorticotropic hormone, with subsequent inhibition of the chemoreceptor trigger zone and vomiting center (5). Considering that the autonomic nervous system is involved in the peripheral mechanism of NV, vagal modulation through the Neiguan (PC6) has proven to be effective (6). Furthermore, acupuncture has fewer side effects than antiemetics, which might be an advantageous factor for cancer patients (6).

Previous systematic reviews have been conducted to establish the effectiveness and safety of acupuncture on NV in patients with cancer. Though there have already been many reviews, we discovered that current studies had not sufficiently reflected the actual clinical settings of cancer patients. First, most studies usually investigated chemotherapy-induced NV (CINV) or radiotherapy-induced NV (RINV). Considering that cancer patients who visit clinics for NV would not been limited to these NV types, it would be valuable to systematically review these all types of NV patients with cancer. Second, it would be necessary to specifically analyze the entire acupuncture treatment regimen for clinicians, as acupuncture treatment comprises complex components, including selection of acupuncture points, number of needles, manipulation after insertion, and depth of insertion. As there have been no established guideline for acupuncture treatment for NV patients with cancer, it would be essential to summarize the detailed treatment protocols in previous randomized controlled trials (RCTs) and to refer these treatment regimens to evaluate the effectiveness and safety.

This study systematically evaluated the efficacy and safety of acupuncture treatment in the management of cancer patients with all types of NV based on a meta-analysis. To propose a more practical therapy for clinical care, we investigated acupuncture treatment protocols according to the Standards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA) guidelines.

This systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We registered this protocol in the PROSPERO database (registration number: CRD42022333811) and published the study protocol (7).

Criteria for inclusion and exclusion

We comprehensively included all patients with cancer and various triggering factors of NV. The patients who complained of nausea and vomiting, regardless of age, sex, nationality, ethnicity, or etiology, were included.

The intervention types were confined to acupuncture treatments involving needle insertion, including manual acupuncture, electroacupuncture, intradermal acupuncture, auricular acupuncture, and laser acupuncture. All these types of acupuncture involve the skin puncture through acupuncture needle or laser; there are some differences in clinical practice, such as applying electronic stimulation (electroacupuncture), embedding short needles with tape for several days (intradermal acupuncture) or maintaining intradermal acupuncture at ear (auricular acupuncture). Other therapies that do not puncture the skin or combine other stimulation methods, including acupressure, transcutaneous electrical acupoint stimulation, warm needling, plum blossom needle, fire needling, cupping and moxibustion, were excluded. Comparative interventions, including active therapies, sham acupuncture (pseudo-acupuncture interventions, non-penetrating sham acupuncture, sham acupuncture at non-acupuncture points, sham acupuncture at selected acupuncture points, and needling at inappropriate acupuncture points), and no treatment were included. Acupuncture, either used alone or in combination with other therapies that were the same as the comparison intervention, was also included. Studies that did not provide the acupuncture point information were excluded.

We included only randomized controlled trials (RCTs) that recruited more than 30 participants to clarify the quality of the study and the effect size of the evidence (8). There were no restrictions on publication language.

Outcomes measures

The primary outcome was the incidence of nausea and vomiting. Other characteristics indicating the severity of nausea and vomiting, such as the duration, frequency, stage, or intensity of symptoms, were included as secondary outcomes.

Literature searches

Studies published up to October 11, 2023, were retrieved from the following three databases: MEDLINE via PubMed, Embase via Ovid, and the Cochrane Central Register of Controlled Trials. Two clinical registries, the National Institutes of Health Clinical Registry (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform, were also screened to reduce the risk of publication bias. Potentially missing eligible studies were manually scanned from the reference lists of other systematic reviews using the following search terms: cancer, tumor/tumor, neoplasm, nausea, vomiting, emesis, acupuncture, and randomized controlled trials. These terms were used alone or in combinations, using “and,” “or” (Supplementary Table 1). The search strategy was tailored to individual databases.

Data selection

The titles and abstracts of the studies were reviewed by two independent researchers (SAK and SBNL) after retrieving all eligible studies in EndNote 21 (Clarivate Analytics) and eliminating duplicate publications. The full texts of all potentially eligible studies were retrieved. Any disagreement regarding data selection was resolved by an arbiter (YSJ). A PRISMA flow diagram showed the study search and screening process (Fig. 1).

Data extraction

The following data were extracted by two researchers (SAK and SBNL): author, year of publication, country, cancer type, cause of NV, sample size, age, interventions, controls, outcome measures, main findings, and adverse events. In addition, to analyze the acupuncture treatment protocols used in the studies, the following data were extracted with reference to the STRICTA guidelines: names of acupuncture points, number of needle insertions, depth of insertion, needle type, needle stimulation, needle retention time, number of treatment sessions, treatment time, setting and context of treatment, and description of the participating acupuncturists. A third reviewer (YSJ) assessed any disagreements.

Quality assessment of included studies

Two authors (SAK and SBNL) independently evaluated the risk of bias (ROB) using the Cochrane Collaboration assessment method (9). The following biases were assessed: selection, performance, attrition, detection, reporting, and other sources of bias. The judgments were low, high, and unclear. The arbiter (YSJ) resolved any disagreements regarding the bias assessment. After transferring the data, analysis and synthesis were conducted using RevMan V. 5.4 software (Cochrane Collaboration, Oxford, UK). For the reporting biases, the funnel plot was analyzed using RevMan V. 5.4.

Data analysis

The effects of treatment were analyzed as risk ratios (RR) with 95% confidence intervals (CI) using a random-effects model as substantial statistical heterogeneity was found. We evaluated heterogeneity for quantifying inconsistency by the I² test and detected statistical heterogeneity with standard χ² test. If the I² value > 50% or the p-value was < 0.100, studies were considered to have significant heterogeneity, and subgroup analysis was conducted to analyze the potential causes. A subgroup analysis was performed according to the treatment periods. Differences were considered statistically significant at p < 0.05. Reporting biases were assessed using funnel plots. RevMan V.5.4 was used to implement the data synthesis for the meta-analysis. Descriptive analysis was performed if the data between trials were inappropriate for merging.

Study characteristics

A total of 1037 publications were identified from databases and clinical registries. Three additional records from other sources were identified. After removing duplicate records, we screened the titles and abstracts of 593 studies. Fifty full-text articles were assessed for eligibility. Of these 50 articles, fifteen studies were finally included in this review. These search procedures are presented in the PRISMA 2020 flowchart in Fig. 1.

In summary, this study included 1,682 patients, with sample sizes ranging from 32 to 324. The cancer types were diverse; six studies included only patients with a single type (e.g., breast, colorectal, gynecologic, or lung cancer), whereas nine studies comprehensively included multiple carcinoma types. The causes of NV include chemotherapy, blood stem cell transplantation, surgery, and radiotherapy. Among these causes, 12 studies (80%) investigated patients with CINV, and seven of these studies presented the type of anticancer drugs. For intervention and control groups, adjuvant pharmacotherapies were administered to patients in 14 studies (93%) to implement acupuncture or placebo treatment. Seven studies (46.5%) used manual acupuncture treatment, seven studies (46.5%) used electroacupuncture treatment, and one study used intradermal acupuncture treatment. Outcome measures included the incidence of NV, whereas other patient self-assessment scales included the efficacy rate, numeric rating scale (NRS), Rhodes Index of Nausea, Vomiting, and Retching (RINVR), and Multinational Association of Supportive Care in Cancer Antiemesis Tool (MAT). Excluding two studies that did not report adverse events (AEs), there were no AEs in seven studies, only a few minor AEs in eight studies, and no serious AEs were observed. The main findings were identified as positive in 11 studies and unclear or negative in four studies (Table 1).

Acupuncture treatment protocol analysis

A total of 11 acupuncture points were used across the 15 trials. Each point was used 1–14 times in various combinations. The most frequently used point was PC6, which was prescribed in 14 of the 15 studies. The second most frequently used point was ST36, which was selected in 11 studies. The following points were seldom used in two or three studies: CV12, LI4, LR3, and ST25. Points rarely used in one study were CV6, LR13, PC5, ST37, and ST39 (Fig. 2). The sites of acupuncture points with the anatomical location terms are presented in Supplementary Table. 2 (10).

Needle stimulation types included manual acupuncture (46.6%), electroacupuncture (46.6%), and intradermal acupuncture treatment (6.8%). In electroacupuncture treatment, the frequency used in most studies was 2–20 Hz, and one study used a mixed frequency of 2/100 Hz. De-qi was induced in 13 studies with rotation, twirling, lifting, or thrusting, whereas 2 studies did not mention it. The number of needle insertions varied between 2 and 14. For needle retention time, 30 minutes was most frequently used (53%), and the next most used was 20 minutes (33%). Exceptionally, intradermal acupuncture was maintained for 3 days. For patients with CINV, the treatment time ranged from 10 minutes to 2 hours, mostly before chemotherapy, of which 30 min was extremely common. In other patients, acupuncture treatment was performed 1 and 2 days after surgery, whereas it was implemented before or after the radiotherapy sessions. The number of treatment sessions varied from 1 to 12 (Table 2).

Table 2

Summary of Acupuncture Treatment Protocol using STRICTA criteria
Author year	Names of acupoints	Number of needle insertions	Depth of insertion (mm)	Needle type	Needle stimulation	Needle retention time (minutes)	Number of treatment sessions	Treatment time	Setting and context of treatment	Description of participating acupuncturists
Shen 2000 (19)	PC6, ST36	4	30 ~ 45	36-gauge (Seirin, Japan)	Electrical (2 ~ 10 Hz, < 26 mA), De qi (rotation)	20	5	2 hours before chemotherapy	Inpatient (Oncology center at a university medical center)	Acupuncture clinician with 3 and 20 years of acupuncture training
Streitberger 2003 (20)	PC6	2	NM	0.25 x 40 mm (Asia med, Germany)	Manual, De qi	20	2	30 minutes before chemotherapy	University of Heidelberg	Two trained acupuncturists
Mehling 2007 (21)	PC6, ST36, additional points according to patients	4 ~ 14	3 ~ 90	34-gauge (Seirin, Japan)	Manual, De qi	20	2	1, 2 days after surgery	University of California, San Francisco	Two licensed acupuncturists
Yang 2009 (22)	ST36	2	25 ~ 30	0.30 x 40 mm	Electrical (NM), De qi (rotation)	30	10	30 minutes before chemotherapy	Jilin Hospital at Changchun, China	NM
Enblom 2012 (23)	PC6	2	15	0.30 x 40 mm (Dongbang, Korea)	Manual, De qi (twirling and lifting)	30	12	Before or after the radiotherapy session	Two Swedish University Hospitals	Seven acupuncture-trained physiotherapists with experience (range 2–12 years)
Beith 2012 (24)	PC6, ST36, LI4,	4	NM	0.20 x 25mm (Viva, China)	Electrical (2 Hz, for a 1.5-second duration pulse width), De qi (rotation)	20	4	2 hours before chemotherapy (each first, second cycles of chemotherapy)	Oncology clinic at the Royal Prince Alfred Hospital, Australia	Two acupuncturists with more than 6 years of training and 10 years of experience
Zhang 2014 (25)	PC6, PC5	4	13 ~ 23	0.30 x 25mm (Jiangsu med, China.)	Electrical (20Hz, 0 ~ 10mA), De qi	60	6	30 minutes before chemotherapy	Inpatient of first affiliated hospital of china medical university, Zhejiang, China	NM
McKeon 2015 (26)	PC6, ST36, LI4, LR3	8	2 ~ 15	0.20 x 30mm (Sensei, China)	Electrical (10 Hz, < 10 mA), De qi (thrusting, twirling)	30	2	10 minutes before chemotherapy	Mater Health Services Adults Day Oncology Unit, Brisbane, Australia	A trained acupuncturist with an advanced diploma of acupuncture with 6 years of clinical practice at the time of the study
Rithirangsriroj 2015 (27)	PC6	2	NM	NM	Manual, De qi (rotation)	30	2	30 minutes before chemotherapy	King Chulalongkorn Memorial Hospital Bangkok, Thailand	A third author of this study
Wang 2018 (28)	PC6, ST36, ST37, ST39 (+ CV12, ST25)	6	30 ~ 70	NM	Electrical (2 Hz, 2 ~ 3 mA), De qi (rotation)	30	1 ~ 3	(1) 1 day before chemotherapy (2) 1 day and 30 minutes before chemotherapy (3) 1 day, 30 minutes before, 1 day after chemotherapy	Ningxia medical university, Yinchuan, China	NM
Wang 2019 (29)	PC6, CV12, ST36	5	20 ~ 30	0.25 x 40mm	Manual, De qi	30	3	30 minutes before or after chemotherapy	Zhejiang Chinese Medical University, China	NM
Li 2020 (30)	PC6, CV12, CV6, ST25, ST36, LR13	10	10–35	0.25 x 40mm (Ande, China)	Electrical (2/100Hz), De qi	30	6	Twice on the first day of chemotherapy, and once consecutively on the following 4 days	Beijing Shijitan Hospital, Beijing Friendship Hospital, Beijing Hospital of Traditional Chinese Medicine, and Guang’ Anmen Hospital	All the acupuncturists who participated in this trial were major in acupuncture for more than 3 years with Chinese medicine practitioner license and had undergone rigorous training in conducting this trial
Cheng 2020 (31)	PC6, ST36	4	NM	0.25 x 40mm (Andi med, China)	Manual, De qi (twirling, rotating)	30	5	30 minutes before or after chemotherapy	Beijing Traditional Chinese Medicine Hospital	Physicians with 3 years of experience performed the acupuncture for patients
Maeng 2022 (32)	PC6, ST36, LI4, LR3 + (HT8, SP2, LR1, SP1, or GB41, SI5, LI1, ST45)	8	NM	0.25 x 40mm (Dongbang, Korea)	Manual, NM	20	3	1 hours before chemotherapy	Kyung Hee University Hospital	Korean medical doctors
Bintoro 2022 (33)	PC6, ST36	4	NM	NM	Intradermal, NM	3days	1	Before chemotherapy	Inpatient, Dr. Cipto Mangunkusumo Hospital, Jakarta	NM
*AT, acupuncture treatment; BSCT, Blood stem cell transplantation; CINV, chemotherapy-induced nausea and vomiting; EA, electroacupuncture treatment; FLIE, Functional Living Index Emesis tool; IA, intradermal acupuncture; MAT, Multinational Association of Supportive Care in Cancer Antiemesis Tool; NRS, numeric rating scale; NV, nausea and vomiting; PT, pharmacotherapy; RINVR, the Rhodes Index of Nausea, Vomiting, and Retching; SA, sham acupuncture; SEA, sham electroacupuncture, SIA, sham intradermal acupuncture.

Quality of included studies

The overall results of the ROB analysis are summarized in Fig. 3. In random sequence generation, 13 studies had a low risk and 2 studies had an unclear risk. In allocation concealment, nine studies had a low risk and six studies had an unclear risk. Regarding the blinding of patients and personnel, 3 studies had a low risk, 3 studies had an unclear risk, and 9 studies had a high risk. Regarding blinding of outcome assessment, eight studies had a low risk, and seven studies had an unclear risk. Fourteen studies were at low risk, and one study had an unclear risk due to incomplete outcome data. Six studies were at low risk and nine studies were at an unclear risk of selective reporting. All studies had a low ROB with regard to other biases.

Funnel plots were analyzed with Egger’s test for all types of acupuncture for nausea (bias estimate: -0.940 (se = 0.397); t = -2.37; p-value = 0.045) and vomiting (bias estimate: -1.029 (se = 0.861); t = -1.20; p-value = 0.2708) respectively (Supplementary Fig. 1).

Effects of acupuncture on nausea

A meta-analysis of acupuncture treatment was conducted according to acute and delayed phases of nausea. The overall meta-analysis demonstrated that acupuncture had no significant effect on patients with nausea (RR: 0.99; 95% CI: 0.89 to 1.10; p = 0.1; I² = 36%; n = 341). In the acute phase, six studies found that acupuncture had no significant effect on patients with nausea (RR: 1.04; 95% CI: 0.90 to 1.20; p = 0.63; I² = 0%; n = 125). In the delayed phase, seven studies found that acupuncture had no significant effect on patients with nausea (RR: 0.94; 95% CI: 0.80 to 1.11; p = 0.49; I² = 61%; n = 216) (Fig. 4).

Effects of acupuncture on vomiting

A meta-analysis of acupuncture treatment was conducted according to the acute and delayed phases of vomiting. The overall meta-analysis demonstrated that acupuncture had no significant effect on patients with vomiting (RR: 0.81; 95% CI: 0.65 to 1.00; p = 0.06; I² = 57%; n = 528). At acute phase, six studies found that acupuncture had no significant effect on patients with vomiting (RR: 0.88; 95% CI: 0.58 to 1.34; p = 0.55; I² = 68%; n = 106). In the delayed phase, seven studies found that acupuncture had a significant effect on patients with insomnia (RR: 0.75; 95% CI: 0.58 to 0.97; p = 0.03; I² = 51%; n = 139) (Fig. 5).

A daily meta-analysis of acupuncture treatment was also performed for the subgroup analysis. We divided the patients into groups for days 1, 2, 3, and 5 or more because there were no data for day 4. On day 1, which was defined as the acute phase, the results were the same as those of the meta-analysis of the acute phase of vomiting. On days 2 and 3, a total of six studies found that acupuncture had no significant effect on patients with vomiting (RR: 0.83; 95% CI: 0.66 to 1.05; p = 0.12; I² = 30%; n = 115; RR: 0.84; 95% CI: 0.67 to 1.06; p = 0.15; I² = 28%; n = 208). On day 5 or more, two studies found that acupuncture had a significant effect on patients with vomiting (RR: 0.56; 95% CI: 0.39 to 0.81; p = 0.002; I² = 0%; n = 92) (Fig. 6).

Fifteen RCTs were extracted for qualitative synthesis, and 10 RCTs were analyzed for quantitative synthesis. In this meta-analysis, we investigated the RR of NV occurrence according to acute and delayed states. The overall effect of acupuncture for nausea and vomiting was not significant. In subgroup analysis, the effect on vomiting was confirmed to be significant in the delayed phase when compared to sham or no treatment. No serious or infectious AEs were reported, and only a few minor AEs, such as local bleeding and bruising at the acupuncture site, were found in patients who were concurrently receiving chemotherapy, radiotherapy, or surgery.

Clinical and research implications

This study had several strengths. First, this study applied stringent outcome values in a meta-analysis using complete control of whether the symptoms occurred rather than partial improvement in symptoms. With these incidence outcomes of complete control, the meta-analysis was identified as insignificant in both nausea and vomiting symptoms. As the heterogeneity was found to be substantial in vomiting symptom, we conducted the subgroup analysis to identify the source of heterogeneity. Included studies varied in intervention treatment period, so we analyzed subgroups according to the treatment period. In this analysis, we also found that significance changed. Though there were no significant results within 24 h, it appeared to be significant in the delayed phase, particularly after 5 days of treatment. Although we could not completely rule out spontaneous remission over time, it was significant that patients who received acupuncture treatment showed more lasting effects than the sham or no treatment groups. In particular, the recent RCT included in this review has identified the long-term effectiveness of acupuncture treatment by continuously evaluating the severity of NV for up to 21 days (11). These lasting effects of acupuncture treatment may be due to spinal, supraspinal, and cortical mechanisms through modulation of the neural circuits (12). This has critical implications for clinicians when setting treatment methods and for researchers when establishing intervention protocols for future trials. For example, the included studies have administered acupuncture treatment shortly (e.g., 30 min, 1 h, or 1 d) before or after a cycle of chemotherapy, radiotherapy, or surgery. Considering its lasting effects, acupuncture treatments for at least 5 days before scheduled anticancer therapy or continuous treatments between therapy cycles might be more efficacious. In addition, although there have been no studies on anticipatory NV, which is one of the most distressing symptoms in cancer patients with NV, pre-administered acupuncture treatment might be effective in preventing anticipatory NV.

Second, we systematically extracted treatment regimen data from each included study and identified several advantages and disadvantages. PC6 was the most frequently prescribed acupuncture point, but ST36 was also frequently used. In addition, CV12, LI4, LR3 and ST 25 were also practiced more than once among total eleven acupuncture points. In previous network analyses, CV12, ST25, ST36, and LR3 have been identified as the main acupuncture points for treating gastrointestinal dysfunction by modulating the 5-hydroxytryptamine system, visceral hypersensitivity, gastrointestinal motility, and mucosal permeability; promoting the secretion of neuropeptide hormones; and activating vagal activity in the nucleus tractus solitaries (13, 14). In ST36, the mechanisms of vagal-adrenal axis modulation through somatosensory autonomic reflexes have been newly determined so that NV could also be alleviated through these specific autonomic pathways (15). These points are commonly applied to fatigue, pain, sleep disorders, and psychological symptoms in cancer patients. As these comorbidities are also risk factors for NV, attenuating these symptoms together might be effective in controlling NV (11, 13, 16). These acupuncture points are also known to be free from AE, as confirmed in our study, considering their location in the abdomen or limbs (17). Therefore, we confirmed both the therapeutic effects and safety of these acupuncture points, so that using these points in combination could be a worthwhile treatment option in clinical practice. Instead, several acupuncture parameters in the protocols seemed to be inappropriate in terms of the dose. Determining a treatment regimen with sufficient dose for specific symptoms is critical in RCTs. Moreover, as acupuncture is a complex and multifaceted intervention, there are numerous components of acupuncture needling procedures, such as the depth of insertion, needle size, treatment period, frequency, and number of needles. In this review, most studies applied treatment in five sessions with fewer than 10 needles. Even for pain, a reliable dose were known that treatments of at least two or more sessions a week for six to twelve weeks (18). Compared to this acupuncture dosage for pain, the doses of the included RCTs were insufficient to achieve optimal therapeutic response, although cancer patients were already physically exhausted and had a low threshold for extrinsic stimuli.

Third, this study established strict inclusion and exclusion criteria for study selection so that the included studies were not rated as high risk for most items in the ROB assessment. For example, there were rigorous criteria for sample size and definition of intervention to draw a valid conclusion and distinctly discriminate between the intervention and control groups. We confined the intervention type to skin-penetrating acupuncture. In our preliminary search, there were several RCTs on acupuncture types without skin penetration, such as acupressure, acupuncture point stimulation, or transcutaneous electrical acupoint stimulation. However, as sham acupuncture using a non-penetrating needle is usually set as the control group, we thought that acupuncture without skin penetration would not be appropriate for the intervention type in RCTs. It became the main reason for the high risk of bias for blinding of personnel as a complete blinding state for clinicians was difficult in performing skin-penetrating acupuncture treatment, even with manipulation for de-qi. However, several studies have specified methodologically rigorous steps to overcome these limitations, such as assigning practitioners as completely independent at every stage of the trial. The included studies also exhibited low selection, attribution, and other biases. Considering the unclear risk of bias in detection and reporting, we suggest methodological improvements in describing the independent statistician, trial registration number of the clinical trial registry, published clinical study protocols, or pilot RCT.

Limitations

This study had several limitations. First, we did not find any significant effect of acupuncture on nausea or acute vomiting. We performed a meta-analysis of the incidence of NV reflecting only complete control of symptoms. Although there were a few validated outcome measurements such as RINVR and MAT, most of the included studies did not apply these outcomes. This would be useful for researchers, as these outcomes evaluated the symptoms of NV in many different items, such as symptom frequency, duration, and patient discomfort, and showed gradual improvements by numerical scoring. Furthermore, a more comprehensive approach that considers other psychological or symptom-related factors (e.g., anxiety, sleep disorders, fatigue, or reducing AEs from pharmacotherapy) as secondary outcome measures would be valuable for understanding cancer patients. Second, there was high heterogeneity in the acupuncture treatment protocol and control group; therefore, there might be specific effects resulting in the underestimation of verum acupuncture treatment effects. In addition, most of the included studies compared acupuncture as an add-on treatment, and we could not specifically evaluate the independent effectiveness of acupuncture. Therefore, it is necessary to formulate and conduct standardized treatment protocols in future studies to confirm the efficacy of acupuncture. For example, meta-regression analysis would be possible with covariates, such as the number of needle insertions, depth of insertion, or needle stimulation. Third, although we attempted to comprehensively include various emetic factors in patients with cancer, most studies were conducted on CINV. This might be because chemotherapy has the highest risk of causing NV in patients with cancer; however, there were no cases of NV due to the invasion of cancer cells, such as in gastrointestinal cancer or advanced cancer. Moreover, all the studies focused on the acute or delayed phases of NV, while anticipatory NV was also one of the most distressing symptoms for cancer patients undergoing chemotherapy cycles.

Further studies should focus on the acupuncture treatment period to explore its preventative effects on acute, delayed, and anticipatory NV with a long-term follow-up evaluation.

In this review, acupuncture treatment showed significant effects on delayed vomiting without any serious adverse events in patients with various cancer types undergoing emetogenic cancer-related therapies. These results suggest that cancer patients with vomiting may experience significant improvement after at least five days of acupuncture therapy. The most frequently used acupuncture points are PC6 and ST36, followed by CV12, LI4, LR3, and ST25. However, we found that it was difficult to identify the adequate acupuncture treatment dosages for an optimal therapeutic response due to the insufficient and heterogenous description of the acupuncture treatment regimen. Therefore, further methodologically high-quality and well-described studies are needed to confirm the standardized acupuncture treatment protocol for cancer patients with NV.

Ethics approval and consent to participate

Not applicable

Consent for publication

Not applicable

Availability of data and materials

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

Competing interests

The authors declare that they have no competing interests.

Funding

None

Author’s contributions

Conceptualization: SBNL. Methodology: S-AK, SBNL. Software: S-AK. Investigation: S-AK, SBNL. Data curation: SJY. Writing – Original Draft: S-AK. Writing, Review & Editing: SBNL, and SJY. Visualization: S-AK. Supervision: SBNL.

Acknowledgments

Not applicable

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Table 1 is available in the Supplementary Files section.

The Impact of Acupuncture on Nausea and Vomiting in Cancer Patients: A Systematic Review and Meta-Analysis

Status:

Version 1

Abstract

Background

Methods

Results

Conclusions

Systematic review registration:

Figures

Background

Methods

Criteria for inclusion and exclusion

Outcomes measures

Literature searches

Data selection

Data extraction

Quality assessment of included studies

Data analysis

Results

Study characteristics

Acupuncture treatment protocol analysis

Quality of included studies

Effects of acupuncture on nausea

Effects of acupuncture on vomiting

Discussion

Clinical and research implications

Limitations

Conclusion

Declarations

References

Table 1

Supplementary Files

Status:

Version 1