Acupuncture for patients with cancer-induced xerostomia: a systematic review protocol.

INTRODUCTION: Xerostomia is a common symptom in patients with cancer. Currently available methods to manage xerostomia include stringent oral hygiene using fluoride agents and antimicrobials, saliva substitutes and sialagogic agents, but side effects such as headache, dizziness and sweating can occur with these therapies. Clinical trials have shown that acupuncture may be effective in treating xerostomia. The objective of this systematic review is to assess the effectiveness and safety of acupuncture treatment for xerostomia caused by cancer. METHODS AND ANALYSIS: This systematic review will incorporate articles identified by electronically searching the following databases: PubMed, MEDLINE, the Cochrane Library, AMED, EMbase, WorldSciNet, Nature, Science Online, China National Knowledge Infrastructure, the Chongqing VIP Chinese Science and Technology Periodical Database, the Wanfang Database and China Biology Medicine Disc from inception to 1 December 2019. Other sources including conference proceedings and reference lists of identified publications and existing systematic reviews will also be searched. Two reviewers will independently search the databases, perform data extraction and assess the quality of studies. Data will be synthesised using either a fixed-effects model or a random-effects model, according to heterogeneity testing. Patient-reported change in the Visual Analogue Scale or the Xerostomia Inventory will be assessed as the primary outcome. Saliva collection, whole saliva production and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 will be evaluated as secondary outcomes. RevMan V. 5.3 will be employed for data analysis. The results will be expressed as risk ratios for dichotomous data and mean differences for continuous data. ETHICS AND DISSEMINATION: This protocol will not evaluate individual patient information or affect patient rights and therefore does not require ethical approval. Results from this review will be disseminated through peer-reviewed journals and conference reports. TRIAL REGISTRATION NUMBER: CRD42019129069. © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Although systematic reviews of acupuncture for radiation-induced xerostomia in patients with head and neck cancer have been previously conducted, the present study will update the evidence base by including multiple clinical trials of the past 10 years.

The study design adheres to all relevant guidelines for systematic reviews and meta-analyses.

Given that some clinical results have been used in published trials, it may not be possible to aggregate all included studies; however, subgroup analyses will be performed based on various outcomes.

Variations in study design and patient characteristics among the studies included in this systematic review will likely lead to high heterogeneity that may limit the quality of the evidence.

Introduction

Xerostomia is typically considered to be a subjective sensation of dry mouth and is associated with a decrease in salivary production, one of the most common symptoms in cancer patients, with a reported prevalence of up to 77% of hospice admissions.1 Cancer-induced xerostomia is caused by multiple factors including the consequences of cancer itself, dehydration, the effect of cancer treatment, especially radiotherapy2–7 and chemotherapy8, the use of opioids, antimuscarinic agents and diuretics and pre-existing comorbidities such as Sjogren’s syndrome.9 The current diagnosis is based on the primary complaint reported by the patient.10 A previous study11 found that patients with cancer reported different degrees of dry mouth, reduced drinking and eating and waking up at night due to dry mouth and that the risk of progression to oral ulcers was higher among this patient population and could significantly affect the quality of life.

Xerostomia can also interfere with patient compliance and may lead to treatment delays resulting in inadequate tumour control12; therefore, effective management is a priority. Current available methods to manage xerostomia include stringent oral hygiene with fluoride agents and antimicrobials, saliva substitutes, sialagogic agents13–21 and cytoprotective agents such as amifostine. Currently, the main treatment for xerostomia is medication such as pilocarpine and ceviline which are approved by the US Food and Drug Administration and are effective in promoting salivation and treating dry mouth. However, these strategies are associated with side effects such as headache, dizziness and sweating.19–21 A systematic review of xerostomia in patients with advanced cancer showed that there was low-quality evidence to support the use of salivary substitutes and stimulants for the treatment of xerostomia symptoms.22

Acupuncture is an important component of complementary medicine and has recently gained popularity as a valid palliative intervention modality.23 Emerging reports also suggest that acupuncture may be effective in treating xerostomia.24 Acupuncture has been shown to increase salivary flow in healthy volunteers,25 26 in patients with Sjogren’s syndrome27 and in patients with radiation-induced salivary gland injury.24 28 29 Some studies have shown that acupuncture can alleviate the symptoms of dry mouth caused by cancer30 31 and radiotherapy.29 32 Acupuncture is commonly used in China as a safe treatment for xerostomia in cancer patients with few adverse effects.

In traditional Chinese medicine theory, acupuncture is considered to regulate qi and blood by stimulating acupuncture points and subsequently improving physiological functions. Although the mechanism of acupuncture remains unclear, some studies have shown that the levels of at least two neuropeptides (vasoactive intestinal peptide and calcitonin gene-related peptide) are increased in the saliva following acupuncture treatment.33 34 Because these substances can stimulate salivary secretion, the production of neuropeptides may be the cause of increased salivary secretion.

Although two systematic reviews of acupuncture for radiation-induced xerostomia in patients with head and neck cancer have been published,35 36 the present study will update the evidence base by including multiple clinical trials published over the past 10 years and will systematically evaluate the effectiveness and safety of acupuncture in treating patients with cancer-related xerostomia caused by various factors. Hence, a comprehensive review of acupuncture treatment of xerostomia caused by cancer may be beneficial to patients, practitioners and health policy makers. Therefore, the objective of this systematic review is to evaluate the effectiveness and safety of acupuncture treatment for xerostomia caused by cancer.

Methods and analysis

Review design

This protocol report is structured in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) statement guidelines.37 The review will be implemented in accordance with the PRISMA statement guidelines.38

Inclusion criteria for study selection

Type of study

All randomised controlled trials (RCTs) of acupuncture therapy for cancer-induced xerostomia will be included in the review. The language is limited to English and Chinese. Non-RCTs, quasi-RCTs, case series, reviews and animal studies will be excluded.

Type of participant

Patients diagnosed with cancer and symptoms of dry mouth will be included. There will be no restrictions on gender, education, ethnicity or tumour stage.

Type of intervention

Experimental interventions

Patients who have undergone acupuncture treatment such as body acupuncture, manual acupuncture and electroacupuncture will be included in the experimental group, along with patients who have received acupuncture alongside other treatments. Studies that evaluated laser acupuncture, transcutaneous electrical nerve stimulation, dry needling, moxibustion or cupping will be excluded. The duration and frequency of treatment are not limited.

Control interventions

The control group will include patients treated with control interventions such as placebo acupuncture, sham acupuncture, herbs, western medicine, no treatment (waiting list control), routine care or conventional therapy.

Outcome measures

Primary outcomes

The primary outcomes will be changes in the Visual Analogue Scale and Xerostomia Inventory.39

Secondary outcomes

Secondary outcomes are saliva collection, whole saliva production and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30.40

Search methods for identification of studies

Data sources

The following databases will be searched: PubMed, MEDLINE, the Cochrane Library, AMED, EMbase, WorldSciNet, Nature, Science Online, China National Knowledge Infrastructure, the Chongqing VIP Chinese Science and Technology Periodical Database, the Wanfang Database and China Biology Medicine Disc. The temporal interval will be the time from database creation to 1 December 2019. The WHO International Clinical Trials Registration Platform and Clinical Trials.gov will also be searched for ongoing experimental and Chinese RCTs related to the disease.

Other search resources

A reference list of potential, qualified studies and related system reviews will be manually retrieved and reviewed to determine the location of other RCTs. For ongoing RCTs, the trial author will be contacted for the most up-to-date clinical data. Furthermore, relevant conference proceedings will be evaluated to identify studies related to this review.

Search strategy

The search terms will include acupuncture (eg, “acupuncture” or “acupuncture points” or “body acupuncture” or “manual acupuncture” or “electroacupuncture”), cancer (eg, “cancer” or” “‘tumor” or “neoplasms” or “carcinoma”), xerostomia (eg, “xerostomia” or “dry mouth” or “salivary gland dysfunction” or “hyposalivation” or “hyposiali” or “salivary gland hypofunction”) and randomzed controlled trial (eg, ‘randomized controlled trial” or “controlled clinical trial” or “random allocation” or ‘randomized” or “randomly” or “double-blind method” or “single-blind method” or “clinical trial”). The following terms will be used in the Chinese database searches: “Zhenjiu”, “Zhenci”, “Dianzhen”, “Kougan”, “Kouqiangganzao”, “Tuoyejianshao”, “Tuoyequefa”, “Ai”, “Aizheng”, “Liu”, “Zhongliu” and “Suijiduizhao”. The search strategy for the PubMed database is shown in table 1; this strategy will be modified appropriately for other databases.

Table 1

Search strategy for the PubMed database

Number	Search terms
1	Acupuncture. Mesh.
2	Acupuncture. ti, ab
3	Acupuncture therapy. Mesh
4	Acupuncture therapy. ti, ab
5	(acupuncture) and (therapy). ti, ab
6	Acupuncture points. Mesh.
7	Acupuncture points. ti, ab
8	Acupuncture*
9	Body acupuncture. ti, ab
10	(body) and (acupuncture). ti, ab
11	Manual acupuncture. ti, ab
12	(manual) and (acupuncture). ti, ab
13	Electroacupuncture. ti, ab
14	(electro) and (acupuncture). ti, ab
15	1 or 2–14
16	Neoplasms. Mesh.
17	Neoplasms. ti, ab.
18	Tumor. Mesh.
19	Tumor. ti, ab.
20	Cancer. Mesh.
21	Cancer. ti, ab.
22	Carcinoma. Mesh.
23	Carcinoma. ti, ab.
24	16 or 17–23
25	Xerostomia. Mesh.
26	Xerostomia. ti, ab.
27	Dry mouth. ti, ab.
28	Salivary gland dysfunction, ti, ab.
29	Hyposalivation. ti, ab.
30	Hyposiali. ti, ab.
31	Salivary gland hypofunction. ti, ab.
32	25 or 26–31
33	randomized controlled trial. pt
34	controlled clinical trial. pt
35	randomized controlled trials. Mesh.
36	random allocation. Mesh.
37	randomized. ti, ab
38	randomly. ti, ab
39	double-blind method. Mesh
40	single-blind method. Mesh
41	clinical trial. pt
42	33 or 34–41
43	15 and 24 and 32 and 42

Data collection and analysis

Selection of studies

Two trained reviewers will independently screen the title and abstract of search results to identify all applicable RCTs. After eliminating duplicate records and ineligible studies, the full text of eligible studies will be reviewed to determine whether they meet the predefined inclusion criteria. Where the researchers are unable to reach a consensus, a third reviewer will make the final judgement.

Data extraction and management

Two investigators will independently extract information from the included literature and enter the relevant data into a unified data statistics table, including the reference ID, first author, publication year, type of cancer, patient age, type of intervention, type of control intervention, sample size of each intervention group, intervention time, randomisation, allocation concealment and blinding methods, outcome measures, primary outcomes and adverse events, duration of follow-up, type and source of financial support and a list of the Standards for Reporting Interventions in Controlled Trials of Acupuncture (STRICTA). Where the reported data are insufficient, the study author will be contacted for further information. Where a consensus on data extraction cannot be obtained through negotiation, a third investigator will make the final judgement.

Assessment of risk of bias and reporting of study quality

The Cochrane collaboration risk-of-bias assessment method will be used independently by the two researchers to assess the quality of included literature and complete the STRICTA checklist.41 The assessments include random sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting and other possible biases. According to the relevant standards in the Cochrane Intervention System Assessment Manual, risk of bias will be classified as low, high and unclear risk. Discrepancies will be resolved through discussions and consensus will be arrived at with a third investigator, who will make the final judgement where a consensus on risk assessment cannot be reached through discussion.

Measures of treatment effect

The effect size will be calculated for each study and combined to generate an overall effect size. For results measured on the same scale, the mean difference and 95% CI will be used for effect evaluation, while the standard mean difference (SMD) will be used for results measured on different scales. Dichotomous data will be recorded as risk ratio (RR).

Unit of analysis issues

Data from patients in RCTs will be used. Where more than one acupuncture group is used in an RCT, separate multiple meta-analyses will be performed for each treatment arm. For trials with a crossover design, data from the first sequence will be used. Where multiple non-acupuncture controls are included, results for all controls will be summarised to analyse the control and intervention groups.

Handling of missing data

For missing data identified during screening and data extraction, the cause of the loss will be determined, and if this is unsuccessful, the missing data will be requested from the study author. If the missing data cannot be obtained, this will be documented and the available data will be extracted and analysed.

Assessment of heterogeneity

A random-effects or fixed-effects model will be used for meta-analysis. According to the Cochrane Handbook for Systematic Reviews of Interventions, heterogeneity can be assessed by a visual check of the forest plot, a heterogeneity x2 test, and Higgins’ I2 statistic.42 43 If the p value is >0.10 and the I2 value is <50%, a fixed-effects model will be used to pool the data. Otherwise, a random-effects model will be used. If there is significant heterogeneity between a set of studies, causes of heterogeneity such as patient characteristics and degree of variation in interventions will be explored. Sensitivity analysis or subgroup analysis will be used to evaluate heterogeneity if applicable.

Assessment of reporting bias

If more than 10 trials are included in the meta-analysis, a funnel plot will be used to assess the reporting biases. Begg and Egger tests will be used to evaluate the asymmetry of the funnel plot and values of p<0.05 will be considered to represent significant publication bias.44

Data synthesis

RevMan 5 software (V. 5.3; Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014) will be used for data analysis. The use of a fixed-effects or random-effects model will be determined based on the level of heterogeneity. For the two categorical variables, RR or odds ratio (OR) and 95% CI will be used. For continuous variables, weighted mean difference or SMD and 95% CI will be used. If there is meaningful heterogeneity that cannot be explained by any assessment (such as a subgroup analysis), no meta-analysis will be performed. If necessary, each subgroup will be carefully considered for subgroup analysis.

Subgroup analysis

Subgroup analyses will be performed based on the heterogeneity of the acupuncture type (including body acupuncture, manual acupuncture and electroacupuncture), control type (including no acupuncture, placebo acupuncture, sham acupuncture, medication or conventional therapy), acupuncture points and clinical differences.

Sensitivity analysis

To test the robustness of the review conclusions, a sensitivity analysis will be performed for the primary outcome according to the following criteria: sample size, heterogeneity quality and statistical model (random-effects or fixed-effects model).

Grading of evidence quality

The Grading of Recommendations Assessment approach will be used to describe the quality of the evidence for the results obtained.45 The assessment includes risk of bias, heterogeneity, indirectness, imprecision and publication bias. The quality of the results will be divided into high, moderate, low and very low.

Discussion

Xerostomia is one of the most common side effects reported during cancer treatment. According to traditional Chinese medicine theory, cancer-induced dry mouth is caused by the cancer itself and the treatment process, resulting in the loss of moisture and nourishment. Patients with tumours have yin deficiency; alternatively, the cancer may readily consume the qi and yin of the body, breaking the balance of qi and blood. Eventually, this imbalance can lead to disordered production and metabolism of body fluid, resulting in dry mouth, which may have serious consequences for patient treatment. Although western medicine is commonly used to treat xerostomia,13–21 shortcomings such as per-cycle administration (daily use), headache, dizziness, sweating and other adverse events, and the high cost of antineoplastic agents render it somewhat inconvenient and limit its clinical application. Acupuncture can regulate qi and blood to improve physiological functions by stimulating acupoints. Previous studies29–32 have reported that acupuncture can prevent the occurrence of dry mouth and increase the secretion of saliva and can therefore be used as adjunctive and even alternative therapy alongside drugs, with fewer side effects and at relatively low cost.

Although multiple RCTs of acupuncture as a treatment for dry mouth caused by cancer have been reported to date, the cumulative evidence for its efficacy has not been systematically evaluated. This study will be the first systematic review of the efficacy of acupuncture in patients with cancer-induced xerostomia. The review will be divided into four sections: identification, study inclusion, data extraction and data synthesis. The resulting evidence may provide important information that will benefit patients, practitioners, health policy makers and acupuncturists.