Description of the condition
Cancer rates have steadily increased over the past few decades, placing a huge burden on healthcare systems worldwide. The global economic burden of cancer has more than doubled during the past 30 years. In 2008, 12.4 million new cancer cases were reported, and it is projected that 27 million new cases of cancer will be reported by 2030 (WHO 2008). Conventional cancer treatments include surgery, radiotherapy, chemotherapy and psychosocial support (WHO 2002). Advances in chemotherapy and radiotherapy in recent years have greatly improved treatment results (WHO 2008). However, cytotoxic drugs and ionising radiation also cause many distressing side effects. Some of these are serious, which may discourage continuation of treatment (Redmond 1996; Robbins 2002; WHO 2008). The side effects most commonly associated with chemotherapy and radiotherapy include fatigue, pain and nausea and vomiting (Stasi 2003; Henry 2008). Other side effects include bone marrow suppression leading to anaemia; hair follicle cell damage leading to alopecia; gastrointestinal damage leading to diarrhoea and oral ulceration and skin reactions to radiation (Robbins 2002; WHO 2008). Although new drug development programmes have been undertaken to reduce the side effects of cancer therapy, satisfactory treatment still is not readily available to a large proportion of patients receiving chemotherapy or radiotherapy, or both. New, effective treatments that can reduce chemotherapy- and radiotherapy-associated adverse effects are needed, especially non-pharmacological, self-management strategies (Redmond 1996; Herrstedt J 2007; Jordan 2007; Ellebaek 2008; Lotfi-Jam 2008; Cho 2010).
Description of the intervention
Moxibustion is a common treatment modality of traditional Chinese medicine that has been used in China and other Asian countries for thousands of years to treat a variety of diseases (Cho 2009). Moxibustion involves burning of herbal preparations containing Artemisia vulgaris on or above the skin at acupuncture points. Moxibustion techniques commonly used in clinical practice to treat side effects of conventional cancer treatment involve either direct moxibustion with a traditional moxa stick (stick-on moxa) (Yu 2003) or indirect moxibustion, achieved by placing insulating materials such as salt, monkshood cake, sliced ginger or garlic between the skin and a burning moxa cone (Chen 2000; Zhao 2007). The leaves of Artemisia vulgaris or mugwort, in Chinese called Ai Ye, are the main material used for moxibustion. Other Chinese herbs may be used in combination with mugwort. Mugwort is considered to be warm, acidic and bitter. It has the ability to warm the body's meridians, thereby promoting better circulation. According to Chinese medicine theory, the meridians are the channels inside the human body that circulate vital energy (in Chinese called Qi and Blood). Besides promoting the flow of vital energy through meridians, moxibustion, which stimulates some specific acupoints located along the meridians upon burning, is considered to have some specific treatment effects, such as strengthening the body's vital energy or facilitating digestion.
How the intervention might work
It has been demonstrated in a systematic review that acupuncture point stimulation, as performed through electroacupuncture and acupressure, may be effective for chemotherapy-induced nausea or vomiting (Ezzo 2006). Moxibustion is widely used in China and in other East Asian countries to reduce cancer pain and fever in cancer patients and to lessen the adverse effects of radiotherapy and chemotherapy (Zhang 2008; Lee 2010). Many clinical studies of moxibustion treatment for cancer patients receiving chemotherapy or radiotherapy have indicated that it could alleviate some of the adverse effects of treatment, such as fatigue, nausea and vomiting, diarrhoea, alopecia and pain, as well as improve quality of life (QoL) (Chen 2000; Jiang 2002; Song 2003; Zhao 2007; Chen 2008; Kuai 2008; Qiu 2008; Shen 2008; Zhang 2008; Kim 2010).
The clinical effects of moxibustion treatment may be attributable to the actions of enhancing immunity, relieving bone marrow suppression and producing an anti-oxidative effect (Huang 1999; Chen 2000; Jiang 2002; Xu 2002; Xu 2003; Yu 2003; Cui 2007; Pei 2007; Zhao 2007). Besides the hyperthermal action induced by burning of moxa, non-thermal factors such as infrared irradiation may have important therapeutic effects by interfering with cellular functions and exerting a killing effect on cancer cells (Schieke 2003; Hattori 2007; Tanaka 2010). Furthermore, the infrared radiation peak (around 7.5 μm) of traditional indirect moxibustion with monkshood cake, ginger slices and garlic slices as the medium matches that of infrared radiation on human skin at some acupoint such as LI 4 (Hegu), indicating involvement of a sympathetic vibration of infrared radiation from indirect moxibustion and the acupoints. It has been proposed that these mechanisms of action (including thermal action, infrared radiation and sympathetic vibration) and their pharmacological effects may contribute to the therapeutic efficacy of moxibustion (Shen 2006). In addition, actions exerted on the acupoints by moxibustion may elicit systemic effects through transmission along meridians.
Why it is important to do this review
Given its potential effect, low cost and simplicity of application, moxibustion could be a valuable adjuvant treatment for many cancer patients. A recently published systematic review on moxibustion for cancer care (Lee 2010) concluded that limited evidence suggests that moxibustion is an effective supportive cancer therapy for reducing nausea and vomiting. In that review however, the outcome measurements were not clearly specified. Furthermore, relevant clinical trials (Qiu 2008; Cheng 2009; Gao 2010) were not included, possibly as the result of limitations in the search strategy and in literature sources. The systematic review we are proposing to conduct will focus primarily on the effectiveness of moxibustion for alleviating side effects of chemotherapy or radiotherapy, or both, in cancer patients. A transparent and clearly defined systematic method will be used to obtain more robust and comprehensive evidence-based information to help answer this research question. Results derived from this systematic review will provide an evidence-based answer for medical practitioners, patients and researchers regarding the effectiveness and safety of moxibustion for cancer patients receiving radiotherapy or chemotherapy, or both.
To evaluate the effectiveness and safety of moxibustion treatment for alleviating side effects associated with chemotherapy or radiotherapy, or both, in cancer patients.
Criteria for considering studies for this review
Types of studies
We will include randomised controlled trials (RCTs). For randomised cross-over trials, only phase 1 data will be included in the review because treatment carryover effects are likely.
Types of participants
We will include participants of any age with any kind of malignant disease receiving chemotherapy or radiotherapy, or both.
Types of interventions
The intervention in the treatment group should include any type of moxibustion treatment, defined as burning moxa on or above any acupoint or at some specified region of the body. Commonly used techniques include direct and indirect moxibustion with a moxa cone and moxibustion with a moxa stick. In direct moxibustion with a moxa cone, a small cone-shaped moxa is placed directly on the skin and is burned; in indirect moxibustion a moxa cone is placed on the skin, is separated by a medium (the medium can be salt, garlic, ginger, monkshood cake or any other herbs) and then is burned. In moxibustion with a moxa stick, a practitioner lights one end of the moxa stick, which is roughly similar to a cigar in shape and size, and holds it for several minutes close to the area being treated until the area turns red. Moxibustion treatments that involve burning materials made of moxa or other medicinal herbs, or a combination, or burning them with the aid of an instrument will also be included in this review because these approaches are usually perceived as traditional moxibustion treatment. Moxa needle therapy, in which a needle is inserted into an acupoint and the end of the needle is wrapped in an ignited moxa, will be excluded from the review because this treatment method also involves acupuncture. The acupuncture treatment combined with moxibustion makes it impossible to evaluate whether the treatment effect is due only to moxibustion.
The intervention in the control group may include a placebo, no treatment or other conventional treatments that are currently accepted and widely used for patients receiving chemotherapy or radiotherapy, or both, and may include treatments for raising white blood cell, red blood cell and haemoglobin levels or for enhancing immunity. Other herbal medicines or complementary medicines will not be accepted as a control intervention.
Basic oncological treatment (chemotherapy, radiotherapy) or supportive care should be identical in the intervention and control groups.
Types of outcome measures
- The incidence and severity of chemotherapy- or radiotherapy-related toxicities if they were reported according to internationally accepted criteria for common toxicities (e.g. World Health Organization (WHO), Eastern Cooperative Oncology Group (ECOG), or National Institutes of Health (NIH) criteria for adverse effects).
- QoL as measured by a validated instrument.
- Patient-reported physical and psychological indices of symptom distress using a validated scale.
- Any other objective outcome measures aimed at assessing side effects of chemotherapy or radiotherapy (e.g. blood cell counts, measures of immunological function).
- Modification or cessation of cancer treatments as the result of side effects or adverse effects.
- Incidences and types of adverse events in the treatment and control groups (including serious and moderate ones), which may or may not be related to moxibustion treatment. A comparison of the possible occurrence of adverse events may be made between the moxibustion treatment group and the control group.
The above outcome measurements will be collected immediately after treatment and at the end of follow-up.
Search methods for identification of studies
We will search for articles in all languages and will undertake translations, if necessary. No date restriction will be applied.
A search strategy will be used to identify relevant randomised controlled trials (RCTs).
We will search the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE and AMED (Allied and Complementary Medicine Database).
The MEDLINE search strategy is listed in Appendix 1. It will be adapted for searching the other databases.
All relevant articles found will be identified on PubMed, and through the 'related articles' feature, further searches for newly published articles will be carried out.
Searching other resources
Registries of randomised trials
We will search the following registries for ongoing trials: Metaregister (http://www.controlled-trials.com/mrct/), Physicians Data Query (http://www.ncbi.nlm.nih.gov/), www.clinicaltrials.gov and www.cancer.gov/clinicaltrials. If ongoing trials that have not been published are identified through these searches, the principal investigators will be approached for relevant data.
We will also search the following Chinese databases: CBM (Chinese BioMedical Literature Database), CMCC (Chinese Medical Current Contents), TCMonline, CDDB (Chinese Dissertation Database), CMAC (China Medical Academic Conference) and Index to Chinese Periodical Literature.
USA CenterWatch Clinical Trials Listing Service (www.CenterWatch.com) and OpenSIGLE (System for Information on Grey Literature in Europe) will also be searched for ongoing and grey literature.
We will check the references of all included studies and relevant reviews to find further relevant articles. We will contact the authors of significant articles or experts in the relevant field for potential eligible studies.
Data collection and analysis
Selection of studies
The search strategy described above will be used to obtain titles and abstracts of studies that may be relevant to the review. These titles and abstracts will be reviewed independently by two review authors who will discard studies that are not eligible for the review and will retain those with relevant data or information. Full-texts of potentially eligible articles will be retrieved for further assessment. Every record will be labelled as include, exclude or unclear. Any disagreement will be resolved by discussion and by consensus. When the article falls into the unclear category, which is characterised by unclear information or missing data, we will contact the trial authors for clarification. We will record any communication with trial authors.
Data extraction and management
Data extraction will be carried out independently by the review authors using a pre-tested data extraction form. When more than one publication of a study is found, reports will be grouped together, and only the publication with the most recent complete data will be used. When relevant outcomes are published only in earlier versions, these data will be used. Any discrepancy between published versions will be highlighted. Any further information required from the original authors will be requested by written correspondence, and relevant information that is obtained in this manner will be included in the review. Disagreements between two review authors will be resolved in consultation with a third review author.
For included trials, data will be abstracted as recommended in Chapter 7 of the Cochrane Handbook for Systematic Reviews of Interventions and will include the following:
- General information: published or unpublished, author, country, publication language, publication year, journal citation.
- Trial design.
- Participants: inclusion and exclusion criteria, total number enrolled and number in each comparison group, baseline characteristics, setting.
- Interventions: administration route, timing of intervention, comparison intervention and any co-intervention, expertise of practitioner.
- Risk of bias in trials (see later).
- Follow-up: length of follow-up, reason for and number of drop-outs and withdrawals, method of analysis.
- Outcomes reported: the incidence and severity of chemotherapy- or radiotherapy-related toxicities, QoL, patient-reported physical and psychological indices of symptom distress based on a validated scale, any other objective outcome measures aimed at assessing side effects of chemotherapy or radiotherapy, modification or cessation of cancer treatments as the result of side effects or adverse effects and incidence and types of adverse events resulting from moxibustion treatment.
- For each outcome: outcome definition (with diagnostic criteria if relevant).
- Unit of measurement (if relevant).
- For scales: upper and lower limits, and whether high or low score is good.
- Results: number of participants allocated to each intervention group.
- For each outcome of interest: sample size and missing participants.
Data on outcomes were extracted as follows:
- For dichotomous outcomes (e.g. adverse events), we will extract the number of participants in each treatment arm who experience the outcome of interest and the number of participants assessed at endpoint to estimate a risk ratio (RR).
- For continuous outcomes (e.g. QoL), we will extract the final value and the standard deviation of the outcome of interest and the number of participants assessed at endpoint in each treatment arm at the end of follow-up to estimate the mean difference (if trials measured outcomes on the same scale) or standardised mean differences (if trials measured outcomes on different scales) between treatment arms and standard error.
The time points at which outcomes were collected and reported will be noted.
Where possible, all data extracted will be relevant to an intention-to-treat analysis, in which participants are analysed in the groups to which they were assigned.
Assessment of risk of bias in included studies
Two review authors will independently assess the risk of bias in the included studies. Any discrepancy will be resolved by discussion and conclusions reached by consensus. If a consensus cannot be reached, a third review author will help to make the final decision.
To detect potential selection bias, performance bias, detection bias, attrition bias and reporting bias, the following six domains will be addressed in the assessment of risk of bias:
- Selection bias:
- Random sequence generation.
- Allocation concealment.
- Performance bias:
- Blinding of participants and personnel (participants and treatment providers).
- Detection bias:
- Blinding of outcome assessment.
- Attrition bias:
- Incomplete outcome data: We will record the proportions of participants whose outcomes were not reported at the end of the study; we will code a satisfactory level of loss to follow up for each outcome, such as:
- Low risk of bias, if fewer than 20% of participants were lost to follow-up and reasons for loss to follow-up were similar in both treatment arms.
- High risk of bias, if more than 20% of participants were lost to follow-up or reasons for loss to follow-up differed between treatment arms.
- Unclear risk of bias if loss to follow-up was not reported.
- Reporting bias:
- Selective reporting of outcomes.
- Other possible sources of bias:
- Baseline characteristics.
We will categorise the risk of bias for each outcome, within and across included studies, into three levels: low, unclear and high risk of bias. On the basis of this assessment, we will use the GRADE system (Higgins 2009) to further evaluate the quality of evidence for each individual outcome. This involves consideration not only of risk of bias (methodological quality) but also of directness of evidence, heterogeneity, precision of effect estimates and risk of publication bias. The empirical evidence for each individual outcome will be graded into four levels: high, moderate, low or very low quality in accordance with the GRADE approach.
Measures of treatment effect
We will use the following measures of the effect of treatment:
- For dichotomous outcomes, we will use the RR with 95% confidence interval (CI). To help determine the applicability of the results to individual participants, the number needed to treat (NNT) will be calculated across a range of assumed control risks.
- For continuous outcomes, we will use the mean difference between treatment arms (with its 95% CI).
Unit of analysis issues
Analysis of outcomes will be based on randomly assigned individuals. Special attention will be given to the design of cluster RCTs, cross-over studies or repeated measures with the same participants.
In the case of multiple intervention groups within a study, pair-wise comparisons relevant to the study objective will be made. If necessary, relevant groups will be combined to make a single comparison or split to make multiple comparisons.
Dealing with missing data
Available case analysis will be conducted. The potential impact of missing data will be considered in the risk of bias table and in interpretation of the results.
We will not impute missing outcome data for the primary outcome. If data are missing, or if only imputed data are reported, we will contact trial authors to request data on outcomes only among participants who were assessed.
Assessment of heterogeneity
When heterogeneity is present, we will first review study components such as participants, interventions and outcomes in the included studies to decide whether the heterogeneity is substantial. We will also assess heterogeneity between studies through visual inspection of forest plots, by estimation of the percentage of heterogeneity between trials that cannot be ascribed to sampling variation (Higgins 2003), by a formal statistical test of the significance of the heterogeneity (Deeks 2001) and, if possible, by subgroup analyses. If evidence of substantial heterogeneity is noted, we will investigate and report on possible reasons.
Assessment of reporting biases
We will investigate reporting bias by using the funnel plot or other corrective analytical methods, depending on the number of trials included in the review (Higgins 2009). Possible reasons, other than publication bias, such as poor methodological quality and true heterogeneity will be explored. If the funnel plots suggest that treatment effects may not be sampled from a symmetrical distribution, as is assumed by the random-effects model, further meta-analyses will be performed using fixed-effects models.
Data will be pooled using the random-effects model but the fixed-effect model will also be analysed to explore the influence of small study effects.
If sufficient clinically similar trials are available, their results will be pooled in meta-analyses.
- For any dichotomous outcomes, the RR will be calculated for each trial and the RRs will then be pooled.
- For continuous outcomes, the mean differences between treatment arms at the end of follow-up will be pooled if all trials measure the outcome on the same scale; otherwise standardised mean differences will be pooled.
If any trials have multiple treatment groups, the ‘shared’ comparison group will be divided into the number of treatment groups, and comparisons between each treatment group and the split comparison group will be treated as independent comparisons.
Random-effects models with inverse variance weighting will be used for all meta-analyses (DerSimonian 1986).
Subgroup analysis and investigation of heterogeneity
If sufficient numbers of trials are available, we will conduct subgroup analyses to explore potential sources of any heterogeneity based on type of cancer, indirect or direct moxibustion, age of participants and duration of moxibustion treatment.
If sufficient numbers of RCTs are found, sensitivity analyses will be applied to explore the following risk of bias influencing factors on the effect estimates: adequacy of sequence generation and blinding. The possible influence of including data from the first period in a cross-over study will also be investigated.
We would like to thank the Cochrane Gynaecological Cancer Review Group for its support. Special thanks are given to Gail Quinn and Jane Hayes for their valuable advice.
Appendix 1. MEDLINE search strategy
- (moxa or moxibustion).mp.
- 1 or 2
- exp Radiotherapy/
- (radiotherap* or radiation).mp.
- (chemoradi* or radiochemo*).mp.
- exp Antineoplastic Agents/
- Antineoplastic Combined Chemotherapy Protocols/
- drug therapy.fs.
- 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11
- 3 and 12
- exp Neoplasms/
- (cancer* or tumor* or tumour* or malignan*or carcinoma* or neoplas*).mp.
- 14 or 15
- 13 and 16
- (animals not (humans and animals)).sh.
- 17 not 18
mp = title, original title, abstract, name of substance word, subject heading word, unique identifier
fs = floating subheading
sh = subject heading
Last assessed as up-to-date: 16 May 2013.
Contributions of authors
- Drafting of the protocol: HWZ, ZXL, WCC.
- Study selection: HWZ, FC.
- Extraction of data from studies: HWZ, FC.
- Entry of data into RevMan/check of data entry: HWZ, FC.
- Carrying out the analysis: HWZ, FC.
- Interpreting the analysis: HWZ, JLT, ZXL.
- Drafting of the final review: HWZ, ZXL, WCC, JLT.
- Disagreement resolution: ZXL.
- Updating of the review: HWZ, FC, ZXL.
Declarations of interest
Sources of support
- The Chinese University of Hong Kong, Hong Kong.
- No sources of support supplied