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Effects of Acupuncture, Tuina, Tai Chi, Qigong, and Traditional Chinese Medicine Five-Element Music Therapy on Symptom Management and Quality of Life for Cancer Patients: A Meta-Analysis

Open ArchivePublished:February 12, 2016DOI:https://doi.org/10.1016/j.jpainsymman.2015.11.027

      Abstract

      Context

      Most cancer patients suffer from both the disease itself and symptoms induced by conventional treatment. Available literature on the clinical effects on cancer patients of acupuncture, Tuina, Tai Chi, Qigong, and Traditional Chinese Medicine Five-Element Music Therapy (TCM-FEMT) reports controversial results.

      Objectives

      The primary objective of this meta-analysis was to evaluate the effect of acupuncture, Tuina, Tai Chi, Qigong, and TCM-FEMT on various symptoms and quality of life (QOL) in patients with cancer; risk of bias for the selected trials also was assessed.

      Methods

      Studies were identified by searching electronic databases (MEDLINE via both PubMed and Ovid, Cochrane Central, China National Knowledge Infrastructure, Chinese Scientific Journal Database, China Biology Medicine, and Wanfang Database). All randomized controlled trials (RCTs) using acupuncture, Tuina, Tai Chi, Qigong, or TCM-FEMT published before October 2, 2014, were selected, regardless of whether the article was published in Chinese or English.

      Results

      We identified 67 RCTs (5465 patients) that met our inclusion criteria to perform this meta-analysis. Analysis results showed that a significant combined effect was observed for QOL change in patients with terminal cancer in favor of acupuncture and Tuina (Cohen's d: 0.21–4.55, P < 0.05), whereas Tai Chi and Qigong had no effect on QOL of breast cancer survivors (P > 0.05). The meta-analysis also demonstrated that acupuncture produced small-to-large effects on adverse symptoms including pain, fatigue, sleep disturbance, and some gastrointestinal discomfort; however, no significant effect was found on the frequency of hot flashes (Cohen's d = −0.02; 95% CI = −1.49 to 1.45; P = 0.97; I2 = 36%) and mood distress (P > 0.05). Tuina relieved gastrointestinal discomfort. TCM-FEMT lowered depression level. Tai Chi improved vital capacity of breast cancer patients. High risk of bias was present in 74.63% of the selected RCTs. Major sources of risk of bias were lack of blinding, allocation concealment, and incomplete outcome data.

      Conclusion

      Taken together, although there are some clear limitations regarding the body of research reviewed in this study, a tentative conclusion can be reached that acupuncture, Tuina, Tai Chi, Qigong, or TCM-FEMT represent beneficial adjunctive therapies. Future study reporting in this field should be improved regarding both method and content of interventions and research methods.

      Key Words

      Introduction

      Cancer is one of the most common causes of death worldwide. It accounted for 7.6 million deaths (around 13% of all deaths) in 2008, and deaths from cancer internationally are projected to rise to more than 11 million in 2030,

      World Health Organization. Cancer. [2008-9-23] Available at: http://www.whoint/mediacentre/factsheets/fs297/en/

      according to the World Health Organization (WHO). Conventional treatment for cancer, such as surgery, chemotherapy, radiotherapy, and endocrine therapy, aiming at curing the disease or prolonging life produces considerable beneficial medical outcomes. However, these treatments cannot eradicate the diseases and are often accompanied by adverse effects. It is acknowledged that most cancer patients suffer from both the disease itself and symptoms induced by conventional treatment, such as fatigue, anxiety, depression, nausea, and pain, and being at an increased risk of developing secondary tumors.
      • Boon H.S.
      • Olatunde F.
      • Zick S.M.
      Trends in complementary/alternative medicine use by breast cancer survivors: comparing survey data from 1998 and 2005.
      • Sirois F.M.
      • Gick M.L.
      An investigation of the health beliefs and motivations of complementary medicine clients.
      • Findley P.A.
      • Sambamoorthi U.
      Preventive health services and lifestyle practices in cancer survivors: a population health investigation.
      Numerous patients report feeling abandoned and isolated after cessation of active treatment,
      • Smithson J.
      • Paterson C.
      • Britten N.
      • et al.
      Cancer patients' experiences of using complementary therapies: polarization and integration.
      which could exacerbate symptoms such as depression and anxiety. This may have an impact on their quality of life (QOL), which has been reported as being lower than other population groups.
      • Monti D.A.
      • Sufian M.
      • Peterson C.
      Potential role of mind-body therapies in cancer survivorship.
      Therefore, for cancer survivors, it is essential to look at ways of improving QOL and long-term health outcomes.
      Nonpharmacologic interventions typically encompass a broad range of psychosocial, behavioral, and environmental strategies that may complement conventional treatment to enhance QOL for cancer patients.
      • Tong G.
      • Geng Q.
      • Cheng J.
      • et al.
      Effects of psycho-behavioral interventions on immune functioning in cancer patients: a systematic review.
      Traditional Chinese nonpharmacologic interventions include a series of approaches such as acupoint stimulation, Chinese massage (referred to as “Tuina”), Tai Chi, Qigong, and Traditional Chinese Medicine Five-Element Music Therapy (TCM-FEMT). The use of these interventions for the management of cancer can be traced back to the Shang Dynasty of China 3500 years ago.
      • Zhou D.H.
      Clinical oncology of Chinese medicine.
      Over the centuries, various interventions such as acupuncture (involving the placement of solid, sterile, stainless steel needles into specific points on the body), moxibustion (stimulating skin thermally by the burning of moxa, also at precise locations or other specific areas),
      • He X.R.
      • Wang Q.
      • Li P.P.
      Acupuncture and moxibustion for cancer-related fatigue: a systematic review and meta-analysis.
      Chinese massage (a wide range of technical manipulations conducted by a practitioner's finger, hand, elbow, knee, or foot applied to muscle or soft tissue at specific body locations),
      • Goats G.C.
      Massage—the scientific basis of an ancient art: part 2. Physiological and therapeutic effects.
      and Qigong have been developed and used in cancer treatment.
      • Liu W.S.
      Application of Chinese medicine in clinical oncology.
      Qigong, a general term for a large range of traditional Chinese energy exercises and therapies, is popularly practiced by a large number of people in Chinese communities. Basically, there are two categories of Qigong: internal qigong vs. external qigong. Internal qigong or qigong exercise is self-directed and involves the use of movements, meditation, and control of breathing patterns. The gentle movements and postures of the exercise are designed to achieve a harmonious flow of energy (qi) in the body so as to improve physical fitness and overall well-being. External qigong is usually performed by a trained practitioner using their hands to direct emitted “qi” energy onto the patient's body in the diagnosis and treatment of various diseases.
      • Chan C.L.
      • Wang C.W.
      • Ho R.T.
      • et al.
      A systematic review of the effectiveness of qigong exercise in supportive cancer care.
      Tai Chi includes relaxation, deep and regulated breathing techniques, and slow movements, and it is an intervention that shares many characteristics with Qigong.
      • Lee M.S.
      • Choi T.Y.
      • Ernst E.
      Tai chi for breast cancer patients: a systematic review.
      Music therapy has been defined as “the clinical and evidence-based use of music interventions to accomplish individualized goals within a therapeutic relationship….”

      American Music Therapy Association. Definitions and quotes about music therapy. Available at: http://www.musictherapy.org/about/quotes/. Accessed August 13, 2012.

      In China, researchers usually apply some traditional music based on the five elements of TCM in their studies, which is called TCM-FEMT.
      • Huang Y.
      • Yang X.
      • Yang Q.
      Effect of traditional Chinese medicine five elements music on cancer-related fatigue of chemotherapy patients.
      In the last decade, the use of these interventions has increased dramatically. According to the WHO, acupuncture is used in at least 78 countries.
      World Health Organization
      WHO traditional medicine strategy 2002-2005.
      Although multiple studies applying these interventions in cancer patients have reported positive outcomes,
      • Huang Y.
      • Yang X.
      • Yang Q.
      Effect of traditional Chinese medicine five elements music on cancer-related fatigue of chemotherapy patients.
      • Sprod L.K.
      • Janelsins M.C.
      • Palesh O.G.
      • et al.
      Health-related quality of life and biomarkers in breast cancer survivors participating in tai chi chuan.
      • Wan S.
      • Huang J.
      • Gao J.
      Influence of acupoint massage on quality of life of tumor patients accepting chemotherapy.
      • Xiang C.
      • Guo Q.
      • Liao J.
      Effect of therapy of traditional Chinese medicine five element music and electroacupuncture on the depression levels of cancer patients.
      • Oh B.
      • Butow P.N.
      • Mullan B.A.
      • et al.
      Effect of medical Qigong on cognitive function, quality of life, and a biomarker of inflammation in cancer patients: a randomized controlled trial.
      others have described mixed evidence.
      • Xiang C.
      • Guo Q.
      • Liao J.
      Effect of therapy of traditional Chinese medicine five element music and electroacupuncture on the depression levels of cancer patients.
      • Deng G.
      • Chan Y.
      • Sjoberg D.
      • et al.
      Acupuncture for the treatment of post-chemotherapy chronic fatigue: a randomized, blinded, sham-controlled trial.
      • Roscoe J.A.
      • Matteson S.E.
      • Morrow G.R.
      • et al.
      Acustimulation wrist bands are not effective for the control of chemotherapy-induced nausea in women with breast cancer.
      • Mustian K.M.
      • Katula J.A.
      • Zhao H.
      A pilot study to assess the influence of tai chi chuan on functional capacity among breast cancer survivors.
      • Chen Z.
      • Meng Z.
      • Milbury K.
      • et al.
      Qigong improves quality of life in women undergoing radiotherapy for breast cancer: results of a randomized controlled trial.
      • Yin Z.L.
      Effect of TCM on quality of life in nasopharyngeal cancer patients after radiotherapy.
      Differences in study design, interventions type, frequency and duration and the therapist in these interventions may produce varying results. Therefore, a systematic review with a meta-analysis of the interventions is needed to more accurately gauge efficacy for cancer patients and evaluate the quality of such studies.
      Although several systematic reviews with or without meta-analysis have addressed this issue,
      • He X.R.
      • Wang Q.
      • Li P.P.
      Acupuncture and moxibustion for cancer-related fatigue: a systematic review and meta-analysis.
      • Chan C.L.
      • Wang C.W.
      • Ho R.T.
      • et al.
      A systematic review of the effectiveness of qigong exercise in supportive cancer care.
      • Chen H.Y.
      • Li S.G.
      • Cho W.C.
      • et al.
      The role of acupoint stimulation as an adjunct therapy for lung cancer: a systematic review and meta-analysis.
      • Choi T.Y.
      • Lee M.S.
      • Ernst E.
      Acupuncture for cancer patients suffering from hiccups: a systematic review and meta-analysis.
      • Garcia M.K.
      • McQuade J.
      • Haddad R.
      • et al.
      Systematic review of acupuncture in cancer care: a synthesis of the evidence.
      • Lee M.S.
      • Choi T.Y.
      • Park J.E.
      • et al.
      Moxibustion for cancer care: a systematic review and meta-analysis.
      • Chao L.F.
      • Zhang A.L.
      • Liu H.E.
      • et al.
      The efficacy of acupoint stimulation for the management of therapy-related adverse events in patients with breast cancer: a systematic review.
      • Lee M.S.
      • Chen K.W.
      • Sancier K.M.
      • et al.
      Qigong for cancer treatment: a systematic review of controlled clinical trials.
      • Yan J.H.
      • Pan L.
      • Zhang X.M.
      • et al.
      Lack of efficacy of Tai Chi in improving quality of life in breast cancer survivors: a systematic review and meta-analysis.
      • Lee M.S.
      • Pittler M.H.
      • Ernst E.
      Is Tai Chi an effective adjunct in cancer care? A systematic review of controlled clinical trials.
      they often have covered only a small section of evidence, restricting their scope to either a specific subpopulation of patients with cancer or a specific type of intervention, or both, thus making broader conclusions difficult. Moreover, many reviews are outdated. Several reviews also have reported the utilization of TCM among cancer patients
      • Li X.
      • Yang G.
      • Li X.
      • et al.
      Traditional Chinese medicine in cancer care: a review of controlled clinical studies published in Chinese.
      • Liu J.
      • Li X.
      • Liu J.
      • et al.
      Traditional Chinese medicine in cancer care: a review of case reports published in Chinese literature.
      • Yang G.
      • Li X.
      • Li X.
      • et al.
      Traditional Chinese medicine in cancer care: a review of case series published in the Chinese literature.
      ; however, a large proportion of the reviews discussed the use of herbal medicine, which was not involved in the interventions. This study aims at closing this gap and producing an overall picture of contemporary research in this field while exploring the hypothesis that acupuncture, Tuina, Tai Chi, Qigong, or TCM-FEMT may contribute to the QOL of cancer patients.

      Methods

      Eligibility Criteria

      Eligibility criteria are detailed following the Participants, Interventions, Controls, Outcomes, and Studies (PICOS) framework
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration.
      :

      Participants

      Participants were adults aged 18 years or older who had been formally diagnosed with cancer of any type (solid and hematologic), any tumor stage, any kind of treatment mode, and any time since diagnosis.

      Interventions

      Approaches including acupoint stimulation, Chinese massage (“Tuina”), Tai Chi, Qigong, TCM-FEMT, alone or in combination, were reviewed. Studies evaluating any types of herbal medicine, point injection, Thai massage, Japanese massage, Swedish-style massage, reflexology, aromatherapy massage, and other music therapy were excluded.

      Controls

      No treatment (usual care) and active (attention placebo) control conditions were both considered. Nevertheless, studies without the use of a control condition were excluded.

      Outcomes

      Primary outcomes were health-related QOL at post-treatment. Among the studies reviewed, overall QOL was measured by the Functional Assessment of Cancer Therapy–Breast or Functional Assessment of Cancer Therapy–General (FACT-B or FACT-G), Karnofsky Performance Status (KPS) score, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30, and the Medical Outcomes Study Short Form–36 (SF-36). Secondary outcomes included cancer-related symptoms and therapy-related adverse events such as pain, flushes, fatigue, sleep disturbance, hair loss, negative mood, diarrhea, flatulence, nausea, and vomiting.

      Studies

      Only randomized controlled trials (RCTs) were considered. All the articles included in this meta-analysis are listed in the References.

      Information Sources

      Studies were identified by 1) searching electronic databases (MEDLINE via both PubMed and Ovid, Cochrane Central, China National Knowledge Infrastructure from 1911 to October 2014; Chinese Scientific Journal Database from 1989 to October 2014; China Biology Medicine from 1978 to October 2014; and Wanfang Database from 1994 to October 2014), 2) scanning reference lists of relevant review articles; and 3) contacting study authors.

      Data Collection

      The search terms in the English and Chinese literature were (cancer OR tumor OR tumour OR neoplas* OR oncolog*), AND (acupoint OR acupuncture OR moxibustion OR TCM OR Chinese massage OR Qigong OR Tai Chi OR TCM Five Element Music Therapy), AND (quality of life OR pain OR nausea OR hot flashes OR hot flushes OR fatigue OR xerostomia OR ileus OR anxiety OR depression OR mood disorder OR sleep disturbance OR insomnia OR dyspnea OR shortness of breath OR peripheral neuropathy OR hiccups OR hiccoughs).
      Data extracted from the studies included year of publication, country of origin, number of participants randomly assigned, mean age, sex, type of tumor, treatment status, type of intervention, duration of intervention, control condition, and outcomes (including assessment instruments).
      All articles were read by two independent reviewers (W. -W. T. and X. -M. T.), and data from the articles were validated and extracted and entered into Excel. Discrepancies between reviewers were resolved by discussion.

      Assessment of Risk of Bias

      The risk of bias was assessed using the Cochrane Handbook for Systematic Reviews of Interventions (RevMan version 5.1.0, The Cochrane Collaboration, 2011). Six components associated with the risk of bias were assessed: generation of the allocation sequence, allocation concealment, masking of outcome assessors, selective outcome reporting, incomplete follow-up, and other potential sources of bias. Trials with a low risk for all six components were defined as having an overall low risk of bias. Trials in which one or more of the six bias components were unclear or had high risk of bias were defined to be at high risk of bias.
      Disagreements were resolved by discussions among the two reviewers and, if necessary, through discussion among the authors. However, there were no disagreements among the two reviewers.

      Statistical Analysis

      The descriptive data for all the included studies were entered into Excel, and statistical analyses were completed using Review Manager 5.0, supplied gratis by the Cochrane organization (www.cochrane.org/cochrane/hbook.htm) for meta-analyses. The effect sizes were calculated as Cohen's d standardized mean effects of the interventions. Individual study effect sizes were synthesized to generate an overall effect size using a random or fixed effects model according to the heterogeneity level, weighted by the inverse of variance. For continuous variables, mean difference was calculated when outcomes were measured using the same scale, and the standardized mean difference was used when different scales were used in different trials, with corresponding 95% CIs. If data for SDs were missing, they were computed for the calculation of statistical pooling of effect size by calculating the trial data using standard error of the mean or 95% CIs.
      For dichotomous variables, the odds ratios were calculated when appropriate summary statistics were reported.
      • Tierney J.F.
      • Stewart L.A.
      • Ghersi D.
      • et al.
      Practical methods for incorporating summary time-to-event data into meta-analysis.
      An odds ratio of more than 1 indicates an advantage for the interventions. We also completed a sensitivity analysis to identify potential outliers by removing each study one by one to examine the individual influence of each study on the overall effect size. Heterogeneity was assessed using Cochrane's Q and I2, which calculates the proportion of variation attributed to heterogeneity. Statistical heterogeneity of trial results was assessed by visual inspection of forest plots, χ2 tests, and the I2 statistic.
      • Higgins J.P.
      • Thompson S.G.
      • Deeks J.J.
      • et al.
      Measuring inconsistency in meta-analyses.
      A P-value greater than 0.10 for χ2 tests and an I2 value of less than 25% were interpreted as signifying a low level of heterogeneity.
      • Higgins J.P.
      • Thompson S.G.
      • Deeks J.J.
      • et al.
      Measuring inconsistency in meta-analyses.
      Primary analyses were performed with a fixed effects model; secondary confirmatory analyses were performed with a random effects model if there was significant heterogeneity. An effect size of 0.8 was considered large, 0.5 was considered medium, and 0.2 was considered small.
      • Faul F.
      • Erdfelder E.
      • Lang A.G.
      • et al.
      G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences.
      A two-tailed P-value of less than 0.05 was considered to be significant.

      Results

      Study Selection

      The search of the English and Chinese literature retrieved 11,166 citations, of which 10,540 records were excluded on the basis of the abstract alone because of nonrelevance or duplication. The full texts of the remaining 626 articles were retrieved for more detailed evaluation, and 489 articles were excluded 1) for including herbs or other medicine (n = 149), 2) interventions combined with other nontraditional methods (n = 79), 3) no RCT (n = 151), 4) no relevant outcomes (n = 72), 5) insufficient information (n = 26), and 6) publication not available (n = 12). An additional five articles were incorporated, gleaned from reference lists, for a total of 142 studies included in this review. Of these, 67 trials (20 in English and 47 in Chinese) covering 5465 patients provided enough data for statistical pooling and were used for quantitative meta-analysis (Fig. 1, Table 1).
      • Huang Y.
      • Yang X.
      • Yang Q.
      Effect of traditional Chinese medicine five elements music on cancer-related fatigue of chemotherapy patients.
      • Sprod L.K.
      • Janelsins M.C.
      • Palesh O.G.
      • et al.
      Health-related quality of life and biomarkers in breast cancer survivors participating in tai chi chuan.
      • Xiang C.
      • Guo Q.
      • Liao J.
      Effect of therapy of traditional Chinese medicine five element music and electroacupuncture on the depression levels of cancer patients.
      • Oh B.
      • Butow P.N.
      • Mullan B.A.
      • et al.
      Effect of medical Qigong on cognitive function, quality of life, and a biomarker of inflammation in cancer patients: a randomized controlled trial.
      • Deng G.
      • Chan Y.
      • Sjoberg D.
      • et al.
      Acupuncture for the treatment of post-chemotherapy chronic fatigue: a randomized, blinded, sham-controlled trial.
      • Roscoe J.A.
      • Matteson S.E.
      • Morrow G.R.
      • et al.
      Acustimulation wrist bands are not effective for the control of chemotherapy-induced nausea in women with breast cancer.
      • Chen Z.
      • Meng Z.
      • Milbury K.
      • et al.
      Qigong improves quality of life in women undergoing radiotherapy for breast cancer: results of a randomized controlled trial.
      ,

      Yu L. Effect of moxibustion on cancer related fatigue Guide of China Medicine 2012;10:591–593.

      • Yang J.L.
      Effects of moxibustion on cancer related fatigue in elderly advanced cancer patients.
      • Yu H.X.
      Effects of moxibustion on gastrointestinal function after surgery in elderly gastric cancer patients.
      • Cheng L.
      Effect of moxibustion moxa at zusanli on cancer-related diarrhea.
      • Lai J.H.
      Chinese massage at Yongquan on gastrointestinal function in cervical cancer patients.
      • Chen F.R.
      • Wang M.
      • Xue J.
      Study on influence of ginger separated moxibustion on quality of life of elderly patients with advanced cancer.
      • Yin Z.L.
      • Meng Z.X.
      • Lin S.Y.
      • et al.
      The intervention effect of chemotherapy in patients with gynecological tumor relaxation training method.
      • Qiang W.M.
      • Dong F.Q.
      • Yan L.
      • et al.
      Comparison of two different exercise programs in breast cancer patients after postoperative adjuvant chemotherapy.
      • Chen L.R.
      • Hou X.C.
      Effect of chiropractic and psychological intervention on patients with cancer pain and bad mood.
      • Zhang Y.M.
      Effects of hand massage therapy on the quality of life in breast cancer patients undergoing chemotherapy.
      • Jiang M.Y.
      Influence of shadowboxing on improving cancer-related fatigue and sleeping quality of patients with advanced lung cancer.
      • Wang H.L.
      • Liu C.C.
      • Wen X.X.
      The effect of a foot massage combined with psychological intervention to improve the sleep quality of patients with cancer.
      • Chen C.F.
      Treatment of moxibustion effecting on cancer-associated diarrhea in 18 cases.
      • Xue W.X.
      Liver cancer after interventional chemotherapy intractable hiccups acupuncture curative effect observation.
      • Chen Y.L.
      Acupressure reduces abdominal distention after laparoscopic resection in colorectal cancer patients.
      • Wan S.Y.
      • Huang J.P.
      • Gao J.
      Influence of acupoint massage plus induced imagining relaxation on quality of life of tumor patients accepting chemotherapy.

      Wang HM, Fan ZM. The clinical study on gastrointestinal function recovery after colorectal carcinoma resection in fast track programme using acupuncture. Master's Thesis. 2011. Available at: http://d.g.wanfangdata.com.cn/Thesis_Y1945947.aspx.

      • Lu Y.
      • Zhang Y.
      • Jing N.C.
      Acupuncture improved quality of life in cancer patients via clinical study.
      • Zhang M.F.
      • Ruan J.W.
      • Gu M.F.
      Effects of acupuncture combined with relaxation training on pain, anxiety and sleep quality in patients with advanced cancer.
      • Pei Y.
      • Yang J.
      • Zhang J.
      To observe the state of depression and anxiety in patients with acupuncture in the treatment of breast cancer.
      • Wang X.P.
      • Ding Y.
      The effect of music therapy on quality of life in patients with chemotherapy for advanced cancer.
      • Li H.Y.
      • Yang D.N.
      Acupuncture recovered gastrointestinal function after surgery for esophageal cancer.
      • Liu H.
      The effect of acupuncture and moxibustion and acupuncture point injection on treatment of pain of hepatocellular carcinoma.
      • Feng Y.
      • Wang X.Y.
      • Li S.D.
      • et al.
      Clinical research of acupuncture on malignant tumor patients for improving depression and sleep quality.
      • Meng Z.Q.
      • Garcia M.K.
      • Chiang J.S.
      • et al.
      Electro-acupuncture to prevent prolonged postoperative ileus: a randomized clinical trial.
      • Nedstrand E.
      • Wyon Y.
      • Hammar M.
      • et al.
      Psychological well-being improves in women with breast cancer after treatment with applied relaxation or electro-acupuncture for vasomotor symptom.
      • Wong R.H.
      • Lee T.W.
      • Sihoe A.D.
      • et al.
      Analgesic effect of electroacupuncture in postthoracotomy pain: a prospective randomized trial.

      Zhu YY. Effect of acupuncture at specific points combined with thumbtach needle on pain and depression in pancreatic cancer patients. Chinese General Practice 2013;16:1923–1925.

      • Zhao B.M.
      Effect of acupuncture on ascites in liver cancer.
      ,
      • Li J.
      Clinical research on treating advanced breast cancer related fatigue by moxibustion.
      • Guo L.Y.
      Effect of acupuncture therapy on cancer–related fatigue of patients with gynecological malignant tumor after chemotherapy.
      • Fu L.P.
      Effect of moxibustion on quality of life in esophageal cancer patients.
      • Chen Y.H.
      Effect of moxibustion on depression and quality of life in patients with advanced gastric cancer.
      • Yan Q.M.
      Effect of moxibustion on ascites in advanced cancer patients.
      • Chen H.T.
      Clinical observation of acupuncture therapy on hiccuping in liver cancer.
      • Luo M.S.
      • Wu S.B.
      Acupuncture for 70 cases of hiccup after operation of primary liver cancer.
      • Bao F.F.
      Effect of acupuncture on hiccups in cancer patients after radio-chemotherapy.
      • Smith C.
      • Carmady B.
      • Thornton C.
      • et al.
      The effect of acupuncture on post-cancer fatigue and well-being for women recovering from breast cancer: a pilot randomised controlled trial.
      • Deng G.
      • Wong W.D.
      • Guillem J.
      • et al.
      A phase II, randomized, controlled trial of acupuncture for reduction of postcolectomy ileus.
      • Ng S.S.
      • Leung W.W.
      • Mak T.W.
      • et al.
      Electroacupuncture reduces duration of postoperative ileus after laparoscopic surgery for colorectal cancer.
      • Johnston M.F.
      • Hays R.D.
      • Subramanian S.K.
      • et al.
      Patient education integrated with acupuncture for relief of cancer-related fatigue randomized controlled feasibility study.
      • Liljegren A.
      • Gunnarsson P.
      • Landgren B.M.
      • et al.
      Reducing vasomotor symptoms with acupuncture in breast cancer patients treated with adjuvant tamoxifen: a randomized controlled trial.
      • Pfister D.G.
      • Cassileth B.R.
      • Deng G.E.
      • et al.
      Acupuncture for pain and dysfunction after neck dissection: results of a randomized controlled trial.
      • Deng G.
      • Rusch V.
      • Vickers A.
      • et al.
      Randomized controlled trial of a special acupuncture technique for pain after thoracotomy.
      • Deng G.
      • Vickers A.
      • Yeung S.
      • et al.
      Randomized, controlled trial of acupuncture for the treatment of hot flashes in breast cancer patients.
      • Yang J.X.
      Effect of Chinese medicine five-tone therapy intervention on the depression state of the chemotherapy patients with breast cancer.
      • Lei Y.Y.
      Effect of five elements music of traditional Chinese medicine on the tumor patients under hyperthermia nursing.
      • Li W.J.
      Effect of Chinese massage on hiccups in patients with liver cancer.
      • Xiao J.
      Effect of Chinese massage combined with point pressure on ventosity in patients with gynecologic cancer.
      • Liu Y.C.
      Effect of Tai Chi on respiratory function in patients with lung cancer.

      Rausch SM. Evaluating psychosocial effects of two intervention, tai chi and spiritual growth groups, in women with breast cancer. MS Thesis. Richmond, VA: College of Humanities and Sciences, Virginia Commonwealth University, 2007. Available at: http://scholarscompass.vcu.edu/etd/819/.

      • He J.H.
      Rehabilitation effect of systematic exercise in adjuvant chemotherapy for breast cancer patients.
      • Janelsins M.C.
      • Davis P.G.
      • Wideman L.
      • et al.
      Effects of Tai Chi Chuan on insulin and cytokine levels in a randomized controlled pilot study on breast cancer survivors.
      • Mustian K.M.
      • Palesh O.G.
      • Flecksteiner S.A.
      Tai Chi Chuan for breast cancer survivors.
      • Wang Y.L.
      • Sun X.Y.
      • Wang Y.B.
      Different exercise on breast cancer patients postoperative upper limb function and the influence of the quality of life.
      • Li P.X.
      Effect of acupuncture on anorexia in advanced gastric cancer patients.
      • Liu X.M.
      • Huang Z.F.
      Acupuncture treatment for intractable hiccup in patients with cancer of 32 cases.
      • Xie X.P.
      Observation of electroacupuncture and pressing auricular point with pill in treating patients with tumor suffering from hiccup.
      • Chen S.Y.
      • Huang L.Q.
      Effect of electroacupuncture treatment on zusanli(st36) for intractable hiccups with malignant tumors of 24 cases.
      Figure thumbnail gr1
      Fig. 1PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) flow diagram of study selection. CNKI = China National Knowledge Infrastructure; CBM = China Biology Medicine; RCT = randomized controlled trial.
      Table 1Descriptive Summary of Studies Included in the Meta-Analysis
      AuthorYearCancer TypeStudy CountrySample SizeExperimental InterventionControl InterventionLength of Intervention (Weeks)Outcome MeasuresRisk of Bias
      Yu L2012MixedChina146Acupoint stimulationUsual care3Fatigue (PFS)High
      Yang JL2012MixedChina180Acupoint stimulationStandard medical care4Fatigue (PFS) and QOL (KPS)High
      Yu HX2012GastricChina68Acupoint stimulationStandard medical care1Hours to first flatus/bowel movement/defecationHigh
      Cheng L2009MixedChina90Acupoint stimulationStandard medical care1Remission rate of diarrheaHigh
      Lai JH2011CervicalChina100Chinese massageStandard medical care1Hours to first flatus/bowel movementHigh
      Chen FR2011MixedChina200Acupoint stimulationUsual care2Nausea and vomit (QLQ-C30)High
      Yin ZL2012NasopharyngealChina43Acupoint stimulationStandard medical care2QOL (QLQ-C30)High
      Qiang WM2011BreastChina120Tai ChiMusic exercises16Vital capacity, BMI, QOL (FACT-B)High
      Chen LR2009ColorectalChina56Chinese massageStandard medical care2Pain (VAS)High
      Zhang YM2012BreastChina60Chinese massageStandard medical care3 DaysQOL (QLSBC)High
      Jiang MY2013LungChina60Tai ChiStandard medical care4Fatigue (BFI) and sleep qualityHigh
      Wang HL2012MixedChina399Chinese massageStandard medical care2Sleep (PSQI), anxiety (SAS), and depression (SDS)High
      Chen CF2012MixedChina36Acupoint stimulationStandard medical care2Remission rate of diarrheaHigh
      Xue WX2011LiverChina42Acupoint stimulationIntramuscular injections2Response rate of hiccupsHigh
      Chen YL2008ColorectalChina37Chinese massageStandard medical careNot reportedHours to first flatus/bowel movementHigh
      Wan SY2011MixedChina134Acupoint stimulationStandard medical care1QOL (QLQ-C30)High
      Wang HM2008ColorectalChina30Acupoint stimulationStandard medical care1Hours to first flatus/bowel movement/defecation, pain (Prince Henry method)High
      Lu Y2005MixedChina62Acupoint stimulationStandard medical care6–8QOL (KPS)High
      Zhang MF2009MixedChina71Acupoint stimulationStandard medical care4QOL (FACT-G), anxiety (SAS), sleep quality (PSQI), and pain (self-made scale)High
      Pei Y2010BreastChina67Acupoint stimulationStandard medical care6Anxiety (SAS) and depression (SDS, HAMD)High
      Wang XP2006MixedChina66Acupoint stimulationIntramuscular injections1Response rate of hiccupsHigh
      Li PX2006MixedChina50Acupoint stimulationStandard medical care4QOL (KPS), appetite, and body weightHigh
      Li HY2008EsophagealChina45Acupoint stimulationStandard medical careUntil first flatusHours to first flatus/nasogastric tube retentionHigh
      Liu H2010LiverChina102Acupoint stimulationStandard medical care2Pain (VAS)High
      Huang YN2012MixedChina80TCM-FEMTStandard medical care12Fatigue (PFS) and QOL (QLQ-C30)High
      Xiang CY2006MixedChina92Acupuncture combined with TCM-FEMTStandard medical care4Depression (SDS, HAMD), QOL (KPS)Moderate
      Feng Y2011MixedChina80Acupoint stimulationStandard medical care4Depression (SDS, HAMD), sleep quality (PSQI)High
      Meng ZQ2010ColonChina75Acupoint stimulationStandard medical care6 Days or until the first bowel movement, whichever came first.QOL (QOLS), hours to first flatus/bowel movementHigh
      Elizabeth N2006BreastSweden38Acupoint stimulationRelaxation12Frequency of hot fiushes per 24 hours, symptoms (KI, VAS), psychological well-being (SCL-90), general mood (Mood Scale)High
      Randolph HL2006LungChina Hong Kong27Acupoint stimulationSham acupuncture1Pain (VAS; The cumulative dose of patient-controlled analgesia morphine used on postoperative day 2)Moderate
      Joseph AR2005BreastUSA96Acupoint stimulationSham or no acupuncture1Nausea and emesis, QOL (FACT-G)High
      Zhu YY2013PancreaticChina68Acupoint stimulationStandard medical care1Pain (NRS), depression (HAMD)High
      Zhao BM2013LiverChina60Acupoint stimulationStandard medical care4QOL (KPS), effective rate of ascitesHigh
      Li J2013BreastChina168Acupoint stimulationStandard medical care8QOL (KPS), fatigue (BFI)High
      Guo LY2014GynecologicChina120Acupoint stimulationStandard medical care3Fatigue (BFI)High
      Fu LP2014EsophagealChina128Acupoint stimulationStandard medical care12QOL (QLQ-C30), curative effectHigh
      Chen YH2013GastricChina60Acupoint stimulationStandard medical care2QOL (SF-36), anxiety (SAS), and depression (SDS)High
      Yan QM2014MixedChina150Acupoint stimulationStandard medical care4QOL(KPS), effective rate of ascitesHigh
      Liu XM2007MixedChina62Acupoint stimulationOral drug3 DaysResponse rate of hiccupsHigh
      Xie XP2005MixedChina101Acupoint stimulationPoint injectionNot reportedResponse rate of hiccupsHigh
      Chen SY2007MixedChina36Acupoint stimulationStandard medical care1Response rate of hiccupsHigh
      Chen HT2006MixedChina60Acupoint stimulationIntramuscular injections10 DaysResponse rate of hiccupsHigh
      Luo M2007LiverChina48Acupoint stimulationIntramuscular injections3 DaysResponse rate of hiccupsHigh
      Bao FF2012MixedChina60Acupoint stimulationIntramuscular injections1Response rate of hiccupsHigh
      Gary D2013MixedUSA74Acupoint stimulationSham acupuncture6Fatigue (BFI), depression (HADS), QOL (FACT-G)Low
      Caroline S2014BreastAustralia30Acupoint stimulationSham acupuncture, wait list control6Well-being (W-BQ12), fatigue (BFI)Moderate
      Gary D2013ColonUSA90Acupoint stimulationSham acupuncture3 DaysTime that the patient first tolerated solid food/passed fiatus or a bowel movement, pain, and nausea (VAS)Low
      Simon SMN2013ColorectalChina Hong Kong165Acupoint stimulationSham or no acupuncture4 DaysTime of first passing fiatus/tolerated a solid diet/walk independently, pain (VAS)Moderate
      Michael FJ2011BreastUSA12Acupoint stimulationUsual care8Fatigue (BFI) and QOL (FACT-Cog)Moderate
      Annelie L2012BreastSweden74Acupoint stimulationSham acupuncture5Severity of hot fiushes and sweating per 24 hoursLow
      David G2010MixedUSA58Acupoint stimulationUsual care4Composite score of pain, function, and activities of daily living (Constant-Murley instrument)Moderate
      Gary D2008MixedUSA106Acupoint stimulationSham acupuncture4Pain (BPI/NRS/MQS)Low
      Gary D2007BreastUSA72Acupoint stimulationSham acupuncture5Hot fiash frequencyLow
      Yang JX2013BreastChina30TCM-FEMTUsual care12Depression (SDS)High
      Lei YY2014MixedChina98TCM-FEMTUsual careNot reportedAnxiety (SAS) and depression (SDS)High
      Li WJ2014LiverChina13Chinese massageIntramuscular injectionsNot reportedResponse rate of hiccupsHigh
      Xiao J2014GynecologicChina151Chinese massageUsual care24 HoursHours to first flatus/bowel movementHigh
      Byeongsang O2012MixedAustralia81QigongUsual care10QOL (FACT-G), cognitive function (EORTC-CF, FACT-Cog)High
      Zhen C2013BreastChina96QigongWait list5Depression (CES-D), fatigue (BFI), sleep quality (PSQI), QOL (FACT-G)High
      Liu YC2014LungChina120Tai ChiUsual care4Vital capacity, maximal inspiratory capacity, total expiration timeHigh
      Rausch SM2007BreastUSA22Tai ChiStandard medical care10QOL (FACT-B)High
      Wang YL2010BreastChina120Tai ChiUsual care24QOL (WHOQOL), function of side upper limbsHigh
      He JH2011BreastChina110Tai ChiUsual care16Vital capacity, body mass index, QOL (FACT-B)High
      Lisa KS2012BreastUSA21Tai ChiPsychosocial therapy12QOL (SF-36)High
      Michelle CJ2011BreastUSA19Tai ChiPsychosocial therapy12Body mass indexModerate
      Mustian KM2008BreastUSA21Tai ChiPsychosocial therapy12QOL (FACIT-F), aerobic capacity, muscular strength, and flexibilityHigh
      PFS = Piper Fatigue Scale; QOL = quality of life; KPS = Karnofsky Performance Score; QLQ-C30 = European Organization for Research and Treatment of Cancer Quality of life Questionnaire–Core 30; BMI = body mass index; FACT-B = Functional Assessment of Cancer Therapy–Breast; VAS = visual analog scale; QLSBC = quality of life of breast cancer; BFI = Brief Fatigue Inventory; PSQI = Pittsburgh Sleep Quality Index; SAS = Self-rating Anxiety Scale; SDS = Self-rating Depression Scale; FACT-G = Functional Assessment of Cancer Therapy–General; HAMD = Hamilton scale for depression; TCM-FEMT = Traditional Chinese Medicine Five-Element Music Therapy; QOLS = Quality of Life Status assessment tool; KI = Kupperman Index; SCL-90 = Symptom Checklist–90; NRS = Numerical Rating Scale; SF-36 = the MOS item Short Form health survey; FACT-Cog = Functional Assessment of Cancer Therapy—Cognitive scale; MQS = Medication Quantification Scale; CES-D = Center for Epidemiologic Studies Depression Scale; WHOQOL = World Health Organization Quality-of-Life Scale; FACIT-F = Functional Assessment of Chronic Illness Therapy–Fatigue survey; HADS = hospital anxiety and depression scale; W-BQ12 = The well-being questionnaire with 12 items; EORTC-CF = European Organization for Research and Treatment of Cancer-Cognitive Function.

      Study Characteristics

      The systematic search covered the period from 1980 to 2013. More than 80% of the studies (51/67) were conducted in China, and the others were from the United States (11/67), Sweden (2/67), and Australia (2/67). The trials comprise 5456 patients. Study participants had a median intervention duration of 4.9 weeks (ranging from 24 hours to 24 weeks), with four reports in Chinese not supplying the length of intervention. Thirty-seven percent of the trials reported mixed cancer, 27% included breast cancer diagnoses, followed by colorectal cancer (9%) and liver cancer (7%). Forty-five trials were of acupoint stimulation, nine of Tai Chi, seven of Chinese massage, three of TCM-FEMT, two of Qigong, and one of acupuncture combined with TCM-FEMT.
      One-third of the studies (22/67) used an active control condition, such as sham acupuncture (n = 9), oral or injectable drug (n = 8), psychosocial therapy (n = 3), music exercise (n = 1), or relaxation (n = 1; Table 1).
      Among the 67 RCTs included in the meta-analysis, the top three outcome measures reported were pain, hiccups, and fatigue, with nine studies each. Evaluation tools for overall QOL were varied, among which KPS score was the most frequently reported (n = 7), followed by the FACT-G (n = 4), European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 (n = 3), and SF-36 (n = 2; Table 2).
      Table 2Summary of Meta-Analysis Results
      ComparisonNo. of StudiesNo. of SubjectsStatistical MethodEffect Size
      General QOL change
       By KPS77624 Studies: MD (IV, random, 95% CI);

      3 Studies: OR (M-H, fixed, 95% CI)
      4.55 (0.75 to 8.34)

      2.32 (1.26 to 4.27)
       By generic QOL scales (e.g., SF-36, WHOQOL)4222SMD (IV, random, 95% CI)3.49 (0.99 to 5.99)
      Cancer-specific QOL change (e.g., FACT-G, FACT-B, or EORTC QLQ-C30)9686SMD (IV, random, 95% CI)0.97 (0.18 to 1.76)
      Symptoms improvement
       Pain (by VAS or NRS)9710SMD (IV, random, 95% CI)−0.35 (−0.60 to −0.09)
       Fatigue
      Response rate by PFS2326OR (M-H, fixed, 95% CI)2.40 (1.40 to 4.13)
      Means by BFI7560MD (IV, random, 95% CI)−1.19 (−2.19 to −0.18)
       Gastrointestinal distress
      By hours to first flatus8671MD (IV, random, 95% CI)−11.52 (−16.50 to −6.54)
      By hours to first bowel movement6461MD (IV, random, 95% CI)−8.22 (−13.50 to −2.95)
      Response rate of diarrhea2126OR (M-H, fixed, 95% CI)3.48 (1.06 to 11.47)
      Nausea and vomit (by subscales of QLQ-C30)2328MD (IV, fixed, 95% CI)−0.21 (−0.30 to −0.11)
      Response rate of hiccups9488OR (M-H, fixed, 95% CI)5.57 (3.42 to 9.08)
       Sleep disturbance (by PSQI)4646MD (IV, random, 95% CI)−2.53 (−4.17 to −0.89)
       Depression (by SDS)7826MD (IV, random, 95% CI)−7.4 3 (−12.96 to −1.91)
       Anxiety (by SAS)4624MD (IV, random, 95% CI)−7.82 (−13.74 to −1.90)
       Hot flushes (by median number/24 hours)3184MD (IV, random, 95% CI)−0.02 (−1.49 to 1.45)
      Other clinical outcomes
       BMI4270SMD (IV, random, 95% CI)−0.28 (−2.08 to −0.61)
       Vital capacity3350MD (IV, random, 95% CI)339.53 (78.5 to 600.56)
      QOL = quality of life; KPS = Karnofsky Performance Score; OR = odds ratio; MD = mean difference; SF-36 = the MOS item Short Form health survey; WHOQOL = World Health Organization Quality-of-Life Scale; SMD = standardized mean difference; FACT-G = Functional Assessment of Cancer Therapy–General; FACT-B = Functional Assessment of Cancer Therapy–Breast; EORTC QLQ-C30 = European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30; VAS = visual analog scale; NRS = Numerical Rating Scale; PFS = Piper Fatigue Scale; BFI = Brief Fatigue Inventory; QLQ-C30 = European Organization for Research and Treatment of Cancer Core Questionnaire; PSQI = Pittsburgh Sleep Quality Index; SDS = Self-rating Depression Scale; SAS = Self-rating Anxiety Scale; BMI = body mass index; M-H = Mantel Haenszel.
      Twenty-three studies valued two or more outcomes.

      Risk of Bias Analysis

      Each trial was evaluated in terms of its risk of bias. Most (50/67) had high risk of bias, 12 of 67 with moderate, and five with low risk of bias. Major sources of risk of bias were lack of blinding, allocation concealment, and incomplete outcome data. Of 67 trials, only 11 studies (10 on acupoint stimulation and one on Tai Chi) described the method of blinding and methods of allocation concealment. Less than half of the reports provided specified numbers and reasons for dropouts by each subject group. No more than 52% provided information on the method of randomization used (Fig. 2).

      Effects of the Interventions on Clinical Outcomes for Cancer Survivors

      Effects are described according to outcome measures: overall QOL (20/67 of the comparisons), adverse symptoms including gastrointestinal distress (21/67), pain (9/67), fatigue (9/67), depression (7/67), anxiety (4/67), sleep disturbance (4/67), flushes (3/67). Other clinical outcomes involved are vital capacity (3/67) and body mass index (BMI; 3/67). Seventeen studies evaluated two or more outcomes (Table 2).

      General QOL

      Eleven trials
      • Sprod L.K.
      • Janelsins M.C.
      • Palesh O.G.
      • et al.
      Health-related quality of life and biomarkers in breast cancer survivors participating in tai chi chuan.
      • Xiang C.
      • Guo Q.
      • Liao J.
      Effect of therapy of traditional Chinese medicine five element music and electroacupuncture on the depression levels of cancer patients.
      • Yang J.L.
      Effects of moxibustion on cancer related fatigue in elderly advanced cancer patients.
      • Lu Y.
      • Zhang Y.
      • Jing N.C.
      Acupuncture improved quality of life in cancer patients via clinical study.
      • Zhao B.M.
      Effect of acupuncture on ascites in liver cancer.
      • Li J.
      Clinical research on treating advanced breast cancer related fatigue by moxibustion.
      • Chen Y.H.
      Effect of moxibustion on depression and quality of life in patients with advanced gastric cancer.
      • Yan Q.M.
      Effect of moxibustion on ascites in advanced cancer patients.
      • Mustian K.M.
      • Palesh O.G.
      • Flecksteiner S.A.
      Tai Chi Chuan for breast cancer survivors.
      • Wang Y.L.
      • Sun X.Y.
      • Wang Y.B.
      Different exercise on breast cancer patients postoperative upper limb function and the influence of the quality of life.
      • Li P.X.
      Effect of acupuncture on anorexia in advanced gastric cancer patients.
      used generic scales (e.g., KPS, SF-36, World Health Organization Quality-of-Life Scale) to assess changes in general QOL scores after acupuncture and Tai Chi. Cancer-specific QOL was measured by the FACT-G, FACT-B, or EORTC QLQ-30 in nine studies.
      • Huang Y.
      • Yang X.
      • Yang Q.
      Effect of traditional Chinese medicine five elements music on cancer-related fatigue of chemotherapy patients.
      • Oh B.
      • Butow P.N.
      • Mullan B.A.
      • et al.
      Effect of medical Qigong on cognitive function, quality of life, and a biomarker of inflammation in cancer patients: a randomized controlled trial.
      • Deng G.
      • Chan Y.
      • Sjoberg D.
      • et al.
      Acupuncture for the treatment of post-chemotherapy chronic fatigue: a randomized, blinded, sham-controlled trial.
      • Roscoe J.A.
      • Matteson S.E.
      • Morrow G.R.
      • et al.
      Acustimulation wrist bands are not effective for the control of chemotherapy-induced nausea in women with breast cancer.
      • Chen Z.
      • Meng Z.
      • Milbury K.
      • et al.
      Qigong improves quality of life in women undergoing radiotherapy for breast cancer: results of a randomized controlled trial.
      • Yin Z.L.
      • Meng Z.X.
      • Lin S.Y.
      • et al.
      The intervention effect of chemotherapy in patients with gynecological tumor relaxation training method.
      • Zhang Y.M.
      Effects of hand massage therapy on the quality of life in breast cancer patients undergoing chemotherapy.
      • Wan S.Y.
      • Huang J.P.
      • Gao J.
      Influence of acupoint massage plus induced imagining relaxation on quality of life of tumor patients accepting chemotherapy.

      Rausch SM. Evaluating psychosocial effects of two intervention, tai chi and spiritual growth groups, in women with breast cancer. MS Thesis. Richmond, VA: College of Humanities and Sciences, Virginia Commonwealth University, 2007. Available at: http://scholarscompass.vcu.edu/etd/819/.

      Fig. 3 shows that a significant combined effect was observed for general QOL change in patients with terminal cancer in favor of acupuncture; Chinese massage improved cancer-specific QOL, and Tai Chi and Qigong had no effect on QOL of breast cancer survivors.
      Figure thumbnail gr3ae
      Fig. 3Forest plots of effect sizes for interventions on QOL. a) Acupuncture on QOL of terminal cancer survivors by means of KPS, b) acupuncture on QOL by remission rate of KPS, c) Tai Chi on QOL of breast cancer patients by generic QOL scales, d) interventions on QOL by cancer-specific QOL scales, e) acupuncture on QOL by cancer-specific QOL scales, f) Chinese massage on QOL by cancer-specific QOL scales, and g) Qigong on QOL by cancer-specific QOL scales. QOL = quality of life; KPS = Karnofsky Performance Score; M-H = Mantel Haenszel.
      Figure thumbnail gr3fg
      Fig. 3Forest plots of effect sizes for interventions on QOL. a) Acupuncture on QOL of terminal cancer survivors by means of KPS, b) acupuncture on QOL by remission rate of KPS, c) Tai Chi on QOL of breast cancer patients by generic QOL scales, d) interventions on QOL by cancer-specific QOL scales, e) acupuncture on QOL by cancer-specific QOL scales, f) Chinese massage on QOL by cancer-specific QOL scales, and g) Qigong on QOL by cancer-specific QOL scales. QOL = quality of life; KPS = Karnofsky Performance Score; M-H = Mantel Haenszel.
      Sensitivity analyses yielded one study
      • Yan Q.M.
      Effect of moxibustion on ascites in advanced cancer patients.
      with a great impact on both effects and heterogeneity for overall QOL evaluated by KPS. Meta-analyses excluding this study showed smaller effect sizes and heterogeneity (d = 2.79; 95% CI = −1.12 to 6.69; P = 0.16; I2 = 77%).

      Adverse Symptoms

      Nine studies
      • Chen L.R.
      • Hou X.C.
      Effect of chiropractic and psychological intervention on patients with cancer pain and bad mood.
      • Liu H.
      The effect of acupuncture and moxibustion and acupuncture point injection on treatment of pain of hepatocellular carcinoma.
      • Nedstrand E.
      • Wyon Y.
      • Hammar M.
      • et al.
      Psychological well-being improves in women with breast cancer after treatment with applied relaxation or electro-acupuncture for vasomotor symptom.
      • Wong R.H.
      • Lee T.W.
      • Sihoe A.D.
      • et al.
      Analgesic effect of electroacupuncture in postthoracotomy pain: a prospective randomized trial.

      Zhu YY. Effect of acupuncture at specific points combined with thumbtach needle on pain and depression in pancreatic cancer patients. Chinese General Practice 2013;16:1923–1925.

      • Deng G.
      • Wong W.D.
      • Guillem J.
      • et al.
      A phase II, randomized, controlled trial of acupuncture for reduction of postcolectomy ileus.
      • Ng S.S.
      • Leung W.W.
      • Mak T.W.
      • et al.
      Electroacupuncture reduces duration of postoperative ileus after laparoscopic surgery for colorectal cancer.
      • Pfister D.G.
      • Cassileth B.R.
      • Deng G.E.
      • et al.
      Acupuncture for pain and dysfunction after neck dissection: results of a randomized controlled trial.
      • Deng G.
      • Rusch V.
      • Vickers A.
      • et al.
      Randomized controlled trial of a special acupuncture technique for pain after thoracotomy.
      including 710 patients evaluated the impact of interventions on pain (eight on acupuncture and one on Chinese massage). A small but significant effect was found in our meta-analysis for acupuncture (d = −0.30; 95% CI= −0.56 to −0.03; P = 0.03; I2 = 59%; Fig. 4a).
      Figure thumbnail gr4ae
      Fig. 4Forest plots of effect sizes for interventions on adverse symptoms. a) Acupuncture on pain; b) acupuncture on remission rate of fatigue by Piper Fatigue Scale; c) acupuncture on fatigue by Brief Pain Inventory; d) acupuncture on hours to first flatus; e) Chinese massage on hours to first flatus; f) acupuncture on hours to first bowel movement; g) Chinese massage on hours to first bowel movement; h) acupuncture on remission rate of diarrhea; i) acupuncture on nausea and vomit; j) acupuncture on hiccups; k) acupuncture, Chinese massage, and Qigong on sleep disturbance; l) acupuncture on sleep disturbance; m) acupuncture, Chinese massage, and TCM-FEMT on depression; n) acupuncture on depression; o) TCM-FEMT on depression; p) acupuncture, Chinese massage, and TCM-FEMT on anxiety; q) acupuncture on anxiety; and r) acupuncture on hot flushes. TCM-FEMT = Traditional Chinese Medicine Five-Element Music Therapy; M-H = Mantel Haenszel.
      Figure thumbnail gr4fj
      Fig. 4Forest plots of effect sizes for interventions on adverse symptoms. a) Acupuncture on pain; b) acupuncture on remission rate of fatigue by Piper Fatigue Scale; c) acupuncture on fatigue by Brief Pain Inventory; d) acupuncture on hours to first flatus; e) Chinese massage on hours to first flatus; f) acupuncture on hours to first bowel movement; g) Chinese massage on hours to first bowel movement; h) acupuncture on remission rate of diarrhea; i) acupuncture on nausea and vomit; j) acupuncture on hiccups; k) acupuncture, Chinese massage, and Qigong on sleep disturbance; l) acupuncture on sleep disturbance; m) acupuncture, Chinese massage, and TCM-FEMT on depression; n) acupuncture on depression; o) TCM-FEMT on depression; p) acupuncture, Chinese massage, and TCM-FEMT on anxiety; q) acupuncture on anxiety; and r) acupuncture on hot flushes. TCM-FEMT = Traditional Chinese Medicine Five-Element Music Therapy; M-H = Mantel Haenszel.
      Figure thumbnail gr4kp
      Fig. 4Forest plots of effect sizes for interventions on adverse symptoms. a) Acupuncture on pain; b) acupuncture on remission rate of fatigue by Piper Fatigue Scale; c) acupuncture on fatigue by Brief Pain Inventory; d) acupuncture on hours to first flatus; e) Chinese massage on hours to first flatus; f) acupuncture on hours to first bowel movement; g) Chinese massage on hours to first bowel movement; h) acupuncture on remission rate of diarrhea; i) acupuncture on nausea and vomit; j) acupuncture on hiccups; k) acupuncture, Chinese massage, and Qigong on sleep disturbance; l) acupuncture on sleep disturbance; m) acupuncture, Chinese massage, and TCM-FEMT on depression; n) acupuncture on depression; o) TCM-FEMT on depression; p) acupuncture, Chinese massage, and TCM-FEMT on anxiety; q) acupuncture on anxiety; and r) acupuncture on hot flushes. TCM-FEMT = Traditional Chinese Medicine Five-Element Music Therapy; M-H = Mantel Haenszel.
      Figure thumbnail gr4qr
      Fig. 4Forest plots of effect sizes for interventions on adverse symptoms. a) Acupuncture on pain; b) acupuncture on remission rate of fatigue by Piper Fatigue Scale; c) acupuncture on fatigue by Brief Pain Inventory; d) acupuncture on hours to first flatus; e) Chinese massage on hours to first flatus; f) acupuncture on hours to first bowel movement; g) Chinese massage on hours to first bowel movement; h) acupuncture on remission rate of diarrhea; i) acupuncture on nausea and vomit; j) acupuncture on hiccups; k) acupuncture, Chinese massage, and Qigong on sleep disturbance; l) acupuncture on sleep disturbance; m) acupuncture, Chinese massage, and TCM-FEMT on depression; n) acupuncture on depression; o) TCM-FEMT on depression; p) acupuncture, Chinese massage, and TCM-FEMT on anxiety; q) acupuncture on anxiety; and r) acupuncture on hot flushes. TCM-FEMT = Traditional Chinese Medicine Five-Element Music Therapy; M-H = Mantel Haenszel.
      Association of interventions and fatigue was evaluated in nine trials
      • Chen Z.
      • Meng Z.
      • Milbury K.
      • et al.
      Qigong improves quality of life in women undergoing radiotherapy for breast cancer: results of a randomized controlled trial.

      Yu L. Effect of moxibustion on cancer related fatigue Guide of China Medicine 2012;10:591–593.

      • Yang J.L.
      Effects of moxibustion on cancer related fatigue in elderly advanced cancer patients.
      • Jiang M.Y.
      Influence of shadowboxing on improving cancer-related fatigue and sleeping quality of patients with advanced lung cancer.
      • Li J.
      Clinical research on treating advanced breast cancer related fatigue by moxibustion.
      • Guo L.Y.
      Effect of acupuncture therapy on cancer–related fatigue of patients with gynecological malignant tumor after chemotherapy.
      • Smith C.
      • Carmady B.
      • Thornton C.
      • et al.
      The effect of acupuncture on post-cancer fatigue and well-being for women recovering from breast cancer: a pilot randomised controlled trial.
      • Deng G.
      • Wong W.D.
      • Guillem J.
      • et al.
      A phase II, randomized, controlled trial of acupuncture for reduction of postcolectomy ileus.
      • Johnston M.F.
      • Hays R.D.
      • Subramanian S.K.
      • et al.
      Patient education integrated with acupuncture for relief of cancer-related fatigue randomized controlled feasibility study.
      involving 886 participants (seven on acupuncture, one on Tai Chi, and one on Qigong). Significant large post-treatment effects were observed for acupuncture (Figs. 4b and 4c).
      Acupuncture was found to relieve gastrointestinal distress including diarrhea,
      • Cheng L.
      Effect of moxibustion moxa at zusanli on cancer-related diarrhea.
      • Chen C.F.
      Treatment of moxibustion effecting on cancer-associated diarrhea in 18 cases.
      nausea, and vomiting.
      • Chen F.R.
      • Wang M.
      • Xue J.
      Study on influence of ginger separated moxibustion on quality of life of elderly patients with advanced cancer.
      • Fu L.P.
      Effect of moxibustion on quality of life in esophageal cancer patients.
      Acupuncture and Chinese massage also relieved hiccups (eight studies on acupuncture, one on Chinese massage),
      • Xue W.X.
      Liver cancer after interventional chemotherapy intractable hiccups acupuncture curative effect observation.
      • Wang X.P.
      • Ding Y.
      The effect of music therapy on quality of life in patients with chemotherapy for advanced cancer.
      • Chen H.T.
      Clinical observation of acupuncture therapy on hiccuping in liver cancer.
      • Luo M.S.
      • Wu S.B.
      Acupuncture for 70 cases of hiccup after operation of primary liver cancer.
      • Bao F.F.
      Effect of acupuncture on hiccups in cancer patients after radio-chemotherapy.
      • Li W.J.
      Effect of Chinese massage on hiccups in patients with liver cancer.
      • Liu X.M.
      • Huang Z.F.
      Acupuncture treatment for intractable hiccup in patients with cancer of 32 cases.
      • Xie X.P.
      Observation of electroacupuncture and pressing auricular point with pill in treating patients with tumor suffering from hiccup.
      • Chen S.Y.
      • Huang L.Q.
      Effect of electroacupuncture treatment on zusanli(st36) for intractable hiccups with malignant tumors of 24 cases.
      and shortened hours to first flatus (five on acupuncture, three on Chinese massage)
      • Yu H.X.
      Effects of moxibustion on gastrointestinal function after surgery in elderly gastric cancer patients.
      • Lai J.H.
      Chinese massage at Yongquan on gastrointestinal function in cervical cancer patients.
      • Chen Y.L.
      Acupressure reduces abdominal distention after laparoscopic resection in colorectal cancer patients.

      Wang HM, Fan ZM. The clinical study on gastrointestinal function recovery after colorectal carcinoma resection in fast track programme using acupuncture. Master's Thesis. 2011. Available at: http://d.g.wanfangdata.com.cn/Thesis_Y1945947.aspx.

      • Li H.Y.
      • Yang D.N.
      Acupuncture recovered gastrointestinal function after surgery for esophageal cancer.
      • Meng Z.Q.
      • Garcia M.K.
      • Chiang J.S.
      • et al.
      Electro-acupuncture to prevent prolonged postoperative ileus: a randomized clinical trial.
      • Ng S.S.
      • Leung W.W.
      • Mak T.W.
      • et al.
      Electroacupuncture reduces duration of postoperative ileus after laparoscopic surgery for colorectal cancer.
      • Xiao J.
      Effect of Chinese massage combined with point pressure on ventosity in patients with gynecologic cancer.
      and hours to first bowel movement (three on acupuncture, three on Chinese massage)
      • Yu H.X.
      Effects of moxibustion on gastrointestinal function after surgery in elderly gastric cancer patients.
      • Lai J.H.
      Chinese massage at Yongquan on gastrointestinal function in cervical cancer patients.
      • Chen Y.L.
      Acupressure reduces abdominal distention after laparoscopic resection in colorectal cancer patients.

      Wang HM, Fan ZM. The clinical study on gastrointestinal function recovery after colorectal carcinoma resection in fast track programme using acupuncture. Master's Thesis. 2011. Available at: http://d.g.wanfangdata.com.cn/Thesis_Y1945947.aspx.

      • Meng Z.Q.
      • Garcia M.K.
      • Chiang J.S.
      • et al.
      Electro-acupuncture to prevent prolonged postoperative ileus: a randomized clinical trial.
      • Xiao J.
      Effect of Chinese massage combined with point pressure on ventosity in patients with gynecologic cancer.
      (Figs. 4d–4j).
      Four trials involving 646 patients evaluated interventions on sleep level using the Pittsburgh Sleep Quality Index (two on acupuncture, one on Chinese massage, and one on Qigong).
      • Chen Z.
      • Meng Z.
      • Milbury K.
      • et al.
      Qigong improves quality of life in women undergoing radiotherapy for breast cancer: results of a randomized controlled trial.
      • Wang H.L.
      • Liu C.C.
      • Wen X.X.
      The effect of a foot massage combined with psychological intervention to improve the sleep quality of patients with cancer.
      • Zhang M.F.
      • Ruan J.W.
      • Gu M.F.
      Effects of acupuncture combined with relaxation training on pain, anxiety and sleep quality in patients with advanced cancer.
      • Feng Y.
      • Wang X.Y.
      • Li S.D.
      • et al.
      Clinical research of acupuncture on malignant tumor patients for improving depression and sleep quality.
      Our meta-analysis showed a significant combined effect of acupuncture on alleviating sleep disturbance (d = −1.66; 95% CI = −2.69 to −0.63; P = 0.002; I2 = 87%; Figs. 4k–4l).
      Our meta-analysis also revealed that interventions significantly lowered emotional distress, including depression (four on acupuncture, two on TCM-FEMT, one on Chinese massage)
      • Xiang C.
      • Guo Q.
      • Liao J.
      Effect of therapy of traditional Chinese medicine five element music and electroacupuncture on the depression levels of cancer patients.
      • Wang H.L.
      • Liu C.C.
      • Wen X.X.
      The effect of a foot massage combined with psychological intervention to improve the sleep quality of patients with cancer.
      • Pei Y.
      • Yang J.
      • Zhang J.
      To observe the state of depression and anxiety in patients with acupuncture in the treatment of breast cancer.
      • Feng Y.
      • Wang X.Y.
      • Li S.D.
      • et al.
      Clinical research of acupuncture on malignant tumor patients for improving depression and sleep quality.
      • Chen Y.H.
      Effect of moxibustion on depression and quality of life in patients with advanced gastric cancer.
      • Yang J.X.
      Effect of Chinese medicine five-tone therapy intervention on the depression state of the chemotherapy patients with breast cancer.
      • Lei Y.Y.
      Effect of five elements music of traditional Chinese medicine on the tumor patients under hyperthermia nursing.
      and anxiety (two on acupuncture, one on TCM-FEMT, one on Chinese massage),
      • Chen H.Y.
      • Li S.G.
      • Cho W.C.
      • et al.
      The role of acupoint stimulation as an adjunct therapy for lung cancer: a systematic review and meta-analysis.
      • Wang H.L.
      • Liu C.C.
      • Wen X.X.
      The effect of a foot massage combined with psychological intervention to improve the sleep quality of patients with cancer.
      • Pei Y.
      • Yang J.
      • Zhang J.
      To observe the state of depression and anxiety in patients with acupuncture in the treatment of breast cancer.
      • Lei Y.Y.
      Effect of five elements music of traditional Chinese medicine on the tumor patients under hyperthermia nursing.
      and exert a large effect (depression: d = −7.43; 95% CI = −12.96 to −1.91; P = 0.008; I2 = 98%; anxiety: d = −7.82; 95% CI = −13.74 to −1.90; P = 0.01; I2 = 97%). Further meta-analysis showed that TCM-FEMT relieved depression while acupuncture had no effect on depression or anxiety (Figs. 4m–4q).
      In three studies
      • Nedstrand E.
      • Wyon Y.
      • Hammar M.
      • et al.
      Psychological well-being improves in women with breast cancer after treatment with applied relaxation or electro-acupuncture for vasomotor symptom.
      • Liljegren A.
      • Gunnarsson P.
      • Landgren B.M.
      • et al.
      Reducing vasomotor symptoms with acupuncture in breast cancer patients treated with adjuvant tamoxifen: a randomized controlled trial.
      • Deng G.
      • Vickers A.
      • Yeung S.
      • et al.
      Randomized, controlled trial of acupuncture for the treatment of hot flashes in breast cancer patients.
      involving 184 breast cancer patients, the effect of acupuncture on hot flashes was evaluated; however, no significant effect was found in the meta-analysis (d = −0.02; 95% CI = −1.49 to 1.45; P = 0.97; I2 = 36%; Fig. 4r).

      Other Clinical Outcomes

      Three trials
      • Mustian K.M.
      • Katula J.A.
      • Zhao H.
      A pilot study to assess the influence of tai chi chuan on functional capacity among breast cancer survivors.
      • He J.H.
      Rehabilitation effect of systematic exercise in adjuvant chemotherapy for breast cancer patients.
      • Janelsins M.C.
      • Davis P.G.
      • Wideman L.
      • et al.
      Effects of Tai Chi Chuan on insulin and cytokine levels in a randomized controlled pilot study on breast cancer survivors.
      involving 249 patients assessed the effect of Tai Chi on the BMI of breast cancer patients and were included in our meta-analysis, which demonstrate a small but significant combined effect (d = −0.28; 95% CI, −0.53 to −0.03; P = 0.03; I2 = 0%). Another three trials
      • Qiang W.M.
      • Dong F.Q.
      • Yan L.
      • et al.
      Comparison of two different exercise programs in breast cancer patients after postoperative adjuvant chemotherapy.
      • He J.H.
      Rehabilitation effect of systematic exercise in adjuvant chemotherapy for breast cancer patients.
      • Janelsins M.C.
      • Davis P.G.
      • Wideman L.
      • et al.
      Effects of Tai Chi Chuan on insulin and cytokine levels in a randomized controlled pilot study on breast cancer survivors.
      evaluated the effect of Tai Chi on vital capacity; a significant effect was observed in the meta-analysis (d = 339.53; 95% CI = 78.50 to 600.56; P = 0.01; I2 = 88%; Fig. 5).
      Figure thumbnail gr5
      Fig. 5Forest plots of effect sizes for Tai Chi on other clinical outcomes. (a) body mass index and (b) vital capacity.

      Discussion

      This is the largest meta-analysis to date on the effects of acupuncture, Tuina, Tai Chi, Qigong, or TCM-FEMT on symptom management and QOL in patients with cancer. In this report, we searched for all the reports in which the interventions were used in clinical cancer trials published before October 2, 2014, regardless of whether the article was published in Chinese or English. This systematic review identified 66 published RCTs (covering 5465 patients) reporting comparisons of treatment against either standard medical care or active control. Although we retrieved studies from many countries around the world, more than half the studies were performed in China. Whereas the studies covered various cancer sites and treatments, the evidence clearly clustered in studies on breast cancer. According to our meta-analyses, acupuncture produced small-to-large effects on adverse symptoms including pain, fatigue, sleep disturbance, and some gastrointestinal discomfort, but no significant effect was found on the frequency of hot flashes and mood distress. Tuina relieved gastrointestinal discomfort, TCM-FEMT lowered depression level, and Tai Chi improved the vital capacity of breast cancer patients.
      In our meta-analysis, the effect size of acupuncture on pain, fatigue, and hiccups are consistent with the reports of previous meta-analyses.
      • Choi T.Y.
      • Lee M.S.
      • Ernst E.
      Acupuncture for cancer patients suffering from hiccups: a systematic review and meta-analysis.
      • Lu L.
      • Liao M.
      • Zeng J.
      • et al.
      Quality of reporting and its correlates among randomized controlled trials on acupuncture for cancer pain: application of the CONSORT 2010 statement and STRICTA.
      A somewhat lower effect (d = 0.76) on clinical efficacy measured by KPS score was reported in an earlier meta-analysis; however, this meta-analysis only included trials on acupuncture in lung cancer.
      • Chan H.Y.
      • Chui Y.Y.
      • Chan C.W.
      • et al.
      Exploring the influence of traditional Chinese medicine on self-care among Chinese cancer patients.
      Larger effect sizes for acupuncture on cancer-specific QOL and fatigue were found in our results than that of other meta-analyses in this field,
      • He X.R.
      • Wang Q.
      • Li P.P.
      Acupuncture and moxibustion for cancer-related fatigue: a systematic review and meta-analysis.
      • Lee M.S.
      • Choi T.Y.
      • Park J.E.
      • et al.
      Moxibustion for cancer care: a systematic review and meta-analysis.
      but these two reviews were based on only a few selected trials on acupuncture and moxibustion and omitted other interventions such as Chinese massage, Tai Chi, Qigong, and TCM-FEMT. One exception is that the significant effects of Tai Chi on BMI are different from a published meta-analysis,
      • Yan J.H.
      • Pan L.
      • Zhang X.M.
      • et al.
      Lack of efficacy of Tai Chi in improving quality of life in breast cancer survivors: a systematic review and meta-analysis.
      which failed to include a high-quality trial.
      • Janelsins M.C.
      • Davis P.G.
      • Wideman L.
      • et al.
      Effects of Tai Chi Chuan on insulin and cytokine levels in a randomized controlled pilot study on breast cancer survivors.
      Strikingly, our meta-analysis demonstrated that acupoint stimulation and Chinese massage exert a significant effect on gastrointestinal discomfort including easing diarrhea, hiccups, nausea and vomiting, and shortening time to first flatus and first bowel movement (Fig. 4).The reduction in the last two outcomes mentioned previously is important for reducing the risk of paralytic ileus by stimulating digestive propulsion, particularly after gastrointestinal surgery. We also found that Chinese massage and TCM-FEMT contribute to the combined effect on QOL in cancer patients but were not involved in any published review.
      Although the forest plots seem to provide considerable evidences for effects of acupuncture, Tuina, Tai Chi, Qigong, and TCM-FEMT on cancer-related symptoms and QOL, some effect sizes are modest. The study heterogeneity may be one of the most important factor contributing to this limited effect. First, interventions differed among studies. Intervention duration ranged from 24 hours to half a year. Different types and stages of disease were used among and even within studies; the studies recruited more than eight types of cancer patients including breast cancer, lung cancer, gastric cancer, and so forth. As well, the overall QOL of cancer patients was evaluated by various tools, including the KPS, SF-36, FACT-B, and other tools used no more than once. Furthermore, peri-intervention or accompanying clinical treatment varied among studies ranging from surgery, radiotherapy, various regimens of chemotherapy, and various combinations thereof. In addition, the number of subjects in some studies was generally too small; the smallest sample size was only 13. This makes the means and SDs of indicators vulnerable to individual outliers and higher or lower effects prone to be detected because of chance. Therefore, the reliability of the evidence presented here is clearly limited.
      Risk of bias was present in many RCTs. More than 80% of the studies were burdened with a high risk of bias; only 17 (29.82%) have low or moderate risk of bias. Only 16% provided information regarding adequate concealment of the randomization sequence and methods of blinding. Because of the nature of acupuncture, Tuina, Tai Chi, Qigong, and TCM-FEMT, it may be difficult to blind participants to intervention delivery. Few trials attempted to blind the outcome assessors to minimize potential methodological bias. Therefore, bias may affect most of the RCTs. Although lack of allocation concealment and blinding may be associated with exaggerated effect estimates for subjective outcomes, the degree of bias seems to be rather limited.
      • Wood L.
      • Egger M.
      • Gluud L.L.
      • et al.
      Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study.
      Incomplete follow-up data pose another problem, although this may be caused by the unfavorable prognoses inherent in many cancer diagnoses. Selective outcome reporting was present in one-third of the studies, sometimes precluding the quantitative analysis of effects—a common problem in clinical trials.
      • Smyth R.M.
      • Kirkham J.J.
      • Jacoby A.
      • et al.
      Frequency and reasons for outcome reporting bias in clinical trials: interviews with trialists.
      Because unreported outcomes were often nonsignificant, this may have inflated the computed effect sizes.
      • Faller H.
      • Schuler M.
      • Richard M.
      • et al.
      Effects of psycho-oncologic interventions on emotional distress and quality of life in adult patients with cancer: systematic review and meta-analysis.
      Low compliance with protocols and lack of motivation to continue participating influence intervention impact and can be other potential sources of bias and also an indicator that the intervention is inappropriate for the recruited subjects. Many studies included only small samples, thus raising the issue of insufficient power.
      • Moyer A.
      • Sohl S.J.
      • Knapp-Oliver S.K.
      • et al.
      Characteristics and methodological quality of 25 years of research investigating psychosocial interventions for cancer patients.
      However, small studies often produced larger effects than large studies did.
      Limitations of our systematic review and any systematic review in general pertain to the potential incompleteness of the evidence reviewed. Although an attempt was made to retrieve both published and unpublished research and to conduct a comprehensive search, some studies may have been missed. Moreover, some of the identified studies could not be retrieved. One other problem is the fact that most of the included trials (51/67) were carried out in Chinese regions that have been shown to produce almost no negative studies.
      • Vickers A.
      • Goyal N.
      • Harland R.
      • et al.
      Do certain countries produce only positive results? A systematic review of controlled trials.
      Moreover, it could be argued about the rationale for some meta-analyses pooling data from too few trials. The main reasons for conducting meta-analyses are to increase power, improve precision, answer questions not asked by individual studies, settle controversies arising from conflicting results, and generate new hypotheses; a meta-analysis can be performed by combining two or more trials.
      • Higgins J.P.T.
      • Green S.
      Cochrane handbook for systematic reviews of interventions.
      However, the use of statistics does not guarantee that the results are valid. In our case, for the evaluation of acupuncture's effect on diarrhea, the conclusions from the meta-analyses are from only two RCTs with small sample sizes; therefore, the conclusions must remain tentative.
      Future RCTs of acupuncture, Tuina, Tai Chi, Qigong, and TCM-FEMT for adverse symptoms and QOL of cancer patients should adhere to accepted standards of trial methodology. The studies included in this review show a number of defects that have been noted by other related reviews, for example, the frequency and duration of treatment, using validated primary outcome measures, adequate statistical tests, and heterogeneous comparison groups. Furthermore, even though it is difficult to blind subjects to some forms of interventions, using assessor blinding is important for reducing bias. We recommend that future publications give detailed information of randomization methods including sequence generation and randomization concealment and blinding information, including whether blinding is used and who was blinded, if available. Detailed reporting according to the requirements presented by the CONSORT (Consolidated Standards of Reporting Trials) statement will make it easier to reach clear conclusions regarding study quality.
      • Schulz K.F.
      • Altman D.G.
      • Moher D.
      • et al.
      CONSORT 2010 statement: updated guidelines for reporting parallel group randomized trials.
      Although there are some clear limitations regarding the body of research reviewed in this study, a tentative conclusion can be reached that at least acupuncture may alleviate some symptoms including pain, fatigue, gastrointestinal distress, sleep disturbance but has no effect on hot flashes. Tuina relieved gastrointestinal discomfort. TCM-FEMT lowered depression level. Tai Chi improved vital capacity of breast cancer patients. Acupuncture and Tuina improved overall QOL, whereas Tai Chi and Qigong exert no effect on QOL of breast cancer survivors. Future study reporting should be improved regarding both research methods and content of interventions.

      Disclosures and Acknowledgments

      No funding was received for this study, and the authors declare no conflicts of interest.
      The authors thank the health informatics experts for their assistance in developing the search strategy.

      References

      1. World Health Organization. Cancer. [2008-9-23] Available at: http://www.whoint/mediacentre/factsheets/fs297/en/

        • Boon H.S.
        • Olatunde F.
        • Zick S.M.
        Trends in complementary/alternative medicine use by breast cancer survivors: comparing survey data from 1998 and 2005.
        BMC Womens Health. 2007; 7: 4
        • Sirois F.M.
        • Gick M.L.
        An investigation of the health beliefs and motivations of complementary medicine clients.
        Soc Sci Med. 2002; 55: 1025-1037
        • Findley P.A.
        • Sambamoorthi U.
        Preventive health services and lifestyle practices in cancer survivors: a population health investigation.
        J Cancer Surviv. 2009; 3: 43-58
        • Smithson J.
        • Paterson C.
        • Britten N.
        • et al.
        Cancer patients' experiences of using complementary therapies: polarization and integration.
        J Health Serv Res Policy. 2010; 15: 54-61
        • Monti D.A.
        • Sufian M.
        • Peterson C.
        Potential role of mind-body therapies in cancer survivorship.
        Cancer. 2008; 112: 2607-2616
        • Tong G.
        • Geng Q.
        • Cheng J.
        • et al.
        Effects of psycho-behavioral interventions on immune functioning in cancer patients: a systematic review.
        J Cancer Res Clin Oncol. 2014; 140: 15-33
        • Zhou D.H.
        Clinical oncology of Chinese medicine.
        People’s Health Publishing House, Beijing2003
        • He X.R.
        • Wang Q.
        • Li P.P.
        Acupuncture and moxibustion for cancer-related fatigue: a systematic review and meta-analysis.
        Asian Pac J Cancer Prev. 2013; 14: 3067-3074
        • Goats G.C.
        Massage—the scientific basis of an ancient art: part 2. Physiological and therapeutic effects.
        Br J Sports Med. 1994; 28: 153-156
        • Liu W.S.
        Application of Chinese medicine in clinical oncology.
        People's Health Publishing House, Beijing2005
        • Chan C.L.
        • Wang C.W.
        • Ho R.T.
        • et al.
        A systematic review of the effectiveness of qigong exercise in supportive cancer care.
        Support Care Cancer. 2012; 20: 1121-1133
        • Lee M.S.
        • Choi T.Y.
        • Ernst E.
        Tai chi for breast cancer patients: a systematic review.
        Breast Cancer Res Treat. 2010; 120: 309-316
      2. American Music Therapy Association. Definitions and quotes about music therapy. Available at: http://www.musictherapy.org/about/quotes/. Accessed August 13, 2012.

        • Huang Y.
        • Yang X.
        • Yang Q.
        Effect of traditional Chinese medicine five elements music on cancer-related fatigue of chemotherapy patients.
        Chin J Mod Nurs. 2012; 18: 1412-1414
        • World Health Organization
        WHO traditional medicine strategy 2002-2005.
        World Health Organization, Geneva, Switzerland2002
        • Sprod L.K.
        • Janelsins M.C.
        • Palesh O.G.
        • et al.
        Health-related quality of life and biomarkers in breast cancer survivors participating in tai chi chuan.
        J Cancer Surviv. 2012; 6: 146-154
        • Wan S.
        • Huang J.
        • Gao J.
        Influence of acupoint massage on quality of life of tumor patients accepting chemotherapy.
        Chin Nurs Res. 2011; 25: 317-318
        • Xiang C.
        • Guo Q.
        • Liao J.
        Effect of therapy of traditional Chinese medicine five element music and electroacupuncture on the depression levels of cancer patients.
        Chin J Nurs. 2006; 41: 969-972
        • Oh B.
        • Butow P.N.
        • Mullan B.A.
        • et al.
        Effect of medical Qigong on cognitive function, quality of life, and a biomarker of inflammation in cancer patients: a randomized controlled trial.
        Support Care Cancer. 2012; 20: 1235-1242
        • Deng G.
        • Chan Y.
        • Sjoberg D.
        • et al.
        Acupuncture for the treatment of post-chemotherapy chronic fatigue: a randomized, blinded, sham-controlled trial.
        Support Care Cancer. 2013; 21: 1735-1741
        • Roscoe J.A.
        • Matteson S.E.
        • Morrow G.R.
        • et al.
        Acustimulation wrist bands are not effective for the control of chemotherapy-induced nausea in women with breast cancer.
        J Pain Symptom Manage. 2005; 29: 376-384
        • Mustian K.M.
        • Katula J.A.
        • Zhao H.
        A pilot study to assess the influence of tai chi chuan on functional capacity among breast cancer survivors.
        J Support Oncol. 2006; 4: 139-145
        • Chen Z.
        • Meng Z.
        • Milbury K.
        • et al.
        Qigong improves quality of life in women undergoing radiotherapy for breast cancer: results of a randomized controlled trial.
        Cancer. 2013; 119: 1690-1698
        • Yin Z.L.
        Effect of TCM on quality of life in nasopharyngeal cancer patients after radiotherapy.
        Chin J Phys Med Rehabil. 2012; 34: 618-620
        • Chen H.Y.
        • Li S.G.
        • Cho W.C.
        • et al.
        The role of acupoint stimulation as an adjunct therapy for lung cancer: a systematic review and meta-analysis.
        BMC Complement Altern Med. 2013; 13: 362
        • Choi T.Y.
        • Lee M.S.
        • Ernst E.
        Acupuncture for cancer patients suffering from hiccups: a systematic review and meta-analysis.
        Complement Ther Med. 2012; 20: 447-455
        • Garcia M.K.
        • McQuade J.
        • Haddad R.
        • et al.
        Systematic review of acupuncture in cancer care: a synthesis of the evidence.
        J Clin Oncol. 2013; 31: 952-960
        • Lee M.S.
        • Choi T.Y.
        • Park J.E.
        • et al.
        Moxibustion for cancer care: a systematic review and meta-analysis.
        BMC Cancer. 2010; 10: 130
        • Chao L.F.
        • Zhang A.L.
        • Liu H.E.
        • et al.
        The efficacy of acupoint stimulation for the management of therapy-related adverse events in patients with breast cancer: a systematic review.
        Breast Cancer Res Treat. 2009; 118: 255-267
        • Lee M.S.
        • Chen K.W.
        • Sancier K.M.
        • et al.
        Qigong for cancer treatment: a systematic review of controlled clinical trials.
        Acta Oncol. 2007; 46: 717-722
        • Yan J.H.
        • Pan L.
        • Zhang X.M.
        • et al.
        Lack of efficacy of Tai Chi in improving quality of life in breast cancer survivors: a systematic review and meta-analysis.
        Asian Pac J Cancer Prev. 2014; 15: 3715-3720
        • Lee M.S.
        • Pittler M.H.
        • Ernst E.
        Is Tai Chi an effective adjunct in cancer care? A systematic review of controlled clinical trials.
        Support Care Cancer. 2007; 15: 597-601
        • Li X.
        • Yang G.
        • Li X.
        • et al.
        Traditional Chinese medicine in cancer care: a review of controlled clinical studies published in Chinese.
        PLoS One. 2013; 8: e60338
        • Liu J.
        • Li X.
        • Liu J.
        • et al.
        Traditional Chinese medicine in cancer care: a review of case reports published in Chinese literature.
        Forschende Komplementarmedizin. 2011; 18: 257-263
        • Yang G.
        • Li X.
        • Li X.
        • et al.
        Traditional Chinese medicine in cancer care: a review of case series published in the Chinese literature.
        Evid Based Complement Alternat Med. 2012; 2012: 751046
        • Liberati A.
        • Altman D.G.
        • Tetzlaff J.
        • et al.
        The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration.
        BMJ. 2009; 339: b2700
      3. Higgins J.P.T. Green S. Cochrane handbook for systematic reviews of interventions version 5.1.0. The Cochrane Collaboration, 2011 (Available at: www.cochranehandbook.org.)
        • Tierney J.F.
        • Stewart L.A.
        • Ghersi D.
        • et al.
        Practical methods for incorporating summary time-to-event data into meta-analysis.
        Trials. 2007; 8: 16
        • Higgins J.P.
        • Thompson S.G.
        • Deeks J.J.
        • et al.
        Measuring inconsistency in meta-analyses.
        BMJ. 2003; 327: 557-560
        • Faul F.
        • Erdfelder E.
        • Lang A.G.
        • et al.
        G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences.
        Behav Res Methods. 2007; 39: 175-191
      4. Yu L. Effect of moxibustion on cancer related fatigue Guide of China Medicine 2012;10:591–593.

        • Yang J.L.
        Effects of moxibustion on cancer related fatigue in elderly advanced cancer patients.
        Chin J Gerontol. 2012; 32: 4408-4410
        • Yu H.X.
        Effects of moxibustion on gastrointestinal function after surgery in elderly gastric cancer patients.
        Zhejiang J Tradit Chin Med. 2012; 47: 284
        • Cheng L.
        Effect of moxibustion moxa at zusanli on cancer-related diarrhea.
        J Nurs Sci. 2009; 24: 43-44
        • Lai J.H.
        Chinese massage at Yongquan on gastrointestinal function in cervical cancer patients.
        Today Nurse. 2011; 14: 124-125
        • Chen F.R.
        • Wang M.
        • Xue J.
        Study on influence of ginger separated moxibustion on quality of life of elderly patients with advanced cancer.
        Chin Nurs Res. 2011; 18: 2951-2952
        • Yin Z.L.
        • Meng Z.X.
        • Lin S.Y.
        • et al.
        The intervention effect of chemotherapy in patients with gynecological tumor relaxation training method.
        Chin J Phys Med Rehabil. 2012; 34: 618-620
        • Qiang W.M.
        • Dong F.Q.
        • Yan L.
        • et al.
        Comparison of two different exercise programs in breast cancer patients after postoperative adjuvant chemotherapy.
        Chin J Nurs. 2011; 46: 537-540
        • Chen L.R.
        • Hou X.C.
        Effect of chiropractic and psychological intervention on patients with cancer pain and bad mood.
        Hebei J Traditional Chin Med. 2009; 31: 1897-1898
        • Zhang Y.M.
        Effects of hand massage therapy on the quality of life in breast cancer patients undergoing chemotherapy.
        Chin J Nurs. 2012; 47: 247-250
        • Jiang M.Y.
        Influence of shadowboxing on improving cancer-related fatigue and sleeping quality of patients with advanced lung cancer.
        Chin Nurs Res. 2013; 27: 420-421
        • Wang H.L.
        • Liu C.C.
        • Wen X.X.
        The effect of a foot massage combined with psychological intervention to improve the sleep quality of patients with cancer.
        Zhejiang Clin Med J. 2012; 14: 1309-1310
        • Chen C.F.
        Treatment of moxibustion effecting on cancer-associated diarrhea in 18 cases.
        Chin J Integr Tradit West Med Digest. 2012; 20: 514-515
        • Xue W.X.
        Liver cancer after interventional chemotherapy intractable hiccups acupuncture curative effect observation.
        Chin J Misdiagnostics. 2011; 11: 3061
        • Chen Y.L.
        Acupressure reduces abdominal distention after laparoscopic resection in colorectal cancer patients.
        Chin J Misdiagnosis. 2008; 8: 7627-7628
        • Wan S.Y.
        • Huang J.P.
        • Gao J.
        Influence of acupoint massage plus induced imagining relaxation on quality of life of tumor patients accepting chemotherapy.
        Chin Nurs Res. 2011; 25: 317-318
      5. Wang HM, Fan ZM. The clinical study on gastrointestinal function recovery after colorectal carcinoma resection in fast track programme using acupuncture. Master's Thesis. 2011. Available at: http://d.g.wanfangdata.com.cn/Thesis_Y1945947.aspx.

        • Lu Y.
        • Zhang Y.
        • Jing N.C.
        Acupuncture improved quality of life in cancer patients via clinical study.
        J Oncol Pract. 2005; 19: 299-301
        • Zhang M.F.
        • Ruan J.W.
        • Gu M.F.
        Effects of acupuncture combined with relaxation training on pain, anxiety and sleep quality in patients with advanced cancer.
        Chin J Phys Med Rehabil. 2009; 31: 674-677
        • Pei Y.
        • Yang J.
        • Zhang J.
        To observe the state of depression and anxiety in patients with acupuncture in the treatment of breast cancer.
        Chin J Inf On Tradit Chin Med. 2010; 17: 62
        • Wang X.P.
        • Ding Y.
        The effect of music therapy on quality of life in patients with chemotherapy for advanced cancer.
        J Clin Med Pract. 2006; 10: 16
        • Li H.Y.
        • Yang D.N.
        Acupuncture recovered gastrointestinal function after surgery for esophageal cancer.
        Jiangsu J Tradit Chin Med. 2008; 40: 83-84
        • Liu H.
        The effect of acupuncture and moxibustion and acupuncture point injection on treatment of pain of hepatocellular carcinoma.
        J Hebei Tradit Chin Med Pharmacol. 2010; 25: 37-38
        • Feng Y.
        • Wang X.Y.
        • Li S.D.
        • et al.
        Clinical research of acupuncture on malignant tumor patients for improving depression and sleep quality.
        J Tradit Chin Med. 2011; 31: 199-202
        • Meng Z.Q.
        • Garcia M.K.
        • Chiang J.S.
        • et al.
        Electro-acupuncture to prevent prolonged postoperative ileus: a randomized clinical trial.
        World J Gastroenterol. 2010; 16: 104-111
        • Nedstrand E.
        • Wyon Y.
        • Hammar M.
        • et al.
        Psychological well-being improves in women with breast cancer after treatment with applied relaxation or electro-acupuncture for vasomotor symptom.
        J Psychosom Obstet Gynaecol. 2006; 27: 193-199
        • Wong R.H.
        • Lee T.W.
        • Sihoe A.D.
        • et al.
        Analgesic effect of electroacupuncture in postthoracotomy pain: a prospective randomized trial.
        Ann Thorac Surg. 2006; 81: 2031-2036
      6. Zhu YY. Effect of acupuncture at specific points combined with thumbtach needle on pain and depression in pancreatic cancer patients. Chinese General Practice 2013;16:1923–1925.

        • Zhao B.M.
        Effect of acupuncture on ascites in liver cancer.
        Health Way. 2013; 12: 411
        • Li J.
        Clinical research on treating advanced breast cancer related fatigue by moxibustion.
        Clin J Chin Med. 2013; 5: 1-4
        • Guo L.Y.
        Effect of acupuncture therapy on cancer–related fatigue of patients with gynecological malignant tumor after chemotherapy.
        J Clin Acupuncture Moxibustion. 2014; 30: 67-70
        • Fu L.P.
        Effect of moxibustion on quality of life in esophageal cancer patients.
        Shaanxi J Tradit Chin Med. 2014; 35: 77-79
        • Chen Y.H.
        Effect of moxibustion on depression and quality of life in patients with advanced gastric cancer.
        J Nurs (China). 2013; 20: 63-65
        • Yan Q.M.
        Effect of moxibustion on ascites in advanced cancer patients.
        J Qilu Nurs. 2014; 20: 123-124
        • Chen H.T.
        Clinical observation of acupuncture therapy on hiccuping in liver cancer.
        J Clin Acupuncture Moxibustion. 2006; 22: 18-19
        • Luo M.S.
        • Wu S.B.
        Acupuncture for 70 cases of hiccup after operation of primary liver cancer.
        World J Acupuncture-Moxibustion. 2007; 17: 52-54
        • Bao F.F.
        Effect of acupuncture on hiccups in cancer patients after radio-chemotherapy.
        Zhejiang J Tradit Chin Med. 2012; 47: 117
        • Smith C.
        • Carmady B.
        • Thornton C.
        • et al.
        The effect of acupuncture on post-cancer fatigue and well-being for women recovering from breast cancer: a pilot randomised controlled trial.
        Acupunct Med. 2013; 31: 9-15
        • Deng G.
        • Wong W.D.
        • Guillem J.
        • et al.
        A phase II, randomized, controlled trial of acupuncture for reduction of postcolectomy ileus.
        Ann Surg Oncol. 2013; 20: 1164-1169
        • Ng S.S.
        • Leung W.W.
        • Mak T.W.
        • et al.
        Electroacupuncture reduces duration of postoperative ileus after laparoscopic surgery for colorectal cancer.
        Gastroenterology. 2013; 144: 307-313.e1
        • Johnston M.F.
        • Hays R.D.
        • Subramanian S.K.
        • et al.
        Patient education integrated with acupuncture for relief of cancer-related fatigue randomized controlled feasibility study.
        BMC Complement Altern Med. 2011; 11: 49
        • Liljegren A.
        • Gunnarsson P.
        • Landgren B.M.
        • et al.
        Reducing vasomotor symptoms with acupuncture in breast cancer patients treated with adjuvant tamoxifen: a randomized controlled trial.
        Breast Cancer Res Treat. 2012; 135: 791-798
        • Pfister D.G.
        • Cassileth B.R.
        • Deng G.E.
        • et al.
        Acupuncture for pain and dysfunction after neck dissection: results of a randomized controlled trial.
        J Clin Oncol. 2010; 28: 2565-2570
        • Deng G.
        • Rusch V.
        • Vickers A.
        • et al.
        Randomized controlled trial of a special acupuncture technique for pain after thoracotomy.
        J Thorac Cardiovasc Surg. 2008; 136: 1464-1469
        • Deng G.
        • Vickers A.
        • Yeung S.
        • et al.
        Randomized, controlled trial of acupuncture for the treatment of hot flashes in breast cancer patients.
        J Clin Oncol. 2007; 25: 5584-5590
        • Yang J.X.
        Effect of Chinese medicine five-tone therapy intervention on the depression state of the chemotherapy patients with breast cancer.
        Chin J Mod Nurs. 2013; 19: 4461-4463
        • Lei Y.Y.
        Effect of five elements music of traditional Chinese medicine on the tumor patients under hyperthermia nursing.
        J Nurses Train. 2014; 29: 335-336
        • Li W.J.
        Effect of Chinese massage on hiccups in patients with liver cancer.
        Yunnan J Tradit Chin Med Materia Med. 2014; 35: 102
        • Xiao J.
        Effect of Chinese massage combined with point pressure on ventosity in patients with gynecologic cancer.
        Yiayao Qianyan. 2014; 16: 332-333
        • Liu Y.C.
        Effect of Tai Chi on respiratory function in patients with lung cancer.
        Chin J Trauma Disabil Med. 2014; 22: 211
      7. Rausch SM. Evaluating psychosocial effects of two intervention, tai chi and spiritual growth groups, in women with breast cancer. MS Thesis. Richmond, VA: College of Humanities and Sciences, Virginia Commonwealth University, 2007. Available at: http://scholarscompass.vcu.edu/etd/819/.

        • He J.H.
        Rehabilitation effect of systematic exercise in adjuvant chemotherapy for breast cancer patients.
        Chin J Rehabil. 2011; 26: 204-206
        • Janelsins M.C.
        • Davis P.G.
        • Wideman L.
        • et al.
        Effects of Tai Chi Chuan on insulin and cytokine levels in a randomized controlled pilot study on breast cancer survivors.
        Clin Breast Cancer. 2011; 11: 161-170
        • Mustian K.M.
        • Palesh O.G.
        • Flecksteiner S.A.
        Tai Chi Chuan for breast cancer survivors.
        Med Sport Sci. 2008; 52: 209-217
        • Wang Y.L.
        • Sun X.Y.
        • Wang Y.B.
        Different exercise on breast cancer patients postoperative upper limb function and the influence of the quality of life.
        Chin J Phys Med Rehabil. 2012; 34: 64-65
        • Li P.X.
        Effect of acupuncture on anorexia in advanced gastric cancer patients.
        N J Tradit Chin Med. 2006; 38: 67-68
        • Liu X.M.
        • Huang Z.F.
        Acupuncture treatment for intractable hiccup in patients with cancer of 32 cases.
        Liaoning J Tradit Chin Med. 2007; 34: 214-215
        • Xie X.P.
        Observation of electroacupuncture and pressing auricular point with pill in treating patients with tumor suffering from hiccup.
        Cancer Res Prev Treat. 2005; 32: 42-43
        • Chen S.Y.
        • Huang L.Q.
        Effect of electroacupuncture treatment on zusanli(st36) for intractable hiccups with malignant tumors of 24 cases.
        J Qilu Nurs. 2007; 13: 43-44
        • Lu L.
        • Liao M.
        • Zeng J.
        • et al.
        Quality of reporting and its correlates among randomized controlled trials on acupuncture for cancer pain: application of the CONSORT 2010 statement and STRICTA.
        Expert Rev Anticancer Ther. 2013; 13: 489-498
        • Chan H.Y.
        • Chui Y.Y.
        • Chan C.W.
        • et al.
        Exploring the influence of traditional Chinese medicine on self-care among Chinese cancer patients.
        Eur J Oncol Nurs. 2014; 18: 445-451
        • Wood L.
        • Egger M.
        • Gluud L.L.
        • et al.
        Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study.
        BMJ. 2008; 336: 601-605
        • Smyth R.M.
        • Kirkham J.J.
        • Jacoby A.
        • et al.
        Frequency and reasons for outcome reporting bias in clinical trials: interviews with trialists.
        BMJ. 2011; 342: c7153
        • Faller H.
        • Schuler M.
        • Richard M.
        • et al.
        Effects of psycho-oncologic interventions on emotional distress and quality of life in adult patients with cancer: systematic review and meta-analysis.
        J Clin Oncol. 2013; 31: 782-793
        • Moyer A.
        • Sohl S.J.
        • Knapp-Oliver S.K.
        • et al.
        Characteristics and methodological quality of 25 years of research investigating psychosocial interventions for cancer patients.
        Cancer Treat Rev. 2009; 35: 475-484
        • Vickers A.
        • Goyal N.
        • Harland R.
        • et al.
        Do certain countries produce only positive results? A systematic review of controlled trials.
        Control Clin Trials. 1998; 19: 159-166
        • Higgins J.P.T.
        • Green S.
        Cochrane handbook for systematic reviews of interventions.
        Wiley-Blackwell, West Sussex, UK2008
        • Schulz K.F.
        • Altman D.G.
        • Moher D.
        • et al.
        CONSORT 2010 statement: updated guidelines for reporting parallel group randomized trials.
        Ann Intern Med. 2010; 152: 726-732