|Year : 2018 | Volume
| Issue : 10 | Page : 600-608
Acupuncture for the relief of hot flashes in breast cancer patients: A systematic review and meta-analysis of randomized controlled trials and observational studies
Xiao-Peng Wang1, Duo-Jun Zhang2, Xiao-Dong Wei3, Jian-Ping Wang3, Dong-Zhi Zhang3
1 Department of General Surgery, Gansu Provincial Hospital, Lanzhou 730000, China
2 Department of Mini-Invasive Surgery, Linhe People's Hospital of Inner Mongolia, Linhe 015000, China
3 Department of Emergency, Gansu Provincial Hospital, Lanzhou 730000, China
|Date of Web Publication||24-Sep-2018|
204#, Donggang West Road, Lanzhou City, Gansu Province
Source of Support: None, Conflict of Interest: None
Objective: To critically assess the effectiveness and safety of acupuncture for treating hot flashes (HFs) among breast cancer (BC) patients, and to get much more highly compelling evidence then to guide clinical practice.
Methods: Comprehensive systematic literature searches were carried out for identifying randomized controlled trials and observational studies (OSs) published before January 2015. The meta-analysis (MA) was performed by Review Manager 5 software if data could be merged routinely, if not descriptions would be given.
Results: A total of 18 studies were eligible ultimately. With respect to HFs frequency, the MA during treatment showed a significant difference (MD = –1.78, 95% confidence intervals [95% CIs]: –3.42-–0.14), but no statistical differences were observed when posttreatment or follow-up period. While electroacupuncture versus applied relaxation, they both helped to promote HFs markedly but did not reveal statistically significance between them. Referring to Kupperman's index, all the treatment brought out great assistance when compared with baseline conditions, and there was significant difference between real acupuncture sham acupuncture (posttreatment: MD = –4.40, 95% CI: –6.77-–2.03; follow-up: MD = –4.30, 95% CI: –6.52-–2.08). In terms of OS, 7 prospective single arm studies focused on exploring the efficacy of traditional acupuncture, and all revealed moderate or great benefit for BC patients suffering from HFs.
Conclusions: Acupuncture still appeared to be an efficacious therapeutic strategy, especially for the less/no side effects. Because of its widespread acceptance and encouraging effectiveness for improving HFs, much more high-quality studies are in need urgently.
Keywords: Acupuncture, breast cancer, hot flashes, meta-analysis, systematic review
|How to cite this article:|
Wang XP, Zhang DJ, Wei XD, Wang JP, Zhang DZ. Acupuncture for the relief of hot flashes in breast cancer patients: A systematic review and meta-analysis of randomized controlled trials and observational studies. J Can Res Ther 2018;14, Suppl S3:600-8
|How to cite this URL:|
Wang XP, Zhang DJ, Wei XD, Wang JP, Zhang DZ. Acupuncture for the relief of hot flashes in breast cancer patients: A systematic review and meta-analysis of randomized controlled trials and observational studies. J Can Res Ther [serial online] 2018 [cited 2020 Apr 1];14:600-8. Available from: http://www.cancerjournal.net/text.asp?2018/14/10/600/183174
| > Introduction|| |
Hot flashes, or hot flushes (HFs), are often described as sudden and transient sensations of heat, intense sweating, typically lasting for 2–4 min, which are possibly accompanied by anxiety and palpitations. Up to now, the pathophysiology of HFs have not been entirely elaborated, and the potential mechanism is hypothesized to be related to the dysfunction of thermoregulatory nucleus.
Breast cancer (BC) is the most prevalent malignancy among women, its incidences range from 19.3 per 100,000 women in Eastern Africa to 89.7 per 100,000 women in Western Europe and about 40 per 100,000 in developing countries, and BC also possesses higher survival rates compared with other types of cancer., Approximately two-thirds of women with a history of BC are suffering from HFs. According to the existing data, HFs occur in about 51–81% of women with BC.,
Hormonal replacement therapy (HRT) is the most well-known and efficacious treatment for markedly alleviating the intensity and frequency of HFs. Yet, the actual safety of these agents is still controversial and disputable. Multiple treatment options that might result in an estrogen deprivation state, such as oophorectomy, antiestrogenic medications, and cytotoxic agents, which are anticipated to have increased risks of HFs. And, the Women's Health Initiative studies have raised plenty of attention on long-term adverse effects pertaining to receiving HRT. Furthermore, the mortality of BC also appears to be aggravated on account of the combined intake of HRT. Thus, the use of any HRT for BC patients continues to be discouraged. Moreover, other pharmacologic agents (e.g., antidepressant) can cause various side effects, including nausea, constipation, mouth dryness, and leading to low patient acceptance.
Due to increasingly heightened concerns on the risks of HRT and other relevant pharmaceuticals, there has been an emphasis on the use of nonhormonal therapies for the management of HFs, including complementary and alternative medicine (CAM) approaches. Traditional acupuncture has shown its potential role as an efficacious maintenance treatment for HFs in BC patients. Several publications have also demonstrated the effect of acupuncture on HFs for BC survivors. Acupuncture could decrease HFs by regulating temperature control through increasing beta-endorphin levels and subsequent inhibition of GnRH. It has been hypothesized that acupuncture regulates neurotransmitters involved in thermoregulation. Yet few studies have demonstrated pronounced clinical benefit on controlling this distressing symptom. With respect to the standard treatment for HFs, none are clinically recommended ever since. Moreover, a great majority of women with BC still prefer to use acupuncture for the treatment of HFs despite limited evidence in support of its efficacy and safety. Besides, previous similar researches failed to put forward definitive conclusions on it. The increasing popularity of acupuncture and its widespread use for HFs require a more comprehensive evaluation of its efficacy and safety.
Evidence-based medicine has located at the top level in the evidence pyramids, ever since the term was coined by Guyatt et al. in his literature published in JAMA in 1992. The primary purpose of this systematic review (SR) and meta-analysis (MA) was to critically explore whether acupuncture therapy could relieve HFs in women with BC and to assess the adverse effects of acupuncture therapy, according to these identified randomized controlled trials (RCTs) and observational studies (OSs).
| > Methods|| |
Protocol and registration
No protocol has been registered in public, yet considered draft with respect to the study exists before manuscript. Besides, this research was critically based on the preferred reporting items for systematic reviews and meta-analysis (PRISMA) items.
Systematic searches were carried out to identified RCTs and OSs of the use of acupuncture in alleviating HFs among women suffering from BC, in any language, from inception to January 31, 2015, using PubMed, the Cochrane Central Register of Controlled Trials, the Cochrane Library, EMBASE, Web of Science, Chinese biomedical literature database, China National Knowledge infrastructure, VIP Database. The keywords are as followed: Acupuncture, acupuncture therapy, electro-acupuncture, flushing, hot flash*, hot flush*, vasomotor symptom*, afternoon fever, tidal fever, hectic fever, acuflash, postmenopaus*, postmenopaus*, premenopaus*, premenopaus*, menopaus*, perimenopaus*, peri-menopaus*, climacteric, vasomotor disorder*, premature ovarian failure, breast neoplasms, BC. All keywords were all performed by the combination of medical subject headings (Mesh) terms (http://scientifi.thomson.com/support/fag/wok3new/medline/#Mesh) and free terms.
Included studies and data analyses
We identified RCTs of acupuncture versus sham acupuncture or no acupuncture or traditional treatments (e.g., hormone therapy), and OSs referring to acupuncture for HFs among BC patients. Participants who had acupuncture treatment within the past 12 months were excluded, and all of them were provided informed consent before enrollment. Acupuncture included traditional acupuncture and electro-acupuncture, rather than moxibustion or acupressure. Because there is no standardized placebo acupuncture treatment, so we identified nonpenetrating needles and insertion of needles into nonacupoints. Two authors extracted data independently and then checked with each other. We included RCTs that met all of the following criteria: (1) Included BC patients with HFs, (2) used acupuncture interventions for HFs management, (3) presented HFs intensity at baseline and after intervention. If data were duplicated or shared in more than one study, the first published or more comprehensive study was included in the final analysis. In addition, we must confirm that the type of clinical problem resulting in HFs is BC, as well as the number of patients, age of patients, other underlying diseases, number of sessions, duration of interventions, acupuncture points, concomitant treatments in detail, and the type of HFs assessment. Further, we extracted the specific information in regard to each intervention in these identified studies. When raw data or changes from baseline were not available, these articles were removed. Then the assessment of risk of bias was conducted independently by two authors using the modified Jadad score, and then was checked by them together. Disagreement was solved by discussion. If the information needed could not be obtained, we contacted with the research authors. Relative risk was calculated for binary outcomes, and for continuous outcomes we conducted standardized mean difference (SMD). P values are two-tailed, and all results were reported with 95% confidence intervals (95% CIs). The SMDs from these identified trials were pooled by MA, to compare the relatively objective effect of acupuncture with that of placebo acupuncture or no acupuncture. We adopted Review Manager 5 (version 5.2, provided by The Cochrane Collaboration, visiting ims.cochrane.org/revman/download. to download) for final analyses. We used a random-effects model if heterogeneity existed (P < 0.10) and a fixed effect model otherwise. Finally, funnel plot analysis was done to assess the publication bias.
| > Results|| |
Through comprehensive literature searches, we identified 1938 studies initially. EndNote X5 (provided by Thomson Reuters, visiting http://endnote.com/downloads/available-updates to download) was applied and 889 duplicates were removed. Then 860 studies were excluded based on titles or abstracts (uncorrelated to the key question: n = 658; animal trials: n = 36; reviews related: n = 166). Afterward, full-text articles were assessed for eligibility in depth. Through sifting layer upon layer strictly, 18 studies included in qualitative synthesis finally, 10 RCTs and 8 OSs, ranging from America (4 studies), Denmark (1 studies), Sweden (3 studies), Norway (2 studies), UK (5 studies), Italy (2 studies), and Korea (1 studies). The reviewers found a paucity of rigorous trials and large heterogeneity of populations, interventions, controls, and outcome measures, which challenged the process of SR and MA, so four studies were identified for merging analysis. [Figure 1] shows PRISMA statement of search flows in details.
|Figure 1: Preferred reporting items for systematic reviews and meta-analysis 2009 flow diagram|
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Participants and descriptions of interventions
Seven hundred thirty-five BC patients complaining about HFs met the specified inclusion criteria, but the neoplasm staging and age varied or were unclear. Six RCTs,,,,, involving 554 participants concentrated upon the comparison of real and sham acupuncture, one RCT upon the comparison of traditional and minimal acupuncture, one RCT upon the comparison of electro-acupuncture and hormone therapy, one RCT upon the comparison of electro-acupuncture and applied relaxation, and one RCT upon the comparison of real acupuncture and venlafaxine. With respect to OSs, seven prospective single-arm trials,,,,,, involving 165 patients focused on the efficacy of traditional acupuncture (namely real acupuncture), and one qualitative single-arm study with 16 participants concentrated on ear acupuncture. The duration of treatment varied to some extents, and the period ranged from 4 to 12 weeks. The summaries of RCTs and OSs of acupuncture for HFs among BC patients were presented in [Table 1]a and [Table 1]b.
Methodological quality of studies
For methodological quality evaluation, 10 RCTs,,,,,,,,, were assessed by two reviewers independently and the results were as followed. Three,, trials adopted randomization software to generate sequences, and three,, studies referred to closed envelope techniques, one referred to central randomization system while three,, studies did not claim the methods of randomization clearly. Allocated concealment was reported in six trials.,,,,, Blinding of participants and personnel was performed in six trials,,,,,, and unclear in four trials.,,, All these trials had no incomplete outcome data or selective reporting. Moreover, whether others bias existed were also unclear. The qualities of these included trials were relatively high. The methodological quality of these included trials is shown comprehensively in [Table 2], [Figure 2] and [Figure 3].
|Table 2: Quality assessment of randomized controlled trials of acupuncture for hot flashes among breast cancer patients|
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|Figure 2: Methodological quality assessments - risk of bias graph (each risk of bias item presented as percentages across all included studies)|
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|Figure 3: Methodological quality assessments - risk of bias summary (each risk of bias item for each included study)|
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Efficacy of acupuncture for hot flashes among breast cancer patients
Comparison of real acupuncture and sham acupuncture for hot flashes
Six RCTs,,,,, involving 407 patients concerned the comparison of real acupuncture versus sham acupuncture. With respect to HFs frequency, the two groups both possessed significant therapeutic effect respectively, when compared with the baseline conditions. The MA of HFs frequency during treatment showed a significant difference (MD = −1.78, 95% CI: −3.42–−0.14), but no statistical differences when posttreatment or follow-up period (MD = −1.60, 95% CI: −4.14–0.94; MD = −2.41, 95% CI: −5.39–0.57). The forest plot on the comparison of real acupuncture and sham acupuncture for HFs is shown in [Figure 4]. On account of data missing and heterogeneity of outcome measures, the data from three trials,, could not be merged. Bao et al. showed that the median change in HFs severity scores was − 11 (mean = −5) for the sham acupuncture group and − 13.5 (mean = −20) for the real acupuncture group. Bokmand and Flyger demonstrated that 16 patients (52%) from real group experienced a significant effect on HFs when compared with seven patients (24%) in the sham group (P < 0.05). The above results indicated both the real and sham acupuncture possessed efficacy for HFs among BC patients.
|Figure 4: The comparison of real acupuncture and sham acupuncture for hot flashes|
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Comparison of electro acupuncture and applied relaxation for hot flashes
One RCT by Nedstrand et al. reported the comparison of eletro acupuncture and applied relaxation, and put forward that they both helped to promote HFs markedly, but no statistically significance between them, neither posttreatment nor follow-up period (MD = −0.40, 95% CI: −2.18–1.38; MD = −0.40, 95% CI: −2.39–1.59). The forest plot on the comparison of eletro acupuncture and applied relaxation for HFs is shown in [Figure 5].
|Figure 5: The comparison of electro acupuncture and applied relaxation for hot flashes|
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Comparison of electro acupuncture and hormone therapy for hot flashes
One RCT by Frisk et al. focused on the comparison of electro-acupuncture and hormone therapy for HFs. For patients from electro-acupuncture, the median number of HFs/24 h decreased from 9.6 at baseline to 4.3 at 12 weeks of treatment (P < 0.001). Women with hormone therapy had a baseline median number of flushes/24 h of 6.6 and 0.0 at 12 weeks. Electro-acupuncture could reduce HFs, but less than the hormone therapy. Due to numerous sides effects deteriorating quality of life seriously, hormone therapy could be no longer recommended, acupuncture should receive more attentions for its plenty of advantages.
Comparison of real acupuncture and venlafaxine for hot flashes
One RCT by Walker et al. exhibited the curative effect of real acupuncture and venlafaxine for HFs. Participants from both groups reported significant decreases in HFs frequency, together with remarkable improvements in quality of life. These changes were nearly equivalent in both groups, indicating that acupuncture was as effective as venlafaxine. By 2 weeks posttreatment, the venlafaxine group experienced significant increases in HFs whereas the HFs in the acupuncture group remained at low levels. Moreover, the venlafaxine group experienced various adverse effects, whereas the acupuncture group experienced no negative adverse effects.
Comparison of traditional and minimal acupuncture for hot flashes
One RCT by Davies was performed to explore the difference of traditional and minimal acupuncture, visual analog scales (VASs) and quality of life were evaluated before and posttreatment. As the number in the sample was only a quarter of the total number estimated to give significance, no significant indicators were achieved. Yet, an encouraging trend for the number of HFs to reduce appeared, and larger numbers were needed to evaluate acupuncture as a treatment of HFs.
Efficacy comparison for Kupperman's index
Referring to Kupperman's index, all the treatments brought out great assistance compared with baseline conditions, and there was significant difference between real acupuncture sham acupuncture (posttreatment: MD = −4.40, 95% CI: −6.77-−2.03; follow-up: MD = −4.30, 95% CI: −6.52-−2.08), but no when electro acupuncture versus applied relaxation (posttreatment: MD = 1.40, 95% CI: −3.06–5.86; follow-up: MD = 1.50, 95% CI: −2.19–5.19) [Figure 6]. One RCT by Frisk et al. reported electro-acupuncture and hormone therapy both had a persistent and significant effect over time, but the latter performed better than electro-acupuncture, to some extent.
Observational studies of traditional and ear acupuncture for hot flashes
Seven prospective single-arm OSs,,,,,, concentrated on the investigation of traditional acupuncture for HFs among BC patients. Cumins and Brunt from the UK revealed that nine of the remaining 21 patients responded satisfactorily to acupuncture, which appears to be of benefit to BC. de Valois et al. from the UK reported that mean HFs frequency reduced by 49.8%, and perceptions of HFs or night sweats as a problem reduced by 2.2 points, indicating that acupuncture was of particular importance to benefit BC. Grazia et al. from Italy demonstrated that 66% of BC participants had a reduction in HFs varying from 50% to 75% compared to baseline. Besides, they recorded 53 mild side effects (15%) in a total of 349 sessions, namely its good tolerance. Jeong et al. from Korea claimed that the severity of HFs was reduced by 70–95%, VAS and HFs score were also significantly alleviated (P < 0.001; P = 0.006), which hitting that acupuncture appeared to provide effective relief from HFs among Korean women suffering from BC. Otte et al. from America displayed that acupuncture could reduce the HFs frequency from baseline to follow-up (P = 0.02), together with the Hot Flash Related Daily Interference Scale (P < 0.05). Porzio et al. from Italy reported, Friedman test analysis suggested that scores related to vasomotor symptoms were significantly improved by acupuncture. Tukmachi from the UK revealed that the frequency of HFs had improved significantly (P < 0.001), all patients claimed benefit and 82% had effective relief. With respect to ear acupuncture, Walker et al. from the UK found the ear acupuncture helpful and relaxing, many reported reductions in HFs frequency, as well as improvements in the overall emotional and physical well-being.
| > Discussion|| |
To date, the effectiveness of acupuncture for HFs is still controversial, due to lack of enough clinical evidence. Previous SRs failed to show any clear conclusion of acupuncture for HFs among BC patients. This raises the dilemma for physicians to recommend for or against acupuncture. Thus, we performed this comprehensive SR to critically evaluate the effect of acupuncture on reducing HFs among BC survivors according to the current studies, thus to guide appropriate clinical applications.
As we all know, the prescription of HRT and other relevant pharmaceuticals have been cut down due to concerns over their potential health risks and adverse reactions when long-term use, then thereby raising a great need of CAM for HFs, especially for BC patients who cannot receive hormone pills.
Worldwide, the utilization of CAM for cancer survivors varied widely, ranging from 7% to 64% globally and averaging 40% in Western countries. According to the data from a newer research, 90% of physicians have prescribed herbs and 87.5% have used traditional Chinese medicine (TCM) themselves in China. Besides, appropriately 97% of BC patients in China prefer to use TCM. As the foremost representative of TCM and one of the oldest healing systems with a history of 5000 years in the world, acupuncture is gaining popularity through the ages, whose the most common use was to improve the quality of life, and HFs could be one of the most depressing symptoms among BC patients. Specifically, acupuncture is known as a relatively efficacious tool to control HFs, especially in China, despite lack of enough clinical evidence. On the basis of Taoist theories of Yin and Yang and Qi, acupuncture possesses its own complete and independent knowledge systems, and has been being practiced throughout the Western world for ages, although HRT performs a superior effect on HFs compared to acupuncture. According to the latest publication, Garcia et al. identified relevant RCTs to evaluate the effectiveness of acupuncture for cancer patients, and they showed that acupuncture appeared efficient to relieve HFs, but the current level of evidence is insufficient to draw a reliable conclusion. Besides, through several laboratory studies and clinical trials, we get to know that acupuncture could help to control HFs for BC survivors by affecting opioid system and central/peripheral nervous systems, involving multicomponent and complex mechanisms.
The results generated by MA displayed that patients benefited from both real acupuncture and sham acupuncture, without significant difference between groups, not only after treatment but also during follow-up period. When compared with hormone therapy, acupuncture still possessed moderate therapeutic effect, but the latter had a potential damaging health risk while acupuncture had few adverse effects. Concerning the comparison of acupuncture and applied relaxation, both treatments could improve HFs equally. Other trials whose data could not be merged also had consistent conclusion that acupuncture was a convenient, effective, and simple treatment for HFs among BC participants.
Certainly, several important limitations of this research must be acknowledged, which primarily focused on inherent methodological challenges. Most notably, how to conduct appropriate active control groups needed more concentrations. On the basis of several relevant studies, it was acknowledged that needling or pressing in the areas around the acupuncture points may be equally efficient, thus the participants in the sham acupuncture group might report reasonably sound effect when compared to the acupuncture group. That is to say, the effect induced by the superficial insertion or press was strong enough to significantly reduce HFs in the responders, whose mechanism might be eliciting peripheral sensory stimulation, and certainly less when compared with acupuncture. Actually, even a very gentle form of placebo, such as minimal or micro-acupuncture, namely, the needle is superficially inserted or left on the skin for a very short time, seems to elicit therapeutic effects. Therefore, further trials using more appropriate placebo are needed, to prove how much more effective acupuncture is than an inert placebo treatment. Nevertheless, high standards of placebo-controlled studies are difficult to achieve, since there are particularly large numbers of components to be controlled for.
Ideally, more rigorous clinical trials with large samples should be conducted to get more persuasive evidence. Yet, there are significant barriers to this type of research on account of the realities of the situation which cannot be settled easily, such as acupuncturist training with high degree of consistency among multiple centers, the normative or similar acupoints, the same courses of therapy, the uniform indexes toward outcomes, diverse cultural differences and educational backgrounds, various recognition degree of physicians and patients toward acupuncture, racial differences which may impact therapeutic effects. All these above factors might influence the relevant data of clinical trials, leading to high heterogeneity and biases, and then interfering clinical reality. The last but not the least is the role of acupuncturists in researches. Different acupuncturists from different organizations or countries might conduct needling variously, and therefore their therapeutic effects probably varied widely. This can create great heterogeneity when merging data. Hence, it is essential and critical to establish precise clinical trial standards to regulate the performance of acupuncturists when they participate clinical researches.
It is of course of great interest and importance to find out if acupuncture would induce adverse events (AEs) when treating HFs for BC survivors. Overall, acupuncture is a minimally invasive and safe treatment, without numerous AEs or absolute contraindications. Still, the common AEs included itching, redness, bleedings, hematoma or pain, etc. Whereas traditional Western medicine including antidepressant and clonidine probably lead to multiple AEs, such as constipation, nausea, and drowsiness, etc. Specifically, a large-scale observational investigation based on three multicentre RCTs of 1968 cases in China demonstrated that acupuncture is a safe therapy with low risk of AEs, and AEs could be reduced by improving the medical environment, ensuring skilled and experienced acupuncturist and establishing a nice relationship of mutual trust between doctor and patient. Obviously, treating BC patients requires extra caution, it should be emphasized that acupuncturists need enough professional knowledge and understanding of different pathological conditions, are well acquainted with possible complications.
All in all, so far, it is not reasonable to make general recommendations regarding the application of acupuncture for HFs among BC patients, and the interpretation toward the conclusion in this article must be also cautious, due to the low or moderate level of the current evidence failed to present consistent conclusions. Still, despite these above limitations, the marked difference warrants attentions, and the inconsistency among these identified studies should be investigated further. In addition, it would be valuable to develop more appropriate control group in relation to subsequent clinical practice, to fully present the actual effectiveness of acupuncture. Overall, the acupuncture as an adjunct to ameliorate HFs is still a relatively sound treatment for BC patients and deserves further verification in the future.
| > Conclusions|| |
The therapeutic effect of acupuncture on HFs among BC survivors is probably multifactorial, and the results of our research support the possibility that acupuncture could reduce HFs for patients suffering from BC.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2]