Chinese Herbal Medicine as an Adjunctive Therapy for Breast Cancer: A Systematic Review and Meta-Analysis

Chinese herbal medicine (CHM) has been widely used as an adjunctive therapy for breast cancer, while its efficacy remains unexplored. The purpose of this study is to evaluate the efficacy of CHM combined with chemotherapy for breast cancer. The study results showed that CHM combined with chemotherapy significantly increased tumor response and KPS as compared to using chemotherapy alone (RR = 1.36; 95% CI = 1.24–1.48; P < 0.00001; RR = 1.38; 95% CI = 1.26–1.52; P < 0.00001, resp.). Besides, CHM as an adjunctive therapy significantly reduced the nausea and vomiting at toxicity grade of III–IV (RR = 0.37; 95% CI = 0.27–0.52; P < 0.00001). Moreover, the combined therapy significantly prevented the decline of WBC in patients under chemotherapy at toxicity grade of III–IV (RR = 0.49; 95% CI = 0.34–0.69; P < 0.00001) and prevented the decline of platelet at toxicity grade of III–IV or I–IV (RR = 0.29; 95% CI = 0.12–0.73; P = 0.008; RR = 0.77; 95% CI = 0.63–0.94; P = 0.009, resp.). This study suggests that CHM combined with chemotherapy in comparison with chemotherapy alone can significantly enhance tumor response, improve KPS, and alleviate toxicity induced by chemotherapy in breast cancer patients. However, a firm conclusion could not be reached due to the lack of high quality trials and large-scale RCTs, so further trials with higher quality and larger scale are needed.


Introduction
Breast cancer is the most common malignancy and the leading cause of cancer mortality in women worldwide [1]. American Cancer Society (ACS) estimates that there will be 246,660 cases of women diagnosed with breast cancer in US and 40,450 women die of the disease during 2016 [2]. The prognosis of newly diagnosed breast cancer patients is determined by the classification of breast cancer. There are at least four main subtypes of breast cancer according to different patterns of gene expression [3,4]. Luminal A tends to have the best prognosis, which comprises estrogen receptor-positive (ER+) and/or progesterone receptorpositive (PR+), human epidermal growth factor receptor 2negative (HER2−), and grade 1 or 2 tumors [3]. Luminal B includes ER+ and/or PR+, HER2+ or HER2−, and grade 3 tumors. The other 2 subtypes confer bad prognosis, which contain the HER2 overexpressing breast cancer (ER−, PR−, and HER2+) and the triple-negative breast cancer (ER−, PR−, and HER−) [4]. Nowadays the standard treatment options for patients with breast cancer include surgery, chemotherapy, radiotherapy, and endocrine therapy [5]. Usually, endocrine therapy remains the core adjuvant therapy for most of the early breast cancer patients who are diagnosed as ER+, while chemotherapy is recommended as the first-line systemic adjuvant modality for most HER2+ and triple-negative breast cancer patients [6]. Unfortunately, even curing surgery may accompany the risk of recurrence and metastasis, patients may produce resistance to chemotherapy, and these treatments can cause serious side effects in short or long term [6,7].
Complementary and alternative medicine (CAM) is widely used by 50% cancer patients, and patients with breast cancer use CAM more frequently than others which is accounting for 63 to 83% [8][9][10][11][12]. The types of CAM used by patients with breast cancer vary between countries. In US and Europe, naturopathy and homeopathy are the most commonly used CAM types, whereas for patients with Chinese background, Chinese herbal medicine (CHM) tends to be the most popular type among cancer patients and 86.4% 2 Evidence-Based Complementary and Alternative Medicine breast cancer patients used CHM for treatment [5,9,13,14]. CHM as an adjuvant therapy to conventional therapy (mainly refers to chemotherapy) has been commonly used to prolong survival time of cancer patients, alleviate clinical symptoms, and minimize the adverse events caused by chemotherapy in Asia [15]. Previous clinical studies suggested that CHM adjuvant therapy might have potential roles in three main parts. First of all, it can improve the quality of life (QoL) and prolong the survival time [16]. Next, it may improve the immune function of breast cancer patients and prevent metastasis and recurrence [17,18]. Finally, it can prevent or reduce toxicity from anticancer agents and enhance the effect of anticancer agents [16,17]. However, there is lack of systematic review to assess the potential efficacy of CHM as an adjuvant therapy for breast cancer. Thus, the aim of this study is to conduct a systematic review to evaluate the efficacy of CHM combined with chemotherapy for breast cancer, using evidence from randomized controlled trials (RCTs) upon tumor response, immune function, adverse events, and QoL.

Methods
RCTs were retrieved from nine databases, theses, and conference papers by using electronic method as well as manual method. LBZ and LRL reviewed these studies independently. The first reviewer extracted the data from included studies and the second reviewer verified them again. Two reviewers rectified the discrepancies according to the original articles. If the consensus still cannot be achieved, a third party (QW) were sought for advising. Studies can be included in the metaanalysis only when they satisfied the criteria.

Search Strategy.
The following databases were retrieved without any language restriction: PubMed, Cochrane Central Register of Controlled Trials, ISI Web of Science, Scopus, CINAHL Plus (EBSCO), EMBASE, China Journal Full-Text Database, China National Knowledge Infrastructure (CNKI), and Chinese Scientific Journal Database. Publications available from the inception of databases to January 2016 were reviewed to find out the appropriate RCTs of CHM for breast cancer. The following terms were searched in the databases: (

Inclusion Criteria.
Only studies which meet all of the following criteria can be included in the meta-analysis. (1) Participants: participants are postoperative breast cancer patients and patients treated by chemotherapy. (2) Type of study: only RCTs were eligible. (3) Type of intervention: studies compared chemotherapy combined with or without CHM. For studies using other agents as the third arm, only the two arms using CHM with or without chemotherapy can be included for meta-analysis. (4) Type of outcome measurement: tumor response and Karnofsky performance score (KPS) were the main outcome measurements; other outcome measurements which contained immunoregulation and reduction in adverse events of chemotherapy were also considered.

Exclusion Criteria.
Studies were excluded if they did not meet the above inclusion criteria. Additionally, trials with one or more of the following conditions were also excluded: (1) nonoriginal research such as review articles or letter to the editors; (2) duplicated publications of other studies; (3) CHM which were used in both treatment group and control group.

Outcome Measures.
Tumor response of CHM on the number of breast cancer patients with complete response (CR) or partial response (PR), as well as those with progressive disease (PD) according to the WHO scale, was investigated [19]. The disappearance of all known tumor lesions is considered as CR, 50% or more reduce in total tumor size of the lesions is considered as PR (determined by two observations not shorter than 4 weeks apart), and PD refers to 25% or more increase in total tumor size of the lesions or the appearance of new lesions. The improved or stable performance status of subjects based on KPS was also examined, in which score of 100 refers to a normal subject without any complaints, score of 70 refers to a patient who is unable to carry on normal activity, score of 50 refers to a patient requires considerable assistance, score of 40 refers to a disabled patient, and score of 30 refers to a patient who is hospitalization-recommended [20]. The efficacy of CHM on relieving the adverse events caused by chemotherapy containing nausea and vomiting and reduction of white blood cell as well as platelet were studied by grading the acute and subacute toxic effects of cancer therapy [21]. The efficacy of CHM on immunoregulation includes the change of mean values of CD3 T cell level, CD4 T cell level, CD8 T cell level, and CD4/CD8 ratio.

Quality
Assessment. Methodological quality of included studies was assessed by using the risk of bias tools in accordance with Cochrane Handbook version 5.1.0 [22]. Risk of bias for assessing the methodological quality of RCTs mainly included six items: selection bias (random sequence generation and allocation concealment), performance bias and detection bias (blinding), attrition bias (incomplete outcome data), reporting bias (selective reporting), and other bias. Each item was ranked as low, high, and unclear risk. The methodological quality of all trials was assessed as the following three levels: low risk of bias (all items were ranked as low risk), unclear risk of bias (at least one item was ranked as unclear risk), or high risk of bias (at least one item was ranked as high risk). At least two reviewers assessed the all trials and any disagreements were solved by the third reviewer consensus.
2.6. Data Analysis. Cochrane Collaboration Review Manage software (RevMan 5.2) was used for data analysis. Dichotomous data were reported as relative risk (RR) with 95% confidence intervals (95% CI) whereas continuous data were expressed as mean ± standard deviation (SD). 2 was used to assess the heterogeneity; if the heterogeneity exists in the pooled studies ( 2 > 50%), a random-effect model was applied; otherwise the fix-effect model was applied [23]. The differences between the treatment groups and control groups were considered to be statistically significant when < 0.05.

Characteristics of the Included Studies.
Overall, 571 studies were retrieved. There were 11 duplicated studies, 127 studies did not investigate outcome of interest (such as only investigated Chinese medicine syndrome scales), 29 studies were literature reviews, 26 studies were animal studies, 9 studies were mechanism studies, 157 were not relevant studies (such as investigated CHM for lymphedema after mastectomy), 50 studies were not using CHM combined with chemotherapy as intervention, and 8 studies were not RCTs. So only 154 studies satisfied the selection criteria, among which 106 studies did not investigate outcome of interest, 9 studies did not use CHM combined with chemotherapy as interventions, 1 study was not RCT, and 5 studies were with incomplete data. There were 33 RCTs included in this metaanalysis [16][17][18] (Figure 1). A sum of 2098 patients was enrolled in these studies, at which 1066 patients participated in CHM combined chemotherapy and 1032 in chemotherapy (two patients dropped out from treatment group, one patient dropped out from control group, and other four patients withdraw or dropped out but did not report the specific number in each group). All patients recruited in the 33 studies were postoperative breast cancer patients, and basically all of the included studies can be evaluated as low risk of bias [16][17][18]. The risk of bias of all included studies was shown in Figures 2 and 3. The course of therapy varied from 2 to 24 weeks in included studies. A list of therapeutic approaches and outcome measurements in each study were listed in Table 1. All studies claimed that the baseline data were comparable containing age, TNM (tumor node metastasis) stage, or histopathology.

Herbs Frequently Used in Breast
Cancer. 30 studies reported herbs and decoctions. Among them, Radix Astragalus, Rhizoma Atractylodis Macrocephalae, and Angelica sinensis are the most frequently used herbs for breast cancer ( Table 2).

Discussion
Recent studies showed a high prevalence of CAM usage among cancer patients, in particular patients with breast cancer [5,8,9,12,14,55]. CHM is an especially popular CAM used for cancer patients, while the efficacy of CHM combined with chemotherapy for patients under breast cancer remains unknown and needs to be further explored due to the language barrier because many studies were published in Chinese language. This study conducted a metaanalysis to statistical analysis of the results from individual studies for the purpose of integrating the findings. In the study, the pooled data has shown that CHM combined with chemotherapy significantly improved the tumor response and performance status of breast cancer patients. Also, we found that the combined therapy significantly decreases adverse events caused by chemotherapeutic interventions as compared with chemotherapy alone, including nausea and vomiting at toxicity grade of III-IV, WBC reduction at toxicity grade of III-IV, and platelet reduction at toxicity grade of I-IV or III-IV (Figures 6(a), 6(b), 6(c), and 6(d)). The efficacy of CHM as an adjuvant therapy to chemotherapy for breast cancer is in line with the findings from meta-analysis of CHM combined therapy for advanced non-small-cell lung cancer, colorectal cancer, nasopharyngeal carcinoma, and hepatocellular carcinoma, which suggest that chemotherapy combined with CHM has an advantage in various cancers [20,[56][57][58].
Tumor response, performance status, toxicity induced by chemotherapy, and immunoregulation were the four major outcome measurements in the study. However, not  32  30  14  28  29  30  35  35  30  24  22   20  17  6  20  18  18  24  22  22  13  15   32  30  16  32  37  30  40  31  30  24  23   28  29  10  28  31  25  33  28  28  21   all included studies simultaneously reported all the four outcomes. For example, Li and Han [52] only reported tumor response and chemotoxicity while Huang et al. [45] reported all four outcomes. Despite that, all available data in these studies were analyzed without any subjective selection. CD3 T cell level, CD4 T cell level, CD8 T cell level, and CD4/CD8 ratio are used as measurements for the evaluation of immunoregulation in breast cancer patients. In this study, we analyzed the mean value of CD3, CD4, CD8, and CD4/CD8 ratio between combined therapy group and chemotherapy group. Although results of these measurements showed that there was a significant improvement in patients treated by chemotherapy combined with CHM, the heterogeneity was also significant when we pooled individual studies which might be caused by different chemotherapy regimens used in different studies [16,25,38,39,45,48,54]. Hence, the efficacy of combined therapy in different chemotherapy regimens compared with chemotherapy alone was further analyzed. Patients treated by CHM combined with CTF (CTX/TAX/5-FU) reported a significant rise of CD3 T cell level as compared with CTF alone (MD = 6.53; 95% CI = 4.80-8.26; < 0.00001; 2 = 13%; 2 studies; 105 patients). For CD4 T cell level, CD8 T cell level, and CD4/CD8 ratio, CHM combined with CTF and CHM combined with CEF (CTX/EPI/5-FU) both reported a significant improvement, while being with a contradictory result of heterogeneity test. For example, in the comparison of CD4 T cell level, the value of 2 in patients treated by CHM combined with CEF was 0%, while that in patients treated by CHM combined with CTF reported was 68%. Similar situations also happened in CD8 T cell level and CD4/CD8 ratio. The variation of heterogeneity test in these studies may be due to the difference of treatment duration and therapeutic dose except that the different chemotherapy regimens are used in different studies.
The study protocol was registered in PROSPERO (International Prospective Register of Systematic Reviews) with registration number CRD42016033965. Although all reviewers in the study received high-quality training of systematic review and we strictly followed the review procedure stated by the Cochrane Collaboration, there were still several limitations in the study. Firstly, most of the included studies did not clearly describe allocation concealment and blinding, which may contribute to overestimate the effect of treatment group and the emergence of bias. Secondly, publication     bias may exist in the study because almost all included studies reported the positive results, while some negative results may be selectively unreported and therefore were not included in the present systematic review. Thirdly, most of the included studies did not provide enough information about methodology such as the way to generate random sequence, intention-to-treat analysis, follow-up, and drop-out rate; the methodological flaws may lead to potential biases. Lastly, different interventions are used in the studies such as different chemotherapy regimens, CHM composition (single herb of compound), oral administration and intravenous injection, treatment duration, or dosage, and all these may lead to heterogeneity among the studies.

Conclusion
The evidence from this systematic review shows that using CHM as an adjuvant therapy to chemotherapy in comparison with chemotherapy alone has advantages in breast cancer patients. However, particular attention should be paid for applying appropriate and scientific research methodologies to explore CHM as a holistic system because of the complex nature of CHM interventions [64]. Moreover, due to the small sample size, the findings of this meta-analysis may not apply to all patients with breast cancer. Therefore more RCTs with high-quality and large scale are worth performing to investigate the other potential interest of CHM as adjuvant therapy in breast cancer patients, such as survival rate, recurrence rate, and local and distant metastasis, shorten the course of chemotherapy, and so forth.