# Danshen Formulae for Cancer: A Systematic Review and Meta-Analysis of High-Quality Randomized Controlled Trials

Authors: Tianqi Wang; Xianjun Fu; Zhenguo Wang
Journal: Evidence-Based Complementary and Alternative Medicine
 (2019)

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## Abstract

Objective. Cancer is one of the most dangerous diseases to human life and there is no radical cure for it. In this paper, we compiled quantities of case history to evaluate the current available evidence of herbal Danshen (Radix Salviae Miltiorrhizae, RSM) formulae for the treatment of cancer by means of the high-quality randomized controlled trials (RCTs).Methods. English and Chinese electronic databases were searched from PubMed, the Cochrane Library, EMBASE, and the China National Knowledge Infrastructure (CNKI), VIP database, Wanfang database until September 2018. The methodological quality of the included studies was evaluated by using the method of Cocharne evidence-based medicine system evaluation, the quality was evaluated by screening the literature that met the requirements, and the Review Manager 5.3 was used for statistical analysis. The pooled odds ratio (OR) with 95% CIs was used to estimate the correlation between Danshen formulae and therapeutic effects.Results. Thirteen RCTs with 1045 participants were identified. The studies investigated the lung cancer (n = 5), leukemia (n = 3), liver cancer (n = 3), breast or colon cancer (n = 1), and gastric cancer (n = 1). A total of 83 traditional Chinese medicines were used in all prescriptions and there were 3 different dosage forms. Meta-analysis suggested that Danshen formulae had a significant effect on RR (response rate) (OR 2.38, 95% CI 1.66-3.42), 1-year survival (OR 1.70 95% CI 1.22-2.36), 3-year survival (OR 2.78, 95% CI 1.62-4.78), and 5-year survival (OR 8.45, 95% CI 2.53-28.27).Conclusion. The current research results showed that Danshen formulae combined with chemotherapy for cancer treatment was better than conventional drug treatment plan alone.


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## Body

## 1. Introduction

Cancer, also known as malignant tumors, can destroy the structure and function of tissues and organs and cause necrotic hemorrhage and infection, and patients may eventually die due to organ failure. In recent years, the incidence of malignant tumors has increased. In the European Union, it is estimated that there are about 1.4 million new cancer cases in a year, including 1.2 million women, and about 70,000 men and 55,000 women die of cancer [1]. In the United States, cancer morbidity and mortality will continue to rise, and lung cancer is expected to remain the number one cancer killer [2].As one of the world's five most intractable diseases, cancer is an incurable disease. If it is not detected and treated in time, it can also be transferred to all parts of the body for growth and reproduction and finally lead to body weight loss, weakness, anemia, loss of appetite fever, damage of viscera function, etc. [3]. The current cancer treatment is mainly surgery, chemotherapy, and radiotherapy, but both of these treatments cannot reduce the recurrence and metastasis after surgery. It is necessary to cooperate with other treatments after the operation [4]. The effects of radiotherapy and chemotherapy are obvious, but the obvious disadvantage is side effects. Cancer patients will be weak because of illness, and their constitution will be worse after chemotherapy and chemotherapy, which will lead to a decline in the quality of life and even make the body weaker and unable to withstand the next treatment [5].Traditional Chinese medicine (TCM) treatment is a traditional treatment method in China. For cancer, combination of traditional Chinese medicine can promote the rehabilitation of patients and prevent postoperative tumor recurrence and metastasis. At the same time, traditional Chinese medicine can reduce side effects by radiotherapy and chemotherapy and improve the quality of life (QOL) of patients and even improve the survival rate [6, 7]. The Radix Salviae Miltiorrhizae (Danshen) originated from “Shen Nong's Herbal Classic” is a well-known TCM herb (China Pharmacopoeia Committee, 2005), and it has been used in clinical practice for over 2000 years. However, there was no consensus on the role of Danshen formulae in cancer treatment [8–20]. To scientifically validate the efficacy and safety of the Danshen formulae, the meta-analysis evaluated the value of Danshen formulae for the treatment of cancer based on high quality randomized controlled trials (RCTs).


## 2. Methods

This systematic review and meta-analysis are based on the Preferred Reporting Items for Systematic Reviews and Meta Analyses: PRISMA statement search strategy [21].


### 2.1. Search Strategy

We conducted literature retrieval through 5 database systems including PubMed, the Cochrane Library, EMBASE, and the China National Knowledge Infrastructure (CNKI), VIP database, Wanfang database. The retrieval deadline was September 2018. The main search terms of this paper included the following three parts: (Traditional Chinese Medicine OR Traditional Medicine, Chinese OR TCM OR Zhong Yi Xue OR Chinese Traditional Medicine OR Chinese Medicine, Traditional OR herbal medicine OR Medicine, Chinese Traditional) AND (Neoplasia OR Neoplasias OR Neoplasm OR Tumors OR Tumor OR Cancer OR Malignant Neoplasms OR Malignant Neoplasm OR Neoplasm, Malignant OR Neoplasms, Malignant OR Malignancy OR Malignancies OR Neoplasms). There was no restriction on the type of language. In addition, we used manual references to previously published system reviews to manually search for additional related research. The specific herb name “Danshen” has not been specifically searched to ensure that as many herbal formulae as possible were included.


### 2.2. Inclusion Criteria

(1) Type of participants: researches involving patients with any type of cancer(2) Type of study: only RCTs that assessed the efficacy and safety of cancer treatment were eligible(3) Type of intervention: Danshen must be included in the herbal formula used in the experimental group. There were no restrictions on the form of the drug (e.g., decoction, injection, pill, and capsule), dosage, frequency, or treatment time. Control group medications include placebo or conventional medication(4) Types of results: the efficacy of cancer treatment was evaluated through OS (overall survival), duration of overall response, duration of stable disease, DFS (disease-free survival), PFS (progression-free survival), TTP (time to progression), TTF (time to failure), DCR (disease control rate), ORR (overall response rate), RR (response rate), CBR (clinical benefit rate), and ORR (objective response rate). Secondary outcome measures were quality of life (QOL) or side effects (such as fatigue, pain, infection/fever, anemia, diarrhea, nausea and vomiting, hair loss, and myelosuppression)(5) RoB scored≥4 points


### 2.3. Exclusion Criteria

If the above conditions were not met, the study was excluded. In addition, the following documents were also excluded: (1) duplicate publications and (2) case series, review, animal studies, and pharmacological experiments, (3) other TCM therapies, such as acupuncture, massage, qigong, moxibustion, and Taiji were included in the study.


### 2.4. Study Selection

The two reviewers selected the study by screening the title and summary of the selected qualifying RCTs independently. Obtain and read the full text of studies that may meet predefined criteria. When the data were duplicated, only the most recent information is selected. The differences in the study choices were resolved by discussion with the latter corresponding author.


### 2.5. Quality Assessment

The methodological quality of the included studies was assessed using the risk of bias (RoB) tools, according to Cochran's Systematic Review Handbook on interventions [22]. Including the following seven contents: (A) random sequence generation (selection bias); (B) allocation concealment (selection bias); (C) blinding of participants and personnel (performance bias); (D) blinding of outcome assessment (detection bias); (E) incomplete outcome data (attrition bias); (F) selective reporting (reporting bias); (G) other bias.


### 2.6. Data Extraction

Two reviewers used predesigned standard data extraction forms to independently extract data from eligible trials. The excerpts were as follows: (1) the year of publication and the name of the first author, the language of publication, the type of cancer; (2) the characteristics of the participants, including the number, gender, age; (3) treatment information, including intervention management details, treatment process, and side effects; (4) measurement of results.


### 2.7. Danshen Formulae Composition

In each study, components of Danshen formula were documented, with a frequency analysis of the types of cancer it treated and common drugs combined with it.


### 2.8. Data Analysis

Dates from eligible researches were aggregated and a quantitative summary was generated by Review Manager 5.3. Egger’s test was carried out by Stata 12.0.


### 2.9. Effect Size

Dichotomous data were reported as odds ratio (OR) with 95% confidence intervals (CI). The OR was deliberate significant at theP< 0.05 level when value 1 was not taken into the 95% CI. The purpose of this article is to explore the effectiveness of the Danshen formulae; therefore, we take the number of positive events as weights.


### 2.10. Heterogeneity

The statistical heterogeneity of the trials was assessed using CochranQ tests and I2 statistics. If there is no absence of heterogeneity or moderate heterogeneity (P > 0.1, I2 < 50%) [23], a fixed effect model (FEM) will be used; otherwise, a random effects model (REM) will be applied.


### 2.11. Publication Bias

If a research project contained more than 10 studies, the funnel plot were used to test publication bias.


### 2.12. Sensitivity Analysis

Sensitivity analysis was performed to test the effect of a single study on the combined effect by removing the individual survey. If the estimated value of the point after deleting a study fell beyond the 95% CI of the total effect amount (or was significantly different from the combined effect amount), we considered the study in question to have exerted a great influence on the combined effect amount and that this study required further review.


## 2.1. Search Strategy

We conducted literature retrieval through 5 database systems including PubMed, the Cochrane Library, EMBASE, and the China National Knowledge Infrastructure (CNKI), VIP database, Wanfang database. The retrieval deadline was September 2018. The main search terms of this paper included the following three parts: (Traditional Chinese Medicine OR Traditional Medicine, Chinese OR TCM OR Zhong Yi Xue OR Chinese Traditional Medicine OR Chinese Medicine, Traditional OR herbal medicine OR Medicine, Chinese Traditional) AND (Neoplasia OR Neoplasias OR Neoplasm OR Tumors OR Tumor OR Cancer OR Malignant Neoplasms OR Malignant Neoplasm OR Neoplasm, Malignant OR Neoplasms, Malignant OR Malignancy OR Malignancies OR Neoplasms). There was no restriction on the type of language. In addition, we used manual references to previously published system reviews to manually search for additional related research. The specific herb name “Danshen” has not been specifically searched to ensure that as many herbal formulae as possible were included.


## 2.2. Inclusion Criteria

(1) Type of participants: researches involving patients with any type of cancer(2) Type of study: only RCTs that assessed the efficacy and safety of cancer treatment were eligible(3) Type of intervention: Danshen must be included in the herbal formula used in the experimental group. There were no restrictions on the form of the drug (e.g., decoction, injection, pill, and capsule), dosage, frequency, or treatment time. Control group medications include placebo or conventional medication(4) Types of results: the efficacy of cancer treatment was evaluated through OS (overall survival), duration of overall response, duration of stable disease, DFS (disease-free survival), PFS (progression-free survival), TTP (time to progression), TTF (time to failure), DCR (disease control rate), ORR (overall response rate), RR (response rate), CBR (clinical benefit rate), and ORR (objective response rate). Secondary outcome measures were quality of life (QOL) or side effects (such as fatigue, pain, infection/fever, anemia, diarrhea, nausea and vomiting, hair loss, and myelosuppression)(5) RoB scored≥4 points


## 2.3. Exclusion Criteria

If the above conditions were not met, the study was excluded. In addition, the following documents were also excluded: (1) duplicate publications and (2) case series, review, animal studies, and pharmacological experiments, (3) other TCM therapies, such as acupuncture, massage, qigong, moxibustion, and Taiji were included in the study.


## 2.4. Study Selection

The two reviewers selected the study by screening the title and summary of the selected qualifying RCTs independently. Obtain and read the full text of studies that may meet predefined criteria. When the data were duplicated, only the most recent information is selected. The differences in the study choices were resolved by discussion with the latter corresponding author.


## 2.5. Quality Assessment

The methodological quality of the included studies was assessed using the risk of bias (RoB) tools, according to Cochran's Systematic Review Handbook on interventions [22]. Including the following seven contents: (A) random sequence generation (selection bias); (B) allocation concealment (selection bias); (C) blinding of participants and personnel (performance bias); (D) blinding of outcome assessment (detection bias); (E) incomplete outcome data (attrition bias); (F) selective reporting (reporting bias); (G) other bias.


## 2.6. Data Extraction

Two reviewers used predesigned standard data extraction forms to independently extract data from eligible trials. The excerpts were as follows: (1) the year of publication and the name of the first author, the language of publication, the type of cancer; (2) the characteristics of the participants, including the number, gender, age; (3) treatment information, including intervention management details, treatment process, and side effects; (4) measurement of results.


## 2.7. Danshen Formulae Composition

In each study, components of Danshen formula were documented, with a frequency analysis of the types of cancer it treated and common drugs combined with it.


## 2.8. Data Analysis

Dates from eligible researches were aggregated and a quantitative summary was generated by Review Manager 5.3. Egger’s test was carried out by Stata 12.0.


## 2.9. Effect Size

Dichotomous data were reported as odds ratio (OR) with 95% confidence intervals (CI). The OR was deliberate significant at theP< 0.05 level when value 1 was not taken into the 95% CI. The purpose of this article is to explore the effectiveness of the Danshen formulae; therefore, we take the number of positive events as weights.


## 2.10. Heterogeneity

The statistical heterogeneity of the trials was assessed using CochranQ tests and I2 statistics. If there is no absence of heterogeneity or moderate heterogeneity (P > 0.1, I2 < 50%) [23], a fixed effect model (FEM) will be used; otherwise, a random effects model (REM) will be applied.


## 2.11. Publication Bias

If a research project contained more than 10 studies, the funnel plot were used to test publication bias.


## 2.12. Sensitivity Analysis

Sensitivity analysis was performed to test the effect of a single study on the combined effect by removing the individual survey. If the estimated value of the point after deleting a study fell beyond the 95% CI of the total effect amount (or was significantly different from the combined effect amount), we considered the study in question to have exerted a great influence on the combined effect amount and that this study required further review.


## 3. Results

### 3.1. Description of Studies

A total of 3209 studies were searched by 4 electronic databases and other sources, and 2664 records were retained after deduplication. Of these, 366 studies were unrelated to cancer, 434 were animal experiments, 462 were mechanical experiments, and 728 were reviews, protocols, experiences, or case reports. By reading the full text, 762 studies, including 103 control interventions were inappropriate, lacking 50 of the control group and 70 items without full text, 200 items were not really RCTs, 99 items did not use the Danshen formula, and 142 included other CAM treatments, such as Acupuncture, Qigong, and 90 methodology that is of low quality. In the end, the study included 13 studies with 1045 patients that met the Cochrane Robb score of 4 and conducted a meta-analysis. A PRISMA flowed graph describe the search process and research options (Figure1).Figure 1
Flow diagram of literature search and selection.


### 3.2. Basic Characters of the Included Studies

The characteristics of the 13 studies included the contents summarized in Table1. All the eligible studies were conducted in China, with four articles published in English [9–11, 13] and the rest in Chinese [8, 12, 14–20]) (Table 1). In this study, there are 6 related lung cancers [9–11, 14, 19, 20], 3 related to Leukemia [12, 17, 18], 3 related to Liver cancer [8, 15, 19], one related to breast or colon cancer [13], and one related to gastric cancer [17] (Table 2). Because leukemia is a kind of malignant clonal disease of hematopoietic stem cells and belongs to the category of cancer, this study also included the research of leukemia. There were 10 RCTs with Overall response rate (RR) [8, 10–12, 14–19], 8 RCTs of them showed that Danshen formulae improved RR [10–14], and 2 RCTs suggested that Danshen formulae did not significantly improve RR [8, 11]. In 5 RCTs with survival rates, 4 RCTs of them indicated that Danshen Formulae improved survival rates [9, 15, 18, 20] and 1 RCT indicated that Danshen formulae did not significantly improve RR [8]. Seven RCTs were with side effects [10, 12–15, 17, 20] (Table 1). And the results showed 605 male patients and 440 female patients included in this study (Table 2). Among the 13 RCTs, 3 different Danshen formulae dosage forms were mentioned, 1 was a granule [17], 1 was a tablet [14], and the rest were decoction [8–13, 15, 16, 18–20]. In 8 Danshen formulae, Danshen plays a major role [8, 9, 12, 14–16, 19, 20] and improves the survival rate of patients; in 3 Danshen formulae, Danshen plays play an auxiliary role [10, 17, 18] and, in 2 RCTs, the real effect is that of other medicinal materials [11, 13]. It should be noted that one study did not involve radiotherapy, chemotherapy, or surgical treatment [19], while the rest were combined Chinese and western medicine (Table 3).Table 1
Basic characteristics of the included studies.
Included trial Publication language Study design and investi-gational sites Type of cancer No.of participants (male/female;age years) Intervention Outcome index Intergroup difference Experimental Control Experimental Control Chen 2012 [8] Chinese RCT,Single cencer;China Primary Liver Cancer 38/11;44.7 41/8;47.1 Danshen formulae Vinorelbine +Cisplatin(NP)+Placebo (Huangqi, Huangjing, Jiaogulan, Lingzhi, Cangzhu, Nvzhenzi, Huanglian et al.) 1.RR; 2.Survival rate;3.Improvement of symptoms 1,2.P>0.05; 3<0.05 Gong 2018 [9] English RCT,Single cencer;China Non-small cell lung cancer (NSCLC) 80/51;40-78 66/42;41-80 Vinorelbine +Cisplatin(NP)+Danshen formulae Platinum-based therapy +Placebo (Jiegeng, Xingren, Yuxingcao, Ziwan, Kuandong, Zhebeimu, Banxia, Hexiancao, Shengdiyu, Huangqin, Dongguazi, Chenpi, Zhuru et al.) 1.Survival Rates;2.MST 1,2.P<0.05 Guo 2017 [10] English RCT, Multi-cente;China NSCLC 20/9;38-77 28/4;38-77 Platinum-based therapy +Danshen formulae Radiotherapy 1.RR;2.Nausea; 3.Vomit;4.QOL; 5.Mildgastric/abdominal heaviness 1,2,3,5.P<0.05;4.P>0.05 Lan 2003 [11] English RCT,Single cencer;China Lung cancer 16/10;70-77 13/8;70-79 Radiotherapy+Danshen formulae DAP RR(1.Short-term effect;2. Long-term effect) 1.P>0.052.P<0.01 Li 2017 [12] Chinese RCT,Single cencer;China Leukemia 10/15;(35.42±15.13 13/12;37.97±13.45 DAP+Jiedu Huayu Fang Radiotherapy+placebo (Xuanshen,Yiyiren, Chenqianzi, Yinchen, Difuzi, Chuanwu, Ganjiang, Rougui, Wuzhuyu, Xiangfuzi, Chenpi, Shanzha, Laifuzi, Sanqi, Ruxiang, Yujin et al.) 1.RR(CR+PR);2.Leukopenia; 3.Platelet(PLT)decreased; 4.Hemoglobin(HGB)decreased 1,3,4.P<0.05;2.P>0.05 Mok 2007 [13] English RCT,Single cencer;China Breast or colon cancer 5/50;32-75 6/50;39-72 Radiotherapy+Danshen formulae Paclitaxel Injection+Cisplatin Injection 1.HGB decreas-ed;2.Leukopenia;3.Neutropenia; 4.Thrombocytopenia;5.Nausea; 6.QOL 1-4,P>0.05;5,6.P<0.05 Shen 2017 [14] Chinese RCT,Single cencer;China NSCLC 22/21;57.2 ±7.3 23/20;56.8±7.5 Paclitaxel Injection+Cisplatin Injection+Zilongjin tablet 3-DCRT 1.RR;2.Leucopenia;3.Erythropenia; 4.Thrombocytopenia;5.Nausea;6.DCR 1,2,3,5,6.P<0.05;4.P>0.05 Wang 2010 [15] Chinese RCT,Single cencer;China Primary liver cancer 28/13;32-68 25/14;33-67 3-DCRT+Aixiao Aixiao Ruanganjian UFTM/FMV 1.RR;2.Leucopenia;3.Platelet descend; 4.Hemoglobin reduction.5.T-cells; 6.Survival rate;7.Nausea 1-7.P<0.05 Wen 1996 [16] Chinese RCT,Single cencer;China Gastric cancer 8/3;47-73 5/3;50-69 UFTM/FMV+Jianpi Kangai mixtures DA/HA/IA 1.RR 1.P<0.05 Xu 2004 [17] Chinese RCT,Single cencer;China Acute myleoid leukemia 19/11;11-65 20/10;12-64 DA/HA/IA+Danshen formulae Radiotherapy+Placebo (TizisheN, huangbai, Baizhu, Gouqi, Huang jing, Tiandong, Maidong, Xuan shen, Nvzhenzi, Hanliancao, Pugonging, Banzhilian, Baihuasheshecao, Xiaoji et al.) 1.RR;2.Aminotransferase 1,2.P<0.05 Yan 1995 [18] Chinese RCT,Single cencer;China Acute leukemia 16/19;14-60 18/17;17-60 Radiotherapy+Danshen formulae General symptomatic treatment+Fufang Banmao Capsule 1.RR;2.Survival rate 1.P<0.05;2.P<0.01 Zeng 2015 [19] Chinese RCT,Single cencer;China Liver cancer 20/4;52.96±7.14 19/5;53.95±10.25 General symptomatic treatment+Fuzhengkangai decoction DDP+VP-16 1.RR;2.ALT;3.AST;4.GGT;5.AFP;6.CR+PR; 7. CR+PR+NC; 8.Survival rates; 9.Nausea;10.Vomiting 1,4,7.P<0.05; 2,3.P<; 5,6,8,9,10.P>0.05 Zhang 2013[20] Chinese RCT,Single cencer;China NSCLC Total:48/30;55±2.1 DDP+VP-16d123+Xidan Tang Vinorelbine +Cisplatin(NP)+Placebo (Huangqi, Huangjing, Jiaogulan, Lingzhi, Cangzhu, Nvzhenzi, Huanglian et al.) 1.Survival rate;2.Nausea, vomiting and loss of appetite 1.P<0.05; 2.P>0.05Table 2
Types of cancer.
Types of cancer Included trial(s) Sex(male/female);Total Frequency Lung cancer Gong 2018 146/93 5 Guo 2017 48/13 Lan 2003 29/18 Shen 2017 45/41 Zhang 2013 48/30 Total:316/195 Leukemia Li 2017 23/27 3 Xu 2004 39/21 Yan 1995 34/36 Total:96/84 Liver cancer Chen 2012 79/19 3 Wang 2010 53/27 Zeng 2015 39/9 Total:171/55 Gastric cancer Wen 1996 11/6 1 Total:11/6 Breast or colon cancer Mok 2007 11/100 1 Total:11/100Table 3
The constituent of Danshen formulae in each included study.
Included trials Chuanxiong formula Ingredient Latin name English name Chinese name Dosage (g) Chen 2012 Gexiazhuyu decotion Radix salviae miltiorrhizae Danshen root Danshen 9 Astragalus mongholicus Milkvetch Root Huangqi 14 Semen persicae Peach seed Taoren 9 Flos carthami Safflowe Honghua 6 Paeoni paeonol Danpi 12 Rhizoma cyperi Nutgrass galingale rhizome Xiangfu 10 Fructus citri aurantii immaturus Immature bitter orange Zhiqiao 12 Agkistrodon seu bungarus Hedyotis diffusa Baihuasheshecao 16 Radix scrophulariae ningpoensis Radix scrophulariae Xuanshen 14  Gong 2018 Jupi Zhuru decoction Radix salviae miltiorrhizae Danshen root Danshen 15 Pericarpium citri reticulatae Dried Tangerine Chenpi 9 Pinellia ternata Rhizoma pinelliae Jiangbanxia 9 Bambusa turdoides munro Bamboo shavings Jiangzhuru 9 Zizyphus jujuba Chinese date Dazao 9 Glycyrrhiza uralensis Liquorice root Gancao 6  Guo 2017 TCM formulae decoction Astragalus mongholicus Milkvetch Root Huangqi 30 Rhizoma atractylodis macrocephalae Largehead atractylodes Baizhu 9 Poria Poria cocos Fuling 15 Radix glehniae Coastal glehnia root Beishashen 30 Radix adenophorae Fourleaf ladybell root Nanshashen 30 Radix asparagi Cochinchinese asparagus root Tiandong 15 Radix ophiopogonIs Dwarf lilyturf tuber Maidong 15 Radix salviae miltiorrhizae Danshen root Danshen 30 Selaginella doederleinii hicr Selaginella doederleinii Shishangbai 30  Lan 2003 TCM formulae decoction Adenophora stricta Radix Adenophorae Shashen 30 Bulbus fritillariae cirrhosae Tendrilleaf fritillary bulb Chuanbeimu 10 Astragalus mongholicus bunge Milkvetch root Huangqi 30 Ophiopogon japonicus Dwarf lilyturf tuber Maidong 15 Fallopia multiflora Tuber fleeceflower root Heshouwu 30 Rehmannia glutinosa Prepared rehmannia root Shudihuang 10 Dioscorea opposita Common Yam Rhizome Shanyao 30 Alismatis Rhizoma Alisma orientale Zexie 15 Fructus Corni Cornus officinalis Shanzhuyu 10 Glycyrrhiza uralensis Liquorice root Gancao 10 Rhizoma Phragmitis Reed rhizome Lugen 30 Lonicera japonica Thunb Lonicera japonica Jinyinhua 15 Morus alba L. White mulberry root-bark Sangbaipi 15 Radix Sophorae Tonkinensis Radix sophorae tonkinensis Shandougen 15 Gypsum fibrosum Gypsum fibrosum Shengshigao 30 Scutellariae baicalensis Radix scutellariae Huangqin 15 Codonopsis pilosula Danshen root Danshen 30 Radix et rhizoma rhei Rhubar Dahuang 15  Li 2017 Jiedu Huayu Fang Lygodium japonicum Indigo Naturals Qingdai Not mentioned Paris polyphylla Smith Flea Zaoxiu Fructus Psoraleae Psoraleae Buguzhi Rhizoma Polygoni Cuspidati Polygonum cuspidatum Huzhang Radix salviae miltiorrhizae Danshen root Danshen Atractylodes macrocephala Koidz Largehead atractylodes rhizo Baizhu Asarum sagittarioides Cremastra appendiculata Shancigu Rhizoma Ligustici Chuanxiong Sichuan lovage rhizome Chuanxiong  Mok 2007 TCM formulae granules Curcuma zedoaria Rhizoma curcumae Ezhu Not mentioned Sparganium simplex Huds Rhizoma spargani Sanleng Radix salviae miltiorrhizae Danshen root Danshen Leonurus artemisia Herba leonuri Yimucao Radix scrophulariae Scrophularia ningpoensis Xuanshen Polyporus Polyporus umbellatus Zhuling Coix lacrymajobi Coix seed Yiyiren Semen Plantaginis Plantain seed Cheqianzi Herba lysimachiae Longhairy antenoron Herb Jinqiancao Spora lygodii Lygodium japonicum Haijinsha  Shen 2017 Zilongjin Tablet Astragalus mongholicus Milkvetch root Huangqi 0.65g per piece Radix angelicae hinensis Chinese angelica Danggui Solanum lyratum thunb Solanum lyratum thunb Baiying Solanum nigrum Nightshade Longkui Radixsalviae miltiorrhizae Danshen root Danshen Portulaca grandiflora hook Scutellariae barbatae Banzhilian Duchesnea indica Duchesnea Shemei Turmeric Curcumae Turmeric Yujin  Wang 2010 Aixiao Ruanganjian Panax ginseng Ginseng Renshen Not mentioned Curcuma zedoaria Rhizoma Curcumae Ezhu Radix salviae miltiorrhizae Danshen root Danshen Semen coicis Coix seed Yiyiren Spreading hedyotis herb Hedyotis diffusa Baihuasheshecao Portulaca grandiflora hook Scutellariae barbatae Banzhilian Bletilla striata Bletilla Baiji Rehmannia glutinosa Smilax glabra Tufuling Semen persicae Peach seed Taoren Rafetus swinhoei Cantharides Banao Lycium dasystemum Pojark Babury wolfberry fruit Gouqizi Trionyx sinensis Trionycis carapax Biejia Rhizoma paridis Flea Zaoxiu Radix sophorae flavescentis Lightyellow sophora root Kushen  Wen 1996 Jianpi Kangai decoction Pseudostellaria heterophylla Radix pseudostellariae Taizishen 12 Atractylodes macrocephala koidz Roasted rhizoma atractylois Chaobaizhu 12 Poria Poria cocos Fuling 12 Rhizoma pinelliae ternatae Pinellia tuber Banxia 12 ericarpium citri reticulatae Tangerine Peel Chenpi 12 Radix salviae miltiorrhizae Danshen root Danshen 20 Sargentodoxa cuneata. Sargent gloryvine Hongteng 20 Smilax china L Smilax china Baqia 30 Concha ostreae Oysters Shengmuli 30 Prunella vulgaris Self heal Xiakucao 30  Xu 2004 TCM formulae decoction Radix astragali seu Milkvetch Root Shenghuangqi Not mentioned Rehmannia glutinosa Libosch Radix rehmanniae Shengdihuang Pseudostellaria heterophylla Radix pseudostellariae Taizishen Dioscorea nipponicaMakino Ningpo yam rhizome Chuanshanlong Radix salviae miltiorrhizae Danshen root Danshen Leonurus artemisia Radix salviae miltiorrhizae Yimucao Periostracum cicadae Cicada Slough Chantui Achyranthes bidentata blume Achyranthes longifolia Huainiuxi  Yan 1995 TCM formulae decoction Astragalus mongholicus Milkvetch root Huangqi 15 Codonopsis pilosula Codonopsis Dangshen 15 Atractylodes macrocephala Koidz Largehead atractylodes rhizo Baizhu 15 Poria Poria cocos Fuling 12 Radix Angelicae Sinensis Chinese angelica Danggui 15 Colla corii Asini colla corii asini Ajiao 15 Lycium dasystemum Pojark Babury Wolfberry Fruit Gouqizi 15 Fructus psoraleae Psoraleae Buguzhi 15 Fallopia multiflora Tuber fleeceflower root Heshouwu 15 Spreading hedyotis Herb Hedyotis diffusa Baihuasheshecao 20 Herba cirsii setosi Common cephalanoplos herb Xiaoji 15 Radix salviae miltiorrhizae Danshen root Danshen 15 Millettia dielsiana Caulis spatholobi Jixueteng 15 Sparganium simplex Huds Rhizoma spargani Sanleng 15 Curcuma zedoaria Rhizoma curcumae Ezhu 15  Zeng 2015 Fuzhengkangai decoction Cynanchum paniculatum Paniculate swallowwort root Xuchangqing 20 Atractylodes macrocephala Largehead atractylodes rhizo Shengbaizhu 15 Turmeric Curcumae Turmeric Yujin 12 Radix salviae miltiorrhizae Danshen root Danshen 30 ArtemisiacapillarisThunb Virgate wormwood herb Yinchen 30 Fructus citri aurantii immatur Immature bitter orange Chaozhishi 15 Portulaca grandiflora hook Scutellariae barbatae Banzhilian 30 Solanum lyratum thunb Solanum lyratum thunb Baiying 20 Astragalus mongholicus Milkvetch root Shenghuangqi 40 Cleistocactus sepium Cuttlebone Wuzeigu 20 Curcuma zedoaria Rhizoma curcumae Ezhu 10 Rhizoma Coptidis Coptis root Huanglian 6 Trichosanthes kirilowii Maxim Pericarpium trichosanthis Gualoupi 15  Zhang 2013 Xidan Tang Astragalus mongholicus Milkvetch root Huangqi 30 Bletilla striata Bletilla Baiji 12 Poria Poria cocos Fuling 15 Ganoderma Lucidum Karst Lucid ganoderma Lingzhi 15 Radix salviae miltiorrhizae Danshen root Danshen 10 Rhizoma Ligustici Chuanxiong Sichuan lovage rhizom Chuanxiong 9 Euchresta japonica Hook Vietnamese sophora root Shandougen 6 Fructus Camptothecae Acuminatae Common Camptotheca Fruit Xishuguo 10 Glycyrrhiza uralensis Liquorice root Gancao 5


### 3.3. Description of the Danshen Formulae

Table2 details the components of the Danshen formulae in each study. 83 kinds of herbs were used in 13 different Danshen formulae and three dosage forms were mentioned, namely, decoction (n=11), tablets (n=1), and formula particles (n=1) (Table 3). The 9 most commonly used herbs were Radix Salviae Miltiorrhizae (frequency=13), Astragalus mongholicus bunge (frequency=8), Rhizoma atractylodis Macrocephalae (frequency=5), Curcuma zedoaria (frequency=4), Agkistrodon seu bungarus (frequency=4), Poria (frequency=4), Adenophora stricta (frequency=3), Glycyrrhiza uralensis (frequency=3), and Portulaca grandiflora hook (frequency=3) (Table 4).Table 4
The top 9 frequency Chinese herb medicines of formulae.
Latinname Englishname Chinese name Frequentcy The total frequency (%) Cumulative percentiles (%) Radix salviae miltiorrhizae Danshen root Danshen 13 100 17.11 Astragalus mongholicus bunge Milkvetch root Huangqi 8 61.54 10.53 Rhizoma atractylodis macrocephalae Largehead atractylodes Poria cocos Baizhu 5 38.46 6.76 Curcuma zedoaria Rhizoma curcumae Ezhu 4 30.77 5.26 Poria Coastal glehnia root Fuling 4 30.77 5.26 Agkistrodon seu bungarus Hedyotis diffusa Baihuasheshecao 3 23.08 3.95 Adenophora stricta Radix Adenophorae Shashen 3 23.08 3.95 Glycyrrhiza uralensis Liquorice root Gancao 3 23.08 3.95 Portulaca grandiflora hook Scutellariae barbatae Banzhilian 3 23.08 3.95


### 3.4. RoB Assessment

The RoB evaluation is shown in Table4. All studies are described as random. Twelve RCTs mentioned random allocation methods, including random sampling, picking method, hospitalization time, completely randomized digital table, and stratified permuted block method, and the rest of the study had only the words “randomized grouping”. 1 RCT explicitly proposed that the study was conducted by a single blind method [9], 2 RCT explicitly proposed the use of double-blind method in the title or abstract [10, 13], and the rest of the studies were relatively vague about the blind method, and we need to get relevant information by reading the full text. As shown in the table, among the 13 studies, 3 articles scored 5 points [9, 10, 13], and the rest were scored 4 points [8, 11, 12, 14–20] (Table 5).Table 5
Risk of bias assessments for included studies.
Included studies A B C D E F G Total Chen 2012 + ? + + + ? + 4 Gong 2018 + ? + + + ? + 5 Guo 2017 + ? ? + + + + 5 Lan 2003 + - + - + ? + 4 Li 2017 + - - ? + + + 4 Mok 2007 + ? + + + + + 5 Shen 2017 + ? - ? + ? + 4 Wang 2010 + - - ? + + + 4 Wen 1996 + ? ? - + + + 4 Xu 2004 + ? ? + + - + 4 Yan 1995 + - ? + + - + 4 Zeng 2015 + - ? ? + + + 4 Zhang 2013 + ? - ? + + + 4 A, random sequence generation (selection bias); B, allocation concealment (selection bias). C, blinding of participants and personnel (performance bias); D, blinding of outcome assessment(detection bias). E, incomplete outcome data (attrition bias); F, selective reporting (reporting bias); G, other bias. +, low risk of bias;–, high risk of bias; ?, unclear risk of bias.


### 3.5. Effectiveness

#### 3.5.1. Cancer Patients Treated with Additional Danshen Formulae Have a Significantly High RR

Ten studies [8, 10–12, 14–19] analyzed RR, indicating the RR of the experimental group was higher than that of the control group (OR 2.38, 95% CI 1.66-3.42) (Figure 2). Heterogeneity testP = 0.21,I2 = 25% showed 13 included articles with no heterogeneity, so the statistical analysis with fixed effects model. Pooled OR with 95% CIs showedZ = 4.71,P<0.00001 (Figure 2), suggesting that the difference was statistically significant. It can be considered that the RR of Danshen formulae with the general treatment regimen was higher to the control scheme without the Danshen formulae.Figure 2
Meta-analysis of RR in experimental group and control group.


#### 3.5.2. 1-Year Survival Rate

The total clinical efficacy rate 1-year survival rate between experimental group and control group was reported in 7 studies [8, 9, 11, 15, 18–20]. Compared with the control group, the 1-year survival rate was significantly improved after adding Danshen formulae (OR 1.70 95% CI 1.22-2.36,Z = 3.13,P=0.002), and there was a low heterogeneity (P = 0.27,I2 = 21%) (Figure 3).Figure 3
Meta-analysis of 1-year survival rate in experimental group and control group.


#### 3.5.3. 3-Year Survival Rate

Four researches [9, 11, 18, 20] focused on 3-year survival rate between two groups. Pooled data showed that Danshen formulae were significantly better at increasing patient’s 3-year survival (OR 2.78, 95% CI 1.62-4.78,Z = 3.70,P=0.0002) with no heterogeneity (P = 0.66,I2 = 0%) (Figure 4).Figure 4
Meta-analysis of 3-year survival rate in experimental group and control group.


#### 3.5.4. 5-Year Survival Rate

Three studies recorded 5-year survival rates [9, 11, 18]. Pooled data indicated that experimental group had a higher 5-year survival rate (OR 8.45, 95% CI 2.53-28.27,Z = 3.74,P = 0.0005) than control group with no heterogeneity (P = 0.76,I2 = 0%) (Figure 5).Figure 5
Meta-analysis of 5-year survival rate in experimental group and control group.


### 3.6. Publication Bias

The funnel plot and further Egger’s test were used to evaluate publication bias for RR of two groups of cancer patients. As the two results, though, showed a left-right asymmetry, but bothP>0.05, suggesting that there was no publication bias (Figures 6 and 7).Figure 6
Funnel plot for RR analysis in experimental group and control group.Figure 7
Egger’s publication bias plot for RR analysis in experimental group and control group (P=1.07).


### 3.7. Sensitivity Analysis

Our sensitivity analysis did not indicate that the results of any individual study would change the final outcome, indicating that none of the studies significantly affected the pooled OR and 95% CI.


### 3.8. Subgroup Analysis

To evaluate the effect of Danshen formulae for different cancers, we did a subgroup analysis. Danshen formulae did not show obvious beneficial effects in gastric cancer (OR 0.90 95% CI 0.06-12.58) and lung cancer (OR 1.81 95% CI 0.98-3.36), while it was good for treatment of leukemia (OR 4.63 95% CI 2.11-10.17) and liver cancer (OR 2.15 95% CI 1.21-3.80). Pooled data indicated that Danshen formulae had beneficial effects during the treatment progress in different cancers (OR 2.38 95% CI 1.66-3.42) (Figure8).Figure 8
The RR analysis of Danshen formulae for different cancers.


## 3.1. Description of Studies

A total of 3209 studies were searched by 4 electronic databases and other sources, and 2664 records were retained after deduplication. Of these, 366 studies were unrelated to cancer, 434 were animal experiments, 462 were mechanical experiments, and 728 were reviews, protocols, experiences, or case reports. By reading the full text, 762 studies, including 103 control interventions were inappropriate, lacking 50 of the control group and 70 items without full text, 200 items were not really RCTs, 99 items did not use the Danshen formula, and 142 included other CAM treatments, such as Acupuncture, Qigong, and 90 methodology that is of low quality. In the end, the study included 13 studies with 1045 patients that met the Cochrane Robb score of 4 and conducted a meta-analysis. A PRISMA flowed graph describe the search process and research options (Figure1).Figure 1
Flow diagram of literature search and selection.


## 3.2. Basic Characters of the Included Studies

The characteristics of the 13 studies included the contents summarized in Table1. All the eligible studies were conducted in China, with four articles published in English [9–11, 13] and the rest in Chinese [8, 12, 14–20]) (Table 1). In this study, there are 6 related lung cancers [9–11, 14, 19, 20], 3 related to Leukemia [12, 17, 18], 3 related to Liver cancer [8, 15, 19], one related to breast or colon cancer [13], and one related to gastric cancer [17] (Table 2). Because leukemia is a kind of malignant clonal disease of hematopoietic stem cells and belongs to the category of cancer, this study also included the research of leukemia. There were 10 RCTs with Overall response rate (RR) [8, 10–12, 14–19], 8 RCTs of them showed that Danshen formulae improved RR [10–14], and 2 RCTs suggested that Danshen formulae did not significantly improve RR [8, 11]. In 5 RCTs with survival rates, 4 RCTs of them indicated that Danshen Formulae improved survival rates [9, 15, 18, 20] and 1 RCT indicated that Danshen formulae did not significantly improve RR [8]. Seven RCTs were with side effects [10, 12–15, 17, 20] (Table 1). And the results showed 605 male patients and 440 female patients included in this study (Table 2). Among the 13 RCTs, 3 different Danshen formulae dosage forms were mentioned, 1 was a granule [17], 1 was a tablet [14], and the rest were decoction [8–13, 15, 16, 18–20]. In 8 Danshen formulae, Danshen plays a major role [8, 9, 12, 14–16, 19, 20] and improves the survival rate of patients; in 3 Danshen formulae, Danshen plays play an auxiliary role [10, 17, 18] and, in 2 RCTs, the real effect is that of other medicinal materials [11, 13]. It should be noted that one study did not involve radiotherapy, chemotherapy, or surgical treatment [19], while the rest were combined Chinese and western medicine (Table 3).Table 1
Basic characteristics of the included studies.
Included trial Publication language Study design and investi-gational sites Type of cancer No.of participants (male/female;age years) Intervention Outcome index Intergroup difference Experimental Control Experimental Control Chen 2012 [8] Chinese RCT,Single cencer;China Primary Liver Cancer 38/11;44.7 41/8;47.1 Danshen formulae Vinorelbine +Cisplatin(NP)+Placebo (Huangqi, Huangjing, Jiaogulan, Lingzhi, Cangzhu, Nvzhenzi, Huanglian et al.) 1.RR; 2.Survival rate;3.Improvement of symptoms 1,2.P>0.05; 3<0.05 Gong 2018 [9] English RCT,Single cencer;China Non-small cell lung cancer (NSCLC) 80/51;40-78 66/42;41-80 Vinorelbine +Cisplatin(NP)+Danshen formulae Platinum-based therapy +Placebo (Jiegeng, Xingren, Yuxingcao, Ziwan, Kuandong, Zhebeimu, Banxia, Hexiancao, Shengdiyu, Huangqin, Dongguazi, Chenpi, Zhuru et al.) 1.Survival Rates;2.MST 1,2.P<0.05 Guo 2017 [10] English RCT, Multi-cente;China NSCLC 20/9;38-77 28/4;38-77 Platinum-based therapy +Danshen formulae Radiotherapy 1.RR;2.Nausea; 3.Vomit;4.QOL; 5.Mildgastric/abdominal heaviness 1,2,3,5.P<0.05;4.P>0.05 Lan 2003 [11] English RCT,Single cencer;China Lung cancer 16/10;70-77 13/8;70-79 Radiotherapy+Danshen formulae DAP RR(1.Short-term effect;2. Long-term effect) 1.P>0.052.P<0.01 Li 2017 [12] Chinese RCT,Single cencer;China Leukemia 10/15;(35.42±15.13 13/12;37.97±13.45 DAP+Jiedu Huayu Fang Radiotherapy+placebo (Xuanshen,Yiyiren, Chenqianzi, Yinchen, Difuzi, Chuanwu, Ganjiang, Rougui, Wuzhuyu, Xiangfuzi, Chenpi, Shanzha, Laifuzi, Sanqi, Ruxiang, Yujin et al.) 1.RR(CR+PR);2.Leukopenia; 3.Platelet(PLT)decreased; 4.Hemoglobin(HGB)decreased 1,3,4.P<0.05;2.P>0.05 Mok 2007 [13] English RCT,Single cencer;China Breast or colon cancer 5/50;32-75 6/50;39-72 Radiotherapy+Danshen formulae Paclitaxel Injection+Cisplatin Injection 1.HGB decreas-ed;2.Leukopenia;3.Neutropenia; 4.Thrombocytopenia;5.Nausea; 6.QOL 1-4,P>0.05;5,6.P<0.05 Shen 2017 [14] Chinese RCT,Single cencer;China NSCLC 22/21;57.2 ±7.3 23/20;56.8±7.5 Paclitaxel Injection+Cisplatin Injection+Zilongjin tablet 3-DCRT 1.RR;2.Leucopenia;3.Erythropenia; 4.Thrombocytopenia;5.Nausea;6.DCR 1,2,3,5,6.P<0.05;4.P>0.05 Wang 2010 [15] Chinese RCT,Single cencer;China Primary liver cancer 28/13;32-68 25/14;33-67 3-DCRT+Aixiao Aixiao Ruanganjian UFTM/FMV 1.RR;2.Leucopenia;3.Platelet descend; 4.Hemoglobin reduction.5.T-cells; 6.Survival rate;7.Nausea 1-7.P<0.05 Wen 1996 [16] Chinese RCT,Single cencer;China Gastric cancer 8/3;47-73 5/3;50-69 UFTM/FMV+Jianpi Kangai mixtures DA/HA/IA 1.RR 1.P<0.05 Xu 2004 [17] Chinese RCT,Single cencer;China Acute myleoid leukemia 19/11;11-65 20/10;12-64 DA/HA/IA+Danshen formulae Radiotherapy+Placebo (TizisheN, huangbai, Baizhu, Gouqi, Huang jing, Tiandong, Maidong, Xuan shen, Nvzhenzi, Hanliancao, Pugonging, Banzhilian, Baihuasheshecao, Xiaoji et al.) 1.RR;2.Aminotransferase 1,2.P<0.05 Yan 1995 [18] Chinese RCT,Single cencer;China Acute leukemia 16/19;14-60 18/17;17-60 Radiotherapy+Danshen formulae General symptomatic treatment+Fufang Banmao Capsule 1.RR;2.Survival rate 1.P<0.05;2.P<0.01 Zeng 2015 [19] Chinese RCT,Single cencer;China Liver cancer 20/4;52.96±7.14 19/5;53.95±10.25 General symptomatic treatment+Fuzhengkangai decoction DDP+VP-16 1.RR;2.ALT;3.AST;4.GGT;5.AFP;6.CR+PR; 7. CR+PR+NC; 8.Survival rates; 9.Nausea;10.Vomiting 1,4,7.P<0.05; 2,3.P<; 5,6,8,9,10.P>0.05 Zhang 2013[20] Chinese RCT,Single cencer;China NSCLC Total:48/30;55±2.1 DDP+VP-16d123+Xidan Tang Vinorelbine +Cisplatin(NP)+Placebo (Huangqi, Huangjing, Jiaogulan, Lingzhi, Cangzhu, Nvzhenzi, Huanglian et al.) 1.Survival rate;2.Nausea, vomiting and loss of appetite 1.P<0.05; 2.P>0.05Table 2
Types of cancer.
Types of cancer Included trial(s) Sex(male/female);Total Frequency Lung cancer Gong 2018 146/93 5 Guo 2017 48/13 Lan 2003 29/18 Shen 2017 45/41 Zhang 2013 48/30 Total:316/195 Leukemia Li 2017 23/27 3 Xu 2004 39/21 Yan 1995 34/36 Total:96/84 Liver cancer Chen 2012 79/19 3 Wang 2010 53/27 Zeng 2015 39/9 Total:171/55 Gastric cancer Wen 1996 11/6 1 Total:11/6 Breast or colon cancer Mok 2007 11/100 1 Total:11/100Table 3
The constituent of Danshen formulae in each included study.
Included trials Chuanxiong formula Ingredient Latin name English name Chinese name Dosage (g) Chen 2012 Gexiazhuyu decotion Radix salviae miltiorrhizae Danshen root Danshen 9 Astragalus mongholicus Milkvetch Root Huangqi 14 Semen persicae Peach seed Taoren 9 Flos carthami Safflowe Honghua 6 Paeoni paeonol Danpi 12 Rhizoma cyperi Nutgrass galingale rhizome Xiangfu 10 Fructus citri aurantii immaturus Immature bitter orange Zhiqiao 12 Agkistrodon seu bungarus Hedyotis diffusa Baihuasheshecao 16 Radix scrophulariae ningpoensis Radix scrophulariae Xuanshen 14  Gong 2018 Jupi Zhuru decoction Radix salviae miltiorrhizae Danshen root Danshen 15 Pericarpium citri reticulatae Dried Tangerine Chenpi 9 Pinellia ternata Rhizoma pinelliae Jiangbanxia 9 Bambusa turdoides munro Bamboo shavings Jiangzhuru 9 Zizyphus jujuba Chinese date Dazao 9 Glycyrrhiza uralensis Liquorice root Gancao 6  Guo 2017 TCM formulae decoction Astragalus mongholicus Milkvetch Root Huangqi 30 Rhizoma atractylodis macrocephalae Largehead atractylodes Baizhu 9 Poria Poria cocos Fuling 15 Radix glehniae Coastal glehnia root Beishashen 30 Radix adenophorae Fourleaf ladybell root Nanshashen 30 Radix asparagi Cochinchinese asparagus root Tiandong 15 Radix ophiopogonIs Dwarf lilyturf tuber Maidong 15 Radix salviae miltiorrhizae Danshen root Danshen 30 Selaginella doederleinii hicr Selaginella doederleinii Shishangbai 30  Lan 2003 TCM formulae decoction Adenophora stricta Radix Adenophorae Shashen 30 Bulbus fritillariae cirrhosae Tendrilleaf fritillary bulb Chuanbeimu 10 Astragalus mongholicus bunge Milkvetch root Huangqi 30 Ophiopogon japonicus Dwarf lilyturf tuber Maidong 15 Fallopia multiflora Tuber fleeceflower root Heshouwu 30 Rehmannia glutinosa Prepared rehmannia root Shudihuang 10 Dioscorea opposita Common Yam Rhizome Shanyao 30 Alismatis Rhizoma Alisma orientale Zexie 15 Fructus Corni Cornus officinalis Shanzhuyu 10 Glycyrrhiza uralensis Liquorice root Gancao 10 Rhizoma Phragmitis Reed rhizome Lugen 30 Lonicera japonica Thunb Lonicera japonica Jinyinhua 15 Morus alba L. White mulberry root-bark Sangbaipi 15 Radix Sophorae Tonkinensis Radix sophorae tonkinensis Shandougen 15 Gypsum fibrosum Gypsum fibrosum Shengshigao 30 Scutellariae baicalensis Radix scutellariae Huangqin 15 Codonopsis pilosula Danshen root Danshen 30 Radix et rhizoma rhei Rhubar Dahuang 15  Li 2017 Jiedu Huayu Fang Lygodium japonicum Indigo Naturals Qingdai Not mentioned Paris polyphylla Smith Flea Zaoxiu Fructus Psoraleae Psoraleae Buguzhi Rhizoma Polygoni Cuspidati Polygonum cuspidatum Huzhang Radix salviae miltiorrhizae Danshen root Danshen Atractylodes macrocephala Koidz Largehead atractylodes rhizo Baizhu Asarum sagittarioides Cremastra appendiculata Shancigu Rhizoma Ligustici Chuanxiong Sichuan lovage rhizome Chuanxiong  Mok 2007 TCM formulae granules Curcuma zedoaria Rhizoma curcumae Ezhu Not mentioned Sparganium simplex Huds Rhizoma spargani Sanleng Radix salviae miltiorrhizae Danshen root Danshen Leonurus artemisia Herba leonuri Yimucao Radix scrophulariae Scrophularia ningpoensis Xuanshen Polyporus Polyporus umbellatus Zhuling Coix lacrymajobi Coix seed Yiyiren Semen Plantaginis Plantain seed Cheqianzi Herba lysimachiae Longhairy antenoron Herb Jinqiancao Spora lygodii Lygodium japonicum Haijinsha  Shen 2017 Zilongjin Tablet Astragalus mongholicus Milkvetch root Huangqi 0.65g per piece Radix angelicae hinensis Chinese angelica Danggui Solanum lyratum thunb Solanum lyratum thunb Baiying Solanum nigrum Nightshade Longkui Radixsalviae miltiorrhizae Danshen root Danshen Portulaca grandiflora hook Scutellariae barbatae Banzhilian Duchesnea indica Duchesnea Shemei Turmeric Curcumae Turmeric Yujin  Wang 2010 Aixiao Ruanganjian Panax ginseng Ginseng Renshen Not mentioned Curcuma zedoaria Rhizoma Curcumae Ezhu Radix salviae miltiorrhizae Danshen root Danshen Semen coicis Coix seed Yiyiren Spreading hedyotis herb Hedyotis diffusa Baihuasheshecao Portulaca grandiflora hook Scutellariae barbatae Banzhilian Bletilla striata Bletilla Baiji Rehmannia glutinosa Smilax glabra Tufuling Semen persicae Peach seed Taoren Rafetus swinhoei Cantharides Banao Lycium dasystemum Pojark Babury wolfberry fruit Gouqizi Trionyx sinensis Trionycis carapax Biejia Rhizoma paridis Flea Zaoxiu Radix sophorae flavescentis Lightyellow sophora root Kushen  Wen 1996 Jianpi Kangai decoction Pseudostellaria heterophylla Radix pseudostellariae Taizishen 12 Atractylodes macrocephala koidz Roasted rhizoma atractylois Chaobaizhu 12 Poria Poria cocos Fuling 12 Rhizoma pinelliae ternatae Pinellia tuber Banxia 12 ericarpium citri reticulatae Tangerine Peel Chenpi 12 Radix salviae miltiorrhizae Danshen root Danshen 20 Sargentodoxa cuneata. Sargent gloryvine Hongteng 20 Smilax china L Smilax china Baqia 30 Concha ostreae Oysters Shengmuli 30 Prunella vulgaris Self heal Xiakucao 30  Xu 2004 TCM formulae decoction Radix astragali seu Milkvetch Root Shenghuangqi Not mentioned Rehmannia glutinosa Libosch Radix rehmanniae Shengdihuang Pseudostellaria heterophylla Radix pseudostellariae Taizishen Dioscorea nipponicaMakino Ningpo yam rhizome Chuanshanlong Radix salviae miltiorrhizae Danshen root Danshen Leonurus artemisia Radix salviae miltiorrhizae Yimucao Periostracum cicadae Cicada Slough Chantui Achyranthes bidentata blume Achyranthes longifolia Huainiuxi  Yan 1995 TCM formulae decoction Astragalus mongholicus Milkvetch root Huangqi 15 Codonopsis pilosula Codonopsis Dangshen 15 Atractylodes macrocephala Koidz Largehead atractylodes rhizo Baizhu 15 Poria Poria cocos Fuling 12 Radix Angelicae Sinensis Chinese angelica Danggui 15 Colla corii Asini colla corii asini Ajiao 15 Lycium dasystemum Pojark Babury Wolfberry Fruit Gouqizi 15 Fructus psoraleae Psoraleae Buguzhi 15 Fallopia multiflora Tuber fleeceflower root Heshouwu 15 Spreading hedyotis Herb Hedyotis diffusa Baihuasheshecao 20 Herba cirsii setosi Common cephalanoplos herb Xiaoji 15 Radix salviae miltiorrhizae Danshen root Danshen 15 Millettia dielsiana Caulis spatholobi Jixueteng 15 Sparganium simplex Huds Rhizoma spargani Sanleng 15 Curcuma zedoaria Rhizoma curcumae Ezhu 15  Zeng 2015 Fuzhengkangai decoction Cynanchum paniculatum Paniculate swallowwort root Xuchangqing 20 Atractylodes macrocephala Largehead atractylodes rhizo Shengbaizhu 15 Turmeric Curcumae Turmeric Yujin 12 Radix salviae miltiorrhizae Danshen root Danshen 30 ArtemisiacapillarisThunb Virgate wormwood herb Yinchen 30 Fructus citri aurantii immatur Immature bitter orange Chaozhishi 15 Portulaca grandiflora hook Scutellariae barbatae Banzhilian 30 Solanum lyratum thunb Solanum lyratum thunb Baiying 20 Astragalus mongholicus Milkvetch root Shenghuangqi 40 Cleistocactus sepium Cuttlebone Wuzeigu 20 Curcuma zedoaria Rhizoma curcumae Ezhu 10 Rhizoma Coptidis Coptis root Huanglian 6 Trichosanthes kirilowii Maxim Pericarpium trichosanthis Gualoupi 15  Zhang 2013 Xidan Tang Astragalus mongholicus Milkvetch root Huangqi 30 Bletilla striata Bletilla Baiji 12 Poria Poria cocos Fuling 15 Ganoderma Lucidum Karst Lucid ganoderma Lingzhi 15 Radix salviae miltiorrhizae Danshen root Danshen 10 Rhizoma Ligustici Chuanxiong Sichuan lovage rhizom Chuanxiong 9 Euchresta japonica Hook Vietnamese sophora root Shandougen 6 Fructus Camptothecae Acuminatae Common Camptotheca Fruit Xishuguo 10 Glycyrrhiza uralensis Liquorice root Gancao 5


## 3.3. Description of the Danshen Formulae

Table2 details the components of the Danshen formulae in each study. 83 kinds of herbs were used in 13 different Danshen formulae and three dosage forms were mentioned, namely, decoction (n=11), tablets (n=1), and formula particles (n=1) (Table 3). The 9 most commonly used herbs were Radix Salviae Miltiorrhizae (frequency=13), Astragalus mongholicus bunge (frequency=8), Rhizoma atractylodis Macrocephalae (frequency=5), Curcuma zedoaria (frequency=4), Agkistrodon seu bungarus (frequency=4), Poria (frequency=4), Adenophora stricta (frequency=3), Glycyrrhiza uralensis (frequency=3), and Portulaca grandiflora hook (frequency=3) (Table 4).Table 4
The top 9 frequency Chinese herb medicines of formulae.
Latinname Englishname Chinese name Frequentcy The total frequency (%) Cumulative percentiles (%) Radix salviae miltiorrhizae Danshen root Danshen 13 100 17.11 Astragalus mongholicus bunge Milkvetch root Huangqi 8 61.54 10.53 Rhizoma atractylodis macrocephalae Largehead atractylodes Poria cocos Baizhu 5 38.46 6.76 Curcuma zedoaria Rhizoma curcumae Ezhu 4 30.77 5.26 Poria Coastal glehnia root Fuling 4 30.77 5.26 Agkistrodon seu bungarus Hedyotis diffusa Baihuasheshecao 3 23.08 3.95 Adenophora stricta Radix Adenophorae Shashen 3 23.08 3.95 Glycyrrhiza uralensis Liquorice root Gancao 3 23.08 3.95 Portulaca grandiflora hook Scutellariae barbatae Banzhilian 3 23.08 3.95


## 3.4. RoB Assessment

The RoB evaluation is shown in Table4. All studies are described as random. Twelve RCTs mentioned random allocation methods, including random sampling, picking method, hospitalization time, completely randomized digital table, and stratified permuted block method, and the rest of the study had only the words “randomized grouping”. 1 RCT explicitly proposed that the study was conducted by a single blind method [9], 2 RCT explicitly proposed the use of double-blind method in the title or abstract [10, 13], and the rest of the studies were relatively vague about the blind method, and we need to get relevant information by reading the full text. As shown in the table, among the 13 studies, 3 articles scored 5 points [9, 10, 13], and the rest were scored 4 points [8, 11, 12, 14–20] (Table 5).Table 5
Risk of bias assessments for included studies.
Included studies A B C D E F G Total Chen 2012 + ? + + + ? + 4 Gong 2018 + ? + + + ? + 5 Guo 2017 + ? ? + + + + 5 Lan 2003 + - + - + ? + 4 Li 2017 + - - ? + + + 4 Mok 2007 + ? + + + + + 5 Shen 2017 + ? - ? + ? + 4 Wang 2010 + - - ? + + + 4 Wen 1996 + ? ? - + + + 4 Xu 2004 + ? ? + + - + 4 Yan 1995 + - ? + + - + 4 Zeng 2015 + - ? ? + + + 4 Zhang 2013 + ? - ? + + + 4 A, random sequence generation (selection bias); B, allocation concealment (selection bias). C, blinding of participants and personnel (performance bias); D, blinding of outcome assessment(detection bias). E, incomplete outcome data (attrition bias); F, selective reporting (reporting bias); G, other bias. +, low risk of bias;–, high risk of bias; ?, unclear risk of bias.


## 3.5. Effectiveness

### 3.5.1. Cancer Patients Treated with Additional Danshen Formulae Have a Significantly High RR

Ten studies [8, 10–12, 14–19] analyzed RR, indicating the RR of the experimental group was higher than that of the control group (OR 2.38, 95% CI 1.66-3.42) (Figure 2). Heterogeneity testP = 0.21,I2 = 25% showed 13 included articles with no heterogeneity, so the statistical analysis with fixed effects model. Pooled OR with 95% CIs showedZ = 4.71,P<0.00001 (Figure 2), suggesting that the difference was statistically significant. It can be considered that the RR of Danshen formulae with the general treatment regimen was higher to the control scheme without the Danshen formulae.Figure 2
Meta-analysis of RR in experimental group and control group.


### 3.5.2. 1-Year Survival Rate

The total clinical efficacy rate 1-year survival rate between experimental group and control group was reported in 7 studies [8, 9, 11, 15, 18–20]. Compared with the control group, the 1-year survival rate was significantly improved after adding Danshen formulae (OR 1.70 95% CI 1.22-2.36,Z = 3.13,P=0.002), and there was a low heterogeneity (P = 0.27,I2 = 21%) (Figure 3).Figure 3
Meta-analysis of 1-year survival rate in experimental group and control group.


### 3.5.3. 3-Year Survival Rate

Four researches [9, 11, 18, 20] focused on 3-year survival rate between two groups. Pooled data showed that Danshen formulae were significantly better at increasing patient’s 3-year survival (OR 2.78, 95% CI 1.62-4.78,Z = 3.70,P=0.0002) with no heterogeneity (P = 0.66,I2 = 0%) (Figure 4).Figure 4
Meta-analysis of 3-year survival rate in experimental group and control group.


### 3.5.4. 5-Year Survival Rate

Three studies recorded 5-year survival rates [9, 11, 18]. Pooled data indicated that experimental group had a higher 5-year survival rate (OR 8.45, 95% CI 2.53-28.27,Z = 3.74,P = 0.0005) than control group with no heterogeneity (P = 0.76,I2 = 0%) (Figure 5).Figure 5
Meta-analysis of 5-year survival rate in experimental group and control group.


## 3.5.1. Cancer Patients Treated with Additional Danshen Formulae Have a Significantly High RR

Ten studies [8, 10–12, 14–19] analyzed RR, indicating the RR of the experimental group was higher than that of the control group (OR 2.38, 95% CI 1.66-3.42) (Figure 2). Heterogeneity testP = 0.21,I2 = 25% showed 13 included articles with no heterogeneity, so the statistical analysis with fixed effects model. Pooled OR with 95% CIs showedZ = 4.71,P<0.00001 (Figure 2), suggesting that the difference was statistically significant. It can be considered that the RR of Danshen formulae with the general treatment regimen was higher to the control scheme without the Danshen formulae.Figure 2
Meta-analysis of RR in experimental group and control group.


## 3.5.2. 1-Year Survival Rate

The total clinical efficacy rate 1-year survival rate between experimental group and control group was reported in 7 studies [8, 9, 11, 15, 18–20]. Compared with the control group, the 1-year survival rate was significantly improved after adding Danshen formulae (OR 1.70 95% CI 1.22-2.36,Z = 3.13,P=0.002), and there was a low heterogeneity (P = 0.27,I2 = 21%) (Figure 3).Figure 3
Meta-analysis of 1-year survival rate in experimental group and control group.


## 3.5.3. 3-Year Survival Rate

Four researches [9, 11, 18, 20] focused on 3-year survival rate between two groups. Pooled data showed that Danshen formulae were significantly better at increasing patient’s 3-year survival (OR 2.78, 95% CI 1.62-4.78,Z = 3.70,P=0.0002) with no heterogeneity (P = 0.66,I2 = 0%) (Figure 4).Figure 4
Meta-analysis of 3-year survival rate in experimental group and control group.


## 3.5.4. 5-Year Survival Rate

Three studies recorded 5-year survival rates [9, 11, 18]. Pooled data indicated that experimental group had a higher 5-year survival rate (OR 8.45, 95% CI 2.53-28.27,Z = 3.74,P = 0.0005) than control group with no heterogeneity (P = 0.76,I2 = 0%) (Figure 5).Figure 5
Meta-analysis of 5-year survival rate in experimental group and control group.


## 3.6. Publication Bias

The funnel plot and further Egger’s test were used to evaluate publication bias for RR of two groups of cancer patients. As the two results, though, showed a left-right asymmetry, but bothP>0.05, suggesting that there was no publication bias (Figures 6 and 7).Figure 6
Funnel plot for RR analysis in experimental group and control group.Figure 7
Egger’s publication bias plot for RR analysis in experimental group and control group (P=1.07).


## 3.7. Sensitivity Analysis

Our sensitivity analysis did not indicate that the results of any individual study would change the final outcome, indicating that none of the studies significantly affected the pooled OR and 95% CI.


## 3.8. Subgroup Analysis

To evaluate the effect of Danshen formulae for different cancers, we did a subgroup analysis. Danshen formulae did not show obvious beneficial effects in gastric cancer (OR 0.90 95% CI 0.06-12.58) and lung cancer (OR 1.81 95% CI 0.98-3.36), while it was good for treatment of leukemia (OR 4.63 95% CI 2.11-10.17) and liver cancer (OR 2.15 95% CI 1.21-3.80). Pooled data indicated that Danshen formulae had beneficial effects during the treatment progress in different cancers (OR 2.38 95% CI 1.66-3.42) (Figure8).Figure 8
The RR analysis of Danshen formulae for different cancers.


## 4. Discussion

### 4.1. Summary of Evidence

In the past decades, much work has been reported in Chinese Herbal Medicine (HCM) in the treatment of cancer [8–20, 24, 25], and Zhang’s review provided evidence for the effectiveness of Danshen in the treatment of cancer [26]. However, there has not been a meta-analysis to study the value of Danshen formulae in cancer treatment. This paper was a systematic review of 13 high-quality RCTs, including 1045 participants, to determine the efficacy and safety of the Danshen formulae for cancer treatment. Our study showed that the Danshen formulae provide statistically significant benefits in improving RR (OR 2.38 95% CI 1.66-3.42), 1-year survival (OR 1.70 95% CI 1.22-2.36), 3-year survival (OR 2.78, 95% CI 1.62-4.78), and 5-year survival rate (OR 8.45, 95% CI 2.53-28.27). Current evidence suggests that Danshen formulae can be used as an effective adjuvant for treat cancer.


### 4.2. Implications for Practice

Modern pharmacological studies were performed on more than 10 tanshinone monomers, including tanshinone I (TNI), tanshinone A (TNIIA), tanshinone B, and cryptotanshinone (CPT), from Danshen root. Tanshinone TNI are the main bioactive components, TNIIA, and implicit tanshinone (CPT); TNIIA activity in salvia miltiorrhiza is the strongest diterpene quinine pigment; TNI and CPT are effective cytotoxic agent and can induce apoptosis and the stagnation of the cell cycle; potential mechanisms involved include raised to promote apoptosis proteins such as p53, Bax, and p21 and inhibit antiapoptotic proteins, including the Bcl-2, survivin, and c-Myc and activated caspase protein to trigger apoptosis, by activating AMP activated protein kinase and extracellular signal regulating kinase (ERK) and suppress the target of pakamycin and 70 kDa ribosomal protein S6 kinase signaling pathways; TNIIA induces autophagic cell death in various cancer cells. Furthermore, TNIIA and TNI can inhibit the migration, invasion, and metastasis of cancer cells by changing the tissue inhibitors of matrix metalloproteinase and/or metalloproteinase [26, 27]. In addition, TNIIA can also promote the differentiation of several cancer cell types and regulate the CCAAT/enhancer binding protein (C/EBP)β and C/EBP homologous protein. Besides, in animal models, the side effects of TNIIA, TNI, and CPT were minimal [28].In addition, Danshen root also has anti-inflammatory effects. TNIIA inhibits the NF-kB induced kinase/IkappaB alpha kinase (NIK/IKKalpha), while ERK1 suppress NF-κB induced by LPS and c-Jun n-terminal kinase (JNK) pathway. The anti-inflammatory effects of TNIIA may be related to the inhibition of the Toll-like receptor (TLR) signaling pathway by TNF receptor-associated factor (TRAF) 2/3/6. TNI significantly inhibits the activity of IIA secreting phospholipase A2 (GIIA), thereby blocking the formation of prostaglandin E2 (PGE2) in LPS-activated macrophages [27, 29]. TNI and CPT also significantly inhibit IL-12 production in LPS-activated macrophages and interferon-γ production in lymphocytes. Recent studies have shown that Salvia miltiorrhiza extract inhibits the production of iNOS and COX-2 by regulating NF-κB and MAPKs, thereby inhibiting the secretion of inflammatory cytokines. In LPS induced RAW264.7 macrophages, salvia miltiorrhiza extract reduced the secretion of nitric oxide (NO), tumor necrosis factor- (TNF-) α, and interleukin 6 (IL-6) and decreased the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and NF-κB. Moreover, salvia miltiorrhiza extract can significantly inhibit the activation of JNK1/2 and ERK1/2 induced by LPS and disrupt the TLR4 dimerization in LPS-induced RAW264.7 macrophages [29]. Therefore, the anti-inflammatory effect of Danshen root is partly due to the blocking of TLR4 dimerization, which can be used in clinical treatment of liver injury and infection during the anticancer strategies.Therefore, Chinese medicine practitioners usually use traditional Chinese medicines similar to Danshen root, such as Scutellaria barbata and Hedyotis diffusa in the treatment of cancer [8–20]. It should be mentioned that the current meta-analysis is the first systematic review of the application of Danshen formulae in cancer-assisted treatment. The current meta-analysis found that Danshen formulae can improve the clinical efficiency in cancer treatment. After the addition of Danshen formulae, RR and survival rates were significantly improved. However, it is not clear which components of Danshen formulae have anticancer effects during the treatment, and what role Danshen root plays, which should be the goal of further research.


### 4.3. Limitations

All literatures for this meta-analysis were from China, among which 4 were in English and the rest were in Chinese, and only one was multicenter study [10]. Blind methods have been described vaguely in many studies and most of the references were scored 4 points. Moreover, all types of researches were single-center studies with a small sample size and lack of data support for multicenter, large RCTs. The funnel plot analysis also found obvious asymmetry between the left and the right of funnel plot, therefore, the effect of Danshen formulae in assisting cancer treatment may be exaggerated. In addition to all of the above, the cycle of cancer treatment is extremely long and an army of patients died as their condition worsens during the treatment process, which leads to follow-up work is difficult, resulting in the inability to obtain valid data for many studies, and some literature related to this study cannot be included. Therefore, to better explore the contribution of Danshen formulae in cancer treatment, more large-scale and higher standard studies are needed.


### 4.4. Implications for Further Studies

Nearly 50% of the RCTs included in our study are related to lung cancer, indicating that Danshen formulae may be more widely used in lung cancer. Lung cancer is one of the most dangerous diseases, and it has a variety of treatment options, but the death rate is stubbornly high [2]. Except lung cancer, the included studies also cover leukemia, liver cancer, breast, colon cancer, and gastric cancer, and our study found that 9 kinds of herbs were used in combination with Danshen root in cancer treatment, suggesting that the pharmacological effects of these drugs together may be a mechanism to improve clinical efficacy and reduce side effects. Therefore, this study provides the basis for the clinical treatment and scientific research of Danshen for cancer. In terms of gender ratio, we found that men have a higher risk of cancer than women (605/440), suggesting that men should pour more attention into prevention of cancer, which was also a limitation of this paper, indicating that we should avoid gender selection bias by recruiting women to a certain extent in future studies. By inputting the dose form of Danshen formulae to statistical analysis, we found that there were 1 used granule preparation, 1 used tablet, and the other 11 used decoctions. Ling proved that TCM preparations more safer, effective, and easier to use than decoctions of traditional Chinese medicine [30], and the present study showed that the clinical curative effect and dosage forms of CHM were interconnected, interdependent, and mutually reinforcing with each other; drug application shall be familiar with drug characteristics on the premise of fully considering disease characteristics and age constitution and patient and choose the appropriate dosage forms, through the appropriate method to give full play to the effect, and make the drug in patients with optimal clinical curative effect [31, 32]. Therefore, rational selection of drug dosage forms is beneficial to enlighten and create new drugs, which can better promote the further development and research of new dosage forms with higher drug absorption rate. In terms of the treatment of cancer, in traditional western medicine, chemotherapy and radiotherapy are the main treatments for cancer. The purpose of these therapies is to kill or destroy cancer cells. Unfortunately, for most cancer treatments, it is difficult to distinguish between cancer cells and normal healthy cells, which leads to damage to normal cells [33, 34]. The results of this injury are known as complications and side effects of cancer treatment. There were 10 included studies showed that the formulae of Danshen had significant effect in reducing the side effect of vomiting and blood toxicity, which suggested that we could cooperate with the Danshen formulae in the treatment of cancer in the future to reduce the gastrointestinal reaction of patients. The results of subgroup analysis suggested that Danshen formulae might be taken advantage of for cancer treatment. At last, the exact pathologic and clinical pharmacological mechanisms of cancer are still largely unknown and should be studied further.


## 4.1. Summary of Evidence

In the past decades, much work has been reported in Chinese Herbal Medicine (HCM) in the treatment of cancer [8–20, 24, 25], and Zhang’s review provided evidence for the effectiveness of Danshen in the treatment of cancer [26]. However, there has not been a meta-analysis to study the value of Danshen formulae in cancer treatment. This paper was a systematic review of 13 high-quality RCTs, including 1045 participants, to determine the efficacy and safety of the Danshen formulae for cancer treatment. Our study showed that the Danshen formulae provide statistically significant benefits in improving RR (OR 2.38 95% CI 1.66-3.42), 1-year survival (OR 1.70 95% CI 1.22-2.36), 3-year survival (OR 2.78, 95% CI 1.62-4.78), and 5-year survival rate (OR 8.45, 95% CI 2.53-28.27). Current evidence suggests that Danshen formulae can be used as an effective adjuvant for treat cancer.


## 4.2. Implications for Practice

Modern pharmacological studies were performed on more than 10 tanshinone monomers, including tanshinone I (TNI), tanshinone A (TNIIA), tanshinone B, and cryptotanshinone (CPT), from Danshen root. Tanshinone TNI are the main bioactive components, TNIIA, and implicit tanshinone (CPT); TNIIA activity in salvia miltiorrhiza is the strongest diterpene quinine pigment; TNI and CPT are effective cytotoxic agent and can induce apoptosis and the stagnation of the cell cycle; potential mechanisms involved include raised to promote apoptosis proteins such as p53, Bax, and p21 and inhibit antiapoptotic proteins, including the Bcl-2, survivin, and c-Myc and activated caspase protein to trigger apoptosis, by activating AMP activated protein kinase and extracellular signal regulating kinase (ERK) and suppress the target of pakamycin and 70 kDa ribosomal protein S6 kinase signaling pathways; TNIIA induces autophagic cell death in various cancer cells. Furthermore, TNIIA and TNI can inhibit the migration, invasion, and metastasis of cancer cells by changing the tissue inhibitors of matrix metalloproteinase and/or metalloproteinase [26, 27]. In addition, TNIIA can also promote the differentiation of several cancer cell types and regulate the CCAAT/enhancer binding protein (C/EBP)β and C/EBP homologous protein. Besides, in animal models, the side effects of TNIIA, TNI, and CPT were minimal [28].In addition, Danshen root also has anti-inflammatory effects. TNIIA inhibits the NF-kB induced kinase/IkappaB alpha kinase (NIK/IKKalpha), while ERK1 suppress NF-κB induced by LPS and c-Jun n-terminal kinase (JNK) pathway. The anti-inflammatory effects of TNIIA may be related to the inhibition of the Toll-like receptor (TLR) signaling pathway by TNF receptor-associated factor (TRAF) 2/3/6. TNI significantly inhibits the activity of IIA secreting phospholipase A2 (GIIA), thereby blocking the formation of prostaglandin E2 (PGE2) in LPS-activated macrophages [27, 29]. TNI and CPT also significantly inhibit IL-12 production in LPS-activated macrophages and interferon-γ production in lymphocytes. Recent studies have shown that Salvia miltiorrhiza extract inhibits the production of iNOS and COX-2 by regulating NF-κB and MAPKs, thereby inhibiting the secretion of inflammatory cytokines. In LPS induced RAW264.7 macrophages, salvia miltiorrhiza extract reduced the secretion of nitric oxide (NO), tumor necrosis factor- (TNF-) α, and interleukin 6 (IL-6) and decreased the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and NF-κB. Moreover, salvia miltiorrhiza extract can significantly inhibit the activation of JNK1/2 and ERK1/2 induced by LPS and disrupt the TLR4 dimerization in LPS-induced RAW264.7 macrophages [29]. Therefore, the anti-inflammatory effect of Danshen root is partly due to the blocking of TLR4 dimerization, which can be used in clinical treatment of liver injury and infection during the anticancer strategies.Therefore, Chinese medicine practitioners usually use traditional Chinese medicines similar to Danshen root, such as Scutellaria barbata and Hedyotis diffusa in the treatment of cancer [8–20]. It should be mentioned that the current meta-analysis is the first systematic review of the application of Danshen formulae in cancer-assisted treatment. The current meta-analysis found that Danshen formulae can improve the clinical efficiency in cancer treatment. After the addition of Danshen formulae, RR and survival rates were significantly improved. However, it is not clear which components of Danshen formulae have anticancer effects during the treatment, and what role Danshen root plays, which should be the goal of further research.


## 4.3. Limitations

All literatures for this meta-analysis were from China, among which 4 were in English and the rest were in Chinese, and only one was multicenter study [10]. Blind methods have been described vaguely in many studies and most of the references were scored 4 points. Moreover, all types of researches were single-center studies with a small sample size and lack of data support for multicenter, large RCTs. The funnel plot analysis also found obvious asymmetry between the left and the right of funnel plot, therefore, the effect of Danshen formulae in assisting cancer treatment may be exaggerated. In addition to all of the above, the cycle of cancer treatment is extremely long and an army of patients died as their condition worsens during the treatment process, which leads to follow-up work is difficult, resulting in the inability to obtain valid data for many studies, and some literature related to this study cannot be included. Therefore, to better explore the contribution of Danshen formulae in cancer treatment, more large-scale and higher standard studies are needed.


## 4.4. Implications for Further Studies

Nearly 50% of the RCTs included in our study are related to lung cancer, indicating that Danshen formulae may be more widely used in lung cancer. Lung cancer is one of the most dangerous diseases, and it has a variety of treatment options, but the death rate is stubbornly high [2]. Except lung cancer, the included studies also cover leukemia, liver cancer, breast, colon cancer, and gastric cancer, and our study found that 9 kinds of herbs were used in combination with Danshen root in cancer treatment, suggesting that the pharmacological effects of these drugs together may be a mechanism to improve clinical efficacy and reduce side effects. Therefore, this study provides the basis for the clinical treatment and scientific research of Danshen for cancer. In terms of gender ratio, we found that men have a higher risk of cancer than women (605/440), suggesting that men should pour more attention into prevention of cancer, which was also a limitation of this paper, indicating that we should avoid gender selection bias by recruiting women to a certain extent in future studies. By inputting the dose form of Danshen formulae to statistical analysis, we found that there were 1 used granule preparation, 1 used tablet, and the other 11 used decoctions. Ling proved that TCM preparations more safer, effective, and easier to use than decoctions of traditional Chinese medicine [30], and the present study showed that the clinical curative effect and dosage forms of CHM were interconnected, interdependent, and mutually reinforcing with each other; drug application shall be familiar with drug characteristics on the premise of fully considering disease characteristics and age constitution and patient and choose the appropriate dosage forms, through the appropriate method to give full play to the effect, and make the drug in patients with optimal clinical curative effect [31, 32]. Therefore, rational selection of drug dosage forms is beneficial to enlighten and create new drugs, which can better promote the further development and research of new dosage forms with higher drug absorption rate. In terms of the treatment of cancer, in traditional western medicine, chemotherapy and radiotherapy are the main treatments for cancer. The purpose of these therapies is to kill or destroy cancer cells. Unfortunately, for most cancer treatments, it is difficult to distinguish between cancer cells and normal healthy cells, which leads to damage to normal cells [33, 34]. The results of this injury are known as complications and side effects of cancer treatment. There were 10 included studies showed that the formulae of Danshen had significant effect in reducing the side effect of vomiting and blood toxicity, which suggested that we could cooperate with the Danshen formulae in the treatment of cancer in the future to reduce the gastrointestinal reaction of patients. The results of subgroup analysis suggested that Danshen formulae might be taken advantage of for cancer treatment. At last, the exact pathologic and clinical pharmacological mechanisms of cancer are still largely unknown and should be studied further.


## 5. Conclusion

Current findings suggested that Danshen formulae offered statistically significant benefits for cancer, which we generally considered safe. Thus, evidence from the existing study supported the use of Danshen formulae as a treatment for cancer. However, this study was based on several small‐sample studies. Therefore, studies with rigorous, large‐scale RCTs of Danshen formulae in treating of cancer were needed to further confirm its efficacy.



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