Effectiveness and Safety of the Traditional Chinese Medicine Treatment (HuoxueHuayu Therapy) for Malignant Tumors: A Systematic Review and Meta-Analysis

Background A malignant tumor is one of the refractory diseases that threaten human life and health. HuoxueHuayu therapy (one of the Traditional Chinese Medicine therapies to promote blood circulation and remove blood stasis) is widely used as an antitumor supplementary method. However, its efficacy and safety are still controversial. Therefore, the objective of this study was to provide evidence-based evidence for HuoxueHuayu therapy in the treatment of malignant tumors and confirm its safety and effectiveness. Methods A systematic search in 8 electronic databases targeted randomized clinical studies evaluating HuoxueHuayu therapy for response evaluation, tumor progression rate, quality of life (QoL), peripheral hemogram, performance status, immunologic function, tumor marker, and blood coagulation function in cancer patients, published from the establishment of the database to December 31, 2020. Risk ratio (RR) was used for counting data, mean difference (MD) or standardized mean difference (SMD) was used for measurement data, and 95% confidence interval (CI) was used as efficacy analysis statistics. Results Our search identified 69 studies, evaluating 4402 patients in total. Randomized controlled trials (RCTs) evaluated gastric (n = 14), lung (n = 18), pancreatic (n = 2), colorectal (n = 10), liver (n = 14), breast (n = 2), ovarian (n = 2), gallbladder (n = 1), esophagus (n = 1), and combined (n = 14) cancers and hematological malignancies (n = 2). The duration of HuoxueHuayu therapy ranged from 3 to 48 weeks. Methodological bias was low in 64 studies and high in 5 studies. HuoxueHuayu therapy was associated with significant improvement in response evaluation (Response Evaluation Criteria in Solid Tumor (RECIST): RR: 1.44, 95% CI: 1.27 to 1.63, I2 = 0%, n = 33 studies; World Health Organization Criteria in Solid Tumors (WHOCIST): RR: 1.40, 95% CI: 1.23 to 1.59, I2 = 0%, n = 26 studies), recurrence rate (RR: 0.85, 95% CI: 0.72 to 0.99, I2 = 0%, n = 2 studies), quality of life, performance status (MD: 5.60, 95% CI: 5.04 to 6.15, p < 0.001), immunologic function (CD3: SMD: 1.23, 95% CI: 0.79 to 1.66, p < 0.001; CD4: SMD: 1.25, 95% CI: 0.77 to 1.74, p < 0.001; CD4/CD8: SMD: 1.05, 95% CI: 0.69 to 1.42, p < 0.001; natural killer cell (NK): SMD: 0.74, 95% CI: 0.32 to 1.15, p < 0.001), tumor marker, and blood coagulation function (D-dimer (D-D); fibrinogen (FIB)). In addition, HuoxueHuayu therapy could reduce toxicity caused by chemotherapy and radiotherapy without risks of liver and kidney injury or bleeding, although the effect on tumor metastasis was uncertain. Conclusions The present update of our systematic review and meta-analyses provided essential evidence for the beneficial effect of HuoxueHuayu therapy to show promise in cancer treatment, improving quality of life, addressing cancer-related symptoms, and reducing toxicity in a secure way.


Introduction
Malignant tumors are the second leading cause of death worldwide [1], and their incidence is increasing year by year [2].According to the 2020 Cancer Statistics report, there were approximately 19.3 million new cancer cases and 10.0 million cancer deaths worldwide.Furthermore, an estimated 28.4 million new cancer cases may occur in 2040, a 47% increase from the cases in 2020 [3].Although significant advances in diagnostic screening, surgical resection, and targeted therapies have been made in recent years, the overall situation of malignant tumor treatment is still not optimistic.For instance, patients who are diagnosed at the middle or advanced stages [4,5] seem to miss the optimum period for surgery [6].Hence, nonsurgical treatments, such as chemotherapy, radiation therapy, or other treatments (nanomedicines) [7], still play a crucial role in the treatment of middle and advanced malignant tumors.However, most chemotherapeutic agents are linked to cancer metastasis, the resistance of the drugs, and side effects [8].In recent years, Chinese herbal medicine, which plays an important role in the treatment of malignant tumors, is believed to have antitumor effects [9].As a complementary therapy, Chinese herbal medicine enables the reduction of the toxicity and adverse reactions induced by surgery, chemotherapy, and radiotherapy, indicating a synergistic effect with other therapies [10].Moreover, compared with other drugs, Chinese herbal medicine, which has been widely used for the treatment of malignant tumors in China, is appreciated for its traits of less toxicity and numerous drug targets [11].According to the theory of Traditional Chinese Medicine (TCM), the formation of a malignant tumor is closely related to blood stasis [12].Studies have shown that malignant tumors have a high risk of metastasis in blood stasis [13], so herbs to promote blood circulation and remove blood stasis (HuoxueHuayu therapy) are often the components of the antitumor formula.
ere is no doubt how difficult and necessary it is to prevent the invasion and metastasis of malignant tumors, which are the most essential biological characteristics of malignant tumors [14].At present, many studies have confirmed that HuoxueHuayu therapy allows the reduction of extension or relapse of malignant tumors [13,15].However, excessive use of blood-activating drugs may damage the integrity of blood vessels and increase the chance of tumor metastasis [16,17].Further, due to the unclear pharmacological mechanism of HuoxueHuayu therapy, there is no consensus regarding the clinical application of this treatment, so whether it can prevent or treat malignant tumor metastasis is controversial.erefore, it is necessary to conduct a systematic evaluation and meta-analysis to provide evidence-based evidence for HuoxueHuayu therapy in treating malignant tumors.

Methods
e review protocol of the previous versions of the systematic review is registered in PROSPERO International Prospective Register of Systematic Reviews (https://www.crd.york.ac.uk/ prospero/display_record.php?%20ID=CRD42021247557) and is developed following the guideline of Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) [18].
2.1.Search Methods.Electronic databases were used, including Embase, PubMed, Elsevier SD, Cochrane Library, Web of Science, Chinese National Knowledge Infrastructure (CNKI), VIP information database, and Wanfang Data Information Site.

Data Extraction and Management.
Two authors (ZHC and AW) independently extracted data from the included studies using Excel.Calibration had been conducted to ensure consistency across reviewers before starting the review.
e following information was extracted using a predetermined data form: general information (title, authors, and year of publication); details of the study (aim, random method, inclusion and exclusion criteria, and method of randomization and allocation); study population (age, sex, sample size, number for analysis, type of cancer, and course of cancer); intervention characteristics (type, duration, and blinding of participants and personnel); outcome (main and additional outcomes, time points, method of outcome assessments, blinding of outcome assessment, and adverse effects).Any disagreements were resolved by consensus or consultation with a third review author.

Assessment of Risk of Bias in the Included Studies.
ree authors (ZHC, AW, and YW) assessed the risk of bias using the Cochrane Collaboration Risk of Bias Tool [19].e tool utilizes 10 items to evaluate various sources of bias, including random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selection reporting (reporting bias), and other bias.All evaluated individual domains were endorsed with a "low" (low risk of bias), "high" (high risk of bias), or unclear (insufficient information provided to assess bias), following guideline criteria.e validity of included studies 2 Evidence-Based Complementary and Alternative Medicine was assessed by the Jadad scale [20], which suggested that 1∼3 were low quality and 4∼7 were high quality.All disagreements among independent bias assessors for a given study item were resolved by team discussion.

Safety Monitoring. Safety monitoring in studies was
accessed by explicit reference to formal protocols for systematic monitoring of adverse events, as well as the number and type of intervention-related adverse events reported in the study.

Data Statistical Analysis Methods.
We combined more than one trial to estimate pooled intervention effect using the meta-analysis when studies examine the same intervention and outcomes with comparable methods in similar populations.Risk ratio (RR) was used for counting data, mean difference (MD) or standardized mean difference (SMD) was used for measurement data, and 95% confidence interval (CI) was used as efficacy analysis statistics.Heterogeneity was estimated by the Q-value together with the I 2 statistic.p < 0.1 of Q-value or I 2 > 50% indicates statistically significant heterogeneity [21,22].e fixed-effect model was used for pooled analysis of homogeneity.e random-effects model was used for data pooled analysis of heterogeneity.Sensitivity analyses were conducted to evaluate the robustness of the pooled results, excluding trials with a high risk of bias.Potential small-study effects, such as publication bias, were explored using Egger's test and funnel plots when at least 10 studies were available, as recommended by the Cochrane Handbook [19].All analyses were conducted using the Review Manager by the Cochrane Collaboration (version 5.4.1 Copenhagen: e Nordic Cochrane Centre).If a meta-analysis is not possible, we provided a narrative summary of the results from individual studies.Subgroup analyses based on age, sex, type of cancer, duration, type of HuoxueHuayu therapy (decoction, injection, capsule, etc.), and type of control group (TCM placebo, chemotherapy, surgery, etc.) were performed to investigate heterogeneity when sufficient data are available.

Evidence Quality Assessment.
e overall quality of the evidence for each outcome was rated by the Grading of Recommendations Assessment, Development and Evaluation profiler (GRADEpro) Guideline Development Tool [23].Two authors (ZC and AW) independently evaluated the overall quality of the body of evidence for each result based on five GRADE criteria, including study limitations, inaccuracies, inconsistencies, indirectness, and publication bias.It is divided into one of four possible ratings (high, medium, low, and very low).Any inconsistencies are resolved by consensus or negotiation with the third review author.

Results
3.1.Literature Search.Figure 1 summarizes the flow of the literature search and publication selection process following PRISMA guidelines.e search returned 1874 results from the 8 databases and 67 additional records through manual search.After removing duplicates, there were 1553 unique papers.Titles and abstracts were then reviewed to determine whether papers met inclusion criteria, which resulted in 303 articles for in-depth, full-text review.Full-text reports were then reviewed to further specify whether publications met inclusion criteria, and a final list of 69 publications (RCTs) was established and subjected to the qualitative analysis.
All studies reported the timing of outcome assessments without other bias.e corresponding forest plots are given in Figure 2.

Tumor Progression Rate.
e tumor progression rate of cancer was assessed via metastasis rate [40] and recurrence rate [40,78].e results showed that HuoxueHuayu therapy was a protective factor in decreasing the recurrence rate (RR: 0.85, 95% CI 0.72 to 0.99, I 2 � 0%, n � 2 studies).Only one study emphasized the effect of HuoxueHuayu therapy on tumor metastasis (RR: 0.83, 95% CI 0.40 to 1.73), and the result was equivocal due to inadequate evidence.

Quality of Life.
Quality of life was assessed in 22 studies using the following criteria: the European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire (EORTC QLQ-C30, 14 studies) [25, 26, 29-31, 33, 34, 48, 53, 58, 68, 84, 85, 91], Functional Assessment of Cancer erapy-Colorectal (FACT-C, 2 studies) [60,62], the European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire for Breast Cancer (EORTC QLQ-BR23, 1 study) [83], and a questionnaire designed by researchers based on international criteria (5 studies) [28,32,64,65,77].In terms of the overall score of the quality of life questionnaire, 18 studies of which outcomes demonstrated five conditions, including quality of life promotion in the experimental group combined with no change in the control group [28,30,31,33,34,48,53,60,62], quality of life promotion in the experimental group combined with the reduction in the control group [32,44,83,91], quality of life promotion in the experimental and control group [25,65,68], no change of quality of life in the experimental group combined with the reduction in the control group [26], and quality of life reduction in the experimental and the control group [77], reflected the significant difference between the experimental group and the control group.Four studies showed similar efficiency in the experimental group and the control group, and two of them manifested a significant quality of life promotion after HuoxueHuayu therapy [29,58].In general, HuoxueHuayu therapy showed a positive trend in improving the quality of life or slowing down the degradation of the quality of life.

Peripheral Hemogram.
Two studies indicated the significant efficiency of HuoxueHuayu therapy in reducing the degree of WBC decline (p < 0.05) [65,88] and improving the hemorheological parameters (plasma viscosity, whole blood reduced high shear viscosity, and low shear viscosity reduction of whole blood) for hematological malignancies (p < 0.05) [89].
ere were no significant differences between the experimental group and the control group in APTT, D-D, or FIB (p < 0.05) except PT (p < 0.05), which meant that HuoxueHuayu therapy could improve blood hypercoagulability in patients with hematologic malignancies without increasing the risk of bleeding.

Additional Outcomes
3.6.1.Performance Status.Performance status was evaluated in 32 studies by the Karnofsky score (KPS).Data from 28 RCTs were pooled for analysis.

Survival Condition.
Five studies introduced survival access using survival rate, median survival time, and progression-free survival.

Overall Quality of Evidence according to Outcome
Measures.Compared HuoxueHuayu therapy with conventional treatment, the overall quality of evidence according to outcome measures was high in 2 results (RECIST; WHO-CIST), moderate in 1 result (KPS score), low in 3 results (recurrence rate, CD4/CD8, and CD3), and very low in 5 results (APTT, PT, CD4, and CD8).e results of GRADE assessments are presented in Table 4.

Discussion
Based on the TCM theory, HuoxueHuayu therapy is prevalently applied for malignant tumor treatment.It is often combined with chemotherapy, radiotherapy, and surgery, and its efficacy has been testified in a large sum of clinical trials.However, the safety of HuoxueHuayu therapy has been controversial, as it seems to promote tumor metastasis and thus makes the cancer therapy uncertain to be recognized in clinics.erefore, we summarized the clinical trials, mainly in RCTs, to illustrate the effect and safety of HuoxueHuayu therapy in this review.To assess the efficiency of HuoxueHuayu therapy, we utilized four main outcomes and five additional outcomes to explain the effects from various aspects.As the main outcome, response evaluation of cancer distinctly reflected the improvement of cancer, typically in the solid tumor before and after treatment, which had been widely accepted by therapeutic evaluation of 12 Evidence-Based Complementary and Alternative Medicine malignant tumors using RECIST and WHOCIST.We employed metastasis rate and recurrence rate as tumor progression rate to evaluate the safety of HuoxueHuayu therapy.In addition, as many researchers were concerned, we focused on the quality of life of patients with cancer in terms of the subjective feeling of patients to estimate the effect of treatment, which was an essential approach in therapeutic evaluation.Some cancers like hematological malignancies could hardly be measured by RECIST and WHOCIST; hence, peripheral hemogram, including WBC, RBC, LYM, PT, PLT, APTT, FDP, and D-D, was used to describe the changing in cancer treatment.Besides that, we added some other outcomes to thoroughly demonstrate the influence of HuoxueHuayu therapy from the perspective of  Evidence-Based Complementary and Alternative Medicine Our finding revealed that HuoxueHuayu therapy minimized the size of tumor combined with conventional treatment, which was better than chemotherapy or radiotherapy alone, meaning that HuoxueHuayu therapy might reinforce the effect of conventional treatments.Nearly all cancer patients suffer from physical and psychological trauma caused by tumors and the toxicity of drugs.We found that the intervention of HuoxueHuayu therapy could improve the quality of life compared to pretreatment or slow down the deterioration of life quality after treatment when adverse effects were inevitable.In particular, HuoxueHuayu therapy might significantly relieve fatigue and increase appetite [84], which was consistent with the results of the KPS score and adverse events.Some researchers regard the KPS score as an assessment of life quality, while the KPS score reflects the behavioral capacity of patients without psychological evaluation, so we extracted the KPS score from a life quality assessment to illustrate, respectively.Huox-ueHuayu therapy manifested a beneficial trend of improving performance status in various tumor types, indicating that patients with cancer were likely to have a better prognosis [93].Just as the results of survival condition reflected, HuoxueHuayu therapy improved prognosis by increasing median survival time [52,76,78] and survival rate [55,76,78].Although there are limited relevant studies, we could not neglect the effect of HuoxueHuayu therapy in prolonging patient survival.
e activity of the immune system concerning cancer is an important factor in the prognosis of patients with cancer.Many cytotoxic chemotherapy drugs have been shown to induce immunogenic cell death [94], while others reduce the number and function of immunosuppressive cells in the tumor microenvironment [95].Chemotherapeutic drugs enhance T lymphocytes, including CD4, CD3 [96], and NK cells in patients with malignant tumors, which are often in the inactive or inhibited state [97].Our findings showed that HuoxueHuayu therapy might have immunomodulatory  Evidence-Based Complementary and Alternative Medicine activity by elevating the T cells and NK cells to suppress tumor growth, acting as potential tumor immunotherapy.e content of CD8 and CD4 maintains a dynamic balance in the healthy state of the body to ensure the normal development of the human immunologic function, but the immune function will be greatly inhibited with high content of CD8, typically in cancer tissues.According to the result, HuoxueHuayu therapy on CD8 levels was not clear, so more evidence would be needed to verify the effect of drug action.
A tumor marker is a substance produced by or associated with a tumor, found in the blood in concentrations higher than in malignancy-free subjects.It is believed that, as potentially good indicators, tumor markers can reflect the severity of diseases and predict tumor recurrence and metastasis to a certain extent.erefore, the decrease in tumor markers could be regarded as a favorable prognostic trend.We discovered that HuoxueHuayu therapy had an obvious advantage in reducing CEA and AFP, but the tumor markers CEA and AFP can be found in various cancers instead of unique cancer, so they lack tumor specificty.ese results were consistent with the improvement of tumor size and life expectancy, meaning that the decline in tumor markers was due to improvements in cancer by HuoxueHuayu therapy.
In this review, we focused on the peripheral hemogram changes in hematologic malignancies and the blood coagulation function.Based on our research, HuoxueHuayu therapy is inclined to regulate the WBC, suggesting that it might have more advantages in preventing infection than conventional treatment.Studies have shown that blood hypercoagulability, which can affect the biological behavior of tumor cells and thus promote tumor development and metastasis, is closely related to the occurrence, development, and prognosis of malignant tumors [98,99].HuoxueHuayu therapy had a trend of the intervention of blood hypercoagulability typically in D-D, FIB, PLT, and hemorheological parameters, without bleeding tendency.Some procoagulant substances can promote tumor cell proliferation, angiogenesis, and distant metastasis [100].Our results showed that HuoxueHuayu therapy was a protective factor in decreasing the recurrence rate, but the result on tumor metastasis was equivocal due to the inadequate evidence, which indicated that the effect of HuoxueHuayu therapy on hypercoagulability and tumor metastasis was not completely synchronized.
TCM considers malignant tumor as a systemic disease, not only the local lesion but also the systemic functions affected by cancer, so the therapy concept is holistic and combined with local treatment, which is the advantage of TCM in the treatment of malignant tumors.Based on the TCM theory, a malignant tumor is closely related to blood stasis, meaning that exposure to blood stasis and qi stagnation for a long time can lead to a "cancerous toxin" which causes cancer.Blood stasis and "cancerous toxin" are homologous, and blood stasis already exists in the initial stage of the tumor, which is conducive to the formation of cancerous toxin to promote tumor metastasis [101,102].Blood   Evidence-Based Complementary and Alternative Medicine stasis is a key etiology factor in the genesis, invasion, and metastasis of tumors, which provides a reliable basis for the treatment of cancer by HuoxueHuayu therapy.However, blood stasis usually influences the development of cancer by combining other pathogenic factors such as qi deficiency, heat, and toxins rather than only by itself, which makes the therapy more compound to concern all the aspects instead of a unique method.In our review, we found that abundant researchers used HuoxueHuayu therapy combined with other methods, including tonifying qi, detoxication, and clearing heat, to implement the integral efficacy.
In terms of the mechanism, HuoxueHuayu prescription was confirmed to refrain tumor cell proliferation [32,44,61,62], adjust the equilibrium of MMP-2/TIMP-2 [44], abnormal miRNA expression such as miRNA-21, miRNA-143, miRNA-145, and miRNA-146a [61,62], VEGF, and Ki-67 [32] to refrain tumor, and play a role in antitumor angiogenesis effect.Besides that, multiple systematic reviews have summarized the potential mechanisms of HuoxueHuayu therapy as follows [103][104][105]: (1) regulating related genes; (2) inhibiting tumor cell proliferation and metastasis; (3) promoting tumor cell apoptosis; (4) inhibiting angiogenesis; (5) modulating immune function; (6) reversing drug resistance of cancer cells.Although the mechanism of reconstitution and regulation of some immune cells and immunosuppressive cells are roughly the same between HuoxueHuayu therapy and HuoxueHuayu therapy combined with tonifying qi, in the intensity of regulation, the later one is superior to the former [105].We should emphasize that HuoxueHuayu therapy achieves therapeutic effects through the action of multiple herbs rather than a single herb or an ingredient of herb, although some herbs have been reported to tend to promote tumor metastasis [15,16,106].
According to this study, we recommended the use of HuoxueHuayu therapy in addition to conventional treatment because it could relieve the side effect of chemotherapy and radiotherapy.
e adverse reaction of the digestive system (nausea, emesis, and diarrhea) and immunosuppression (leucopenia) was prone to be the prominent target of HuoxueHuayu therapy, which might be related to its effect on improving gastric motility and strengthening gastrointestinal and immune function [107][108][109].It was positive to see that HuoxueHuayu therapy improved blood circulation and reduced blood viscosity without any bleeding cases reported, indicating its reliable safety and accessibility.Meanwhile, HuoxueHuayu therapy could lower the accidence of hepatic injury without any reported renal injury, confirming that it not only avoided enhancing the toxicity but also reduced the risk of adverse events by combining it with conventional treatment.

Limitations and Suggestions for Future
Research.We confronted some limitations based on published literature so that our conclusion might be conserved.First, the included papers were limited to English and Chinese, especially Chinese that accounted for the majority, which would lead to publication bias.Second, because of the deficient research, we could not provide a confirmed conclusion on some outcomes such as the intervention of HuoxueHuayu therapy on tumor metastasis, so it is still hard to recognize its stimulation or inhibition.We are still prone to believe that HuoxueHuayu therapy can suppress tumor metastasis and prolong the survival time because, among a robust and growing body of evidence, the effect of HuoxueHuayu therapy on antitumor metastasis has been confirmed by animal and in vitro experiments [110][111][112].
ird, due to the inconsistent measurement and heterogeneity of outcomes reported in these studies, the meta-analysis was by necessity limited to the most common outcome measures without full coverage quantification of results.Fourth, the pooling of studies that were done for meta-analysis did not consider the diversity and complexity of patients with tumors across studies and thus limited the inferences that could be drawn regarding the benefits of HuoxueHuayu therapy to specific cancer types.Lastly, the quality of evidence according to outcome measures is concentrated in low or very low due to inconsistency, imprecision, and publication bias, so rigorously designed studies will need to be undertaken to confirm the conclusions.In terms of demographic features, future reviews should further stratify results based on the type of cancer, age, or other groupings.Meanwhile, whether the forms or the dose of herbs contributing to HuoxueHuayu therapy will influence the curative effect or not should be studied deeply.

Conclusion
In conclusion, our findings would supplement current effective therapies by providing essential evidence for the beneficial effect of HuoxueHuayu therapy.We systematically summarized the effects of HuoxueHuayu therapy on the improvement of cancer, recurrence rate, quality of life, performance status, immunologic function, blood status, and immunity of patients with malignant tumors to confirm that it showed promise in cancer treatment, improving quality of life, addressing cancer-related symptoms, and securely reducing toxicity.Besides, HuoxueHuayu therapy demonstrated its therapeutic effect on various malignant tumors through the compatibility of TCM rather than merely depending on a few herbs.In further efforts to strengthen uniformity in clinical trial reporting, more extensive and methodologically sound trials with more extended follow-up periods are needed.

Figure 1 :
Figure 1: Summary of the flow of our literature search according to the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines.(a) Risk ratio of RECIST for the experimental and control groups.(b) Risk ratio of WHOCIST for the experimental and control groups.

4
Complementary and Alternative Medicine

Figure 3 :
Figure 3: Performance status of HuoxueHuayu therapy for malignant tumor (KPS score).(a) CD3 level of HuoxueHuayu therapy for malignant tumor.(b) CD4 level of HuoxueHuayu therapy for malignant tumor.(c) CD8 level of HuoxueHuayu therapy for malignant tumor.(d) CD4/CD8 level of HuoxueHuayu therapy for malignant tumor.(e) NK level of HuoxueHuayu therapy for malignant tumor.

Figure 5 :
Figure 5: Blood coagulation function of HuoxueHuayu therapy for malignant tumor (APTT and PT).
mentioned the allocation concealment

Table 2 :
General study characteristics of included studies (RCTs).

Table 3 :
Quality assessment of the included studies.