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Clinical Efficacy and Safety of Traditional Medicine Preparations Combined With Chemotherapy for Advanced Pancreatic Cancer: A Systematic Review and Meta-Analysis

Background Traditional medicine preparations (TMPs) combined with chemotherapy is widely used for patients with advanced pancreatic cancer (APC); however, its efficacy and safety are still unclear. The purpose of this meta-analysis was to evaluate the clinical efficacy and safety of TMPs combined with chemotherapy for the treatment of APC. Methods A systematic search of eight electronic databases for randomized controlled trials (RCTs) was conducted from inception to October 15, 2021. Tumor response was identified as primary outcome, whereas quality of life (QoL), cancer biomarkers, and adverse drug reactions (ADRs) were identified as secondary outcomes. Quality of the evidence for each outcome was evaluated by GRADE profiler. Results In total, 31 RCTs involving 1,989 individuals were included. This meta-analysis showed that TMPs combined with chemotherapy significantly improved the objective response rate (ORR) (RR=1.64, 95% CI [1.43 to 1.88], p <0.00001), disease control rate (DCR) (RR=1.29, 95% CI [1.21 to 1.38], p <0.00001), and QoL (continuous data: SMD=0.81, 95% CI [0.44 to 1.18], p <0.0001, dichotomous data: RR=1.44, 95% CI [1.22 to 1.70], p<0.0001), compared to those with chemotherapy alone. In addition, the combined treatment group also had lower levels of CA19-9 (SMD=-0.46, 95% CI [-0.90 to -0.02], p=0.04) and CEA (SMD=-0.55, 95% CI [-0.93 to -0.17], p=0.004). Moreover, TMPs reduced the ADRs during chemotherapy. Conclusion This systematic review suggests that TMPs combined with chemotherapy might be a potential option to enhance therapeutic effects and reduce ADRs during the treatment of APC. However, more high-quality randomized controlled trials with more participants are needed. Systematic Review Registration https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=209825, identifier PROSPERO Number: CRD42021264938.


INTRODUCTION
Pancreatic cancer is recognized as a highly deadly malignant tumor with approximately equivalent number of new cases (496,000) and deaths (466,000 cases) annually (1). Remarkably, the incidence of pancreatic cancer has increased significantly by 39.3% between 2007 and 2017, thus ranking among top five actively growing cancers worldwide (2). Despite its 5-year survival rates are only 10-25% (3,4), and surgery remains the only possible cure for pancreatic cancer. Unfortunately, the sobering reality is that only less than 20% of patients have a chance of undergoing surgery due to the lack of prominent symptoms at early stages of this disease (5) and the most patients are often diagnosed with local vessel involvement or distant metastases. Systemic chemotherapy plays an important role for the management of advanced pancreatic cancer (APC) and can aid to prolong survival (6). However, the median total survival of APC is only approximately 6 to 11 months (7,8). Meanwhile, several adverse drug reactions (ADRs) of chemotherapy (neutropenia, anemia, neurotoxicity etc.) have severely affected the treatment outcome of patients with APC (9,10). Thus, APC contributes to substantial burden to individuals and society.
In order to prolong the long-term survival while preserving the quality of life (QoL) of patients, the search for novel complementary treatment combined with chemotherapy becomes crucial.
Traditional medicine preparations (TMPs) are defined as any formulation of medicinal herbs including extracts of herbs, herbal injection, Chinese proprietary medicine, or selfprepared herbal decoctions prescribed by practitioners, with the advantages of easy availability, low price, and generally exhibit few ADRs. A number of experimental studies have shown that several plant extracts such as curcumin (11), bitter melon juice (12), elemene (13) etc. can exhibit significant efficacy against different cancers. These natural compounds function as potent anti-neoplastic agents by interfering with multiple cellular processes, but limited chemical stability and oral bioavailability have hampered their rapid clinical translation which might be improved by nanoformulations (11). There are several reports in literature describing the beneficial effects of many TMPs in cancer treatment for improving clinical efficacy and safety (14)(15)(16).
Over the past 20 years, some clinical studies have been published describing the application of TMPs for the treatment of APC but their findings are relatively less convincing because of the potential use of small sample size. Therefore, we have performed a meta-analysis to systematically analyze the results of these prior studies, which aimed to evaluate the efficacy and safety of TMPs combined with chemotherapy for APC, thus hoping to provide an important reference for the clinicians.

Study Design
This systemic review and meta-analysis strictly followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Guidelines (17). Its registered number in PROSPERO is CRD42020209825.

Patients
Patients diagnosed with unresectable (locally advanced and/or metastatic) or stage III-IV pancreatic cancer through the histological and cytological diagnostic criteria, and TNM staging systems were included. The baseline data of patients in the two groups were comparable. There were no restrictions on age or sex.

Interventions
The experimental group received TMPs combined with chemotherapy. The TMPs included extracts of herbs, patented herbal products, or self-prepared herbal decoctions prescribed by practitioners. The administration or formulation of TMPs including decoction, granule, capsule, or injection were not limited. The control group received the same chemotherapy regimen alone.

Primary Outcome
The primary outcome was tumor response assessed using the objective response rate (ORR) and disease control rate (DCR), measured separately before the start of each trial and at the end of the follow-up time, according to the WHO (18) and RECIST (19) criteria. Trials not stating evaluation criteria were also included and subgroup analysis was carried out thereafter.

Secondary Outcomes
The secondary outcomes were defined as the QoL, cancer biomarkers, and ADRs. The interventions were considered to be effective for QoL when the Karnofsky Performance Status (KPS) score was no more than 10 points lower after treatment. Comparisons were also made for the mean ± standardized difference (SD) of KPS scores before and after treatment was also allowed. Cancer biomarker levels were assessed by measuring the CA19-9 and CEA levels separately before the start of each trial and at the end of the follow-up time. The mean ± SD changes in CA19-9 and CEA levels were synthesized to evaluate the differences between the two groups. ADRs were evaluated by calculating the number of people at stage 0-IV cancer experiencing gastrointestinal toxicity (nausea, vomiting, and diarrhea), myelosuppression (leukopenia, decreased hemoglobin, and thrombopenia), hair loss, liver dysfunction, and renal dysfunction, according to the WHO or NCI recommendations for grading acute and subacute toxicity. The interventions were considered to lead to ADRs when patients had levels III-IV.

Types of Studies
All published randomized controlled trials (RCTs) published were included. Quasi-randomized trials were excluded. Only full journal publications with sufficient data for analysis were included. The language was not restricted.

Exclusion Criteria
The exclusion criteria were the following: (1) simultaneous other types of primary tumors; (2) the TMPs were not fixed within 1 study; (3) unspecified or inconsistent observation nodes between two groups within 1 study; (4) insufficient data; (5) irregular outcome evaluation criteria; and (6) duplicated data.

Data Extraction
Two reviewers (G. Zhu and S. He) independently imported the studies into Endnote X9 software. After the exclusion of duplicate studies, the remaining studies were determined independently by two reviewers (H. Yu and B. Shi) by reading the title, abstract, and full text. Any disagreement arising during this process was discussed or decided by a third reviewer (J. Hu). Two reviewers (Y. Li and Z. Yao) imported the relevant data from the included studies into EpiData 3.1. The extracted data included the basic information (title, first author, year of publication, sample size ratio, sex ratio, age range, etc.), methods (blind methods, random methods, interventions, etc.), and outcomes. When relevant data were incomplete, we contacted the author or included an explanation in our article.

Assessment of Risk of Bias
Three reviewers (J. Hu, J. Jiang and X. Zhang) independently evaluated the included studies using the Cochrane risk of bias tool for RCTs according to the guidance of the Cochrane Handbook for Systematic Review of Interventions (version 5.1.0), which includes the following seven bias domains: selection bias due to random sequence generation, selection bias due to allocation concealment, performance bias due to blinding of participants and personnel, detection bias due to blinding of outcome assessment, attrition bias due to incomplete outcome data, reporting bias due to selective reporting, and other biases. The overall judgment on the risk of bias for each domain had three response options (low/high/unclear) (20). Any disagreement arising from this process was resolved by consensus or by a third reviewer (R. Liu).

Strategy for Data Synthesis
Two reviewers (J. Hu and J. Jiang) conducted a meta-analysis on the included studies using Review Manager 5.3. The risk ratio (RR) was used to present the dichotomous data, whereas the standardized mean difference (SMD) was used to present continuous data. The 95% confidence intervals (CIs) were defined, and statistical significance was set at p<0.05. Cochran's Q test and the I² statistic were used to assess heterogeneity. The heterogeneity among different trials was described by the I² index, indicating a high statistical heterogeneity at > 50%. If heterogeneity (p ≥ 0.10, I² ≤ 50%) was rejected, a fixed-effects model (FEM) was used to synthesize the RR, SMD, and their 95% CI. Otherwise, a random-effects model (REM) was utilized. Sensitivity analysis was performed by sequentially excluding each trial to examine the robustness of the results. Publication bias was evaluated according to the nonparametric trim-and-fill analysis of publication bias and Egger's test when there were more than 10 included studies.

Analysis of Subgroups or Subsets
According to the KPS score, drug delivery of TMPs, the number of chemotherapy drug, chemotherapy regimen, follow-up time, and different herbs or combination of herbs, subgroup analysis was performed to reveal the clinical heterogeneity and its influence on outcomes.

Assessment of Evidence Quality
Two reviewers (M. Cheng and J. Hu) independently evaluated the quality of evidence for each outcome by GRADE profiler, which included the following five domains: risk of bias, inconsistency, indirectness, imprecision, and publication bias. The overall judgment on the quality of the evidence for each outcome had four response options (high/moderate/low/very low) (21). Any disagreement arising from this process was resolved by consensus or by a third reviewer (R. Liu).

Literature Screening Results
A total of 1,884 studies were obtained in the primary search and references screening, and 1,427 studies were included after the elimination of 457 duplicated studies. A total of 80 studies were selected after screening the titles, abstracts. Ultimately, 31 eligible studies were included in the final meta-analysis after reading the full text, according to the inclusion and exclusion criteria. The literature screening process is illustrated in Figure 1.

Assessment of Methodological Bias Risk
The assessment of the methodological bias risk of each trial included is shown in Figure 2. Only 17 trials (22, 24-26, 28-34, 37, 38, 44, 48, 49, 51) reportedly used a random sequence generation including random number table, envelope, bayesian algorithm and centralized interactive voice response system. Unclear selection bias existed because 14 trials did not describe random sequence generation. Just 1 trial (34) reported allocation concealment. Except for 2 trials (33,34), studies failed to report the blinding method, which led to unclear performance and detection biases. None of the trials reported any loss to followup. All trials had low risk on attrition and reporting bias. The ORR and DCR evaluation criteria in 1 trial (32) did not coincide with our study which might influence results. Some unclear information, including KPS score, gender, age at the time of inclusion, and evaluation criteria of outcomes, in 10 trials (23,30,32,33,36,37,39,43,44,48,49) might lead to other potential bias. The quality of the TMPs was shown in Table 1, 14 trials (34,37,(39)(40)(41)(42)(43)(45)(46)(47)(48)(49)(50)(51)(52) described an approved TMPs having clear manufacturer, production batch number and marketing authorisation in China. 1 trial (33) described in detail the product quality control was assured and monitored by acquiring raw material from designated source provinces, establishing fingerprinting, measuring the concentrations of certain compounds in the extract, and comparing the high performance liquid chromatography fingerprinting. 1 trial (50) only described the provider of TMPs. The rest 15 trials (22-32, 35, 36, 38, 44) used self-prepared herbal decoctions prescribed by practitioners but did not describe the origin, processing method or dosage of herbs and none of them described a quality control method.

Tumor Response
A total of 29 trials assessing 1,739 and 1,703 cases reported ORR and DCR, respectively ( Figure 3 and Figure 4). As shown in the figures, there was low heterogeneity between trials as per Cochran's Q test and Higgins's I² (I² = 0%, I² = 22%); therefore, the FEM was used to synthesize data from different trials. The results of the meta-analysis showed that TMPs combined with chemotherapy increased ORR (RR=1. 64

Quality of Life
Nine trials with 600 individuals reported the QoL by using continuous data ( Figure 5), whereas four trials with 274 individuals reported it using dichotomous data ( Figure 6) according to the KPS scale.
In the continuous data, high heterogeneity was observed in QoL (I² = 78%); therefore, REM was used to synthesize data from different trials. The results of the meta-analysis showed that TMPs combined with chemotherapy increased QoL (SMD=0.81, 95% CI [0.44 to 1.18], p <0.0001), compared to chemotherapy alone. To demonstrate the reason for the statistical heterogeneity of the results, subgroup analysis was performed (Table S1 and Figures S1-S5). The drug delivery of TMPs might be the reason for the heterogeneity in QoL ( Figure S2).
In the dichotomous data, no heterogeneity was observed in QoL (I² = 0%); therefore, FEM was used to synthesize data from different trials. The results of the meta-analysis showed that TMPs combined with chemotherapy increased QoL (RR=1.44, 95% CI [1.22 to 1.70], p<0.0001), compared to chemotherapy alone.

Cancer Biomarkers
Five trials with 371 individuals reported cancer biomarkers ( Figure 7). Statistical heterogeneity was demonstrated in CA19-9 (I² = 76%), and CEA (I² = 61%); therefore, REM was used to synthesize SMD. The results of the meta-analysis showed that TMPs combined with chemotherapy reduced the level of CA19-9 (SMD=-0.46, 95% CI [-0.90 to -0.02], p=0.04), and CEA (SMD=-0.55, 95% CI [-0.93 to -0.17], p=0.004), compared to chemotherapy alone. To demonstrate the reason for the statistical heterogeneity of the results, a subgroup analysis was performed (Tables S2, S3 and Figures S6-S9). The follow-up time might be the reason for the heterogeneity in CA19-9 ( Figure S7) and the number of chemotherapy drug might be the reason for the heterogeneity in CEA ( Figure S8).         Table 2 and Figure 8).
Minimal heterogeneity was observed in decreased hemoglobin (I² = 1%), whereas no heterogeneity (I² = 0%) was observed in others. FEM was used to synthesize data from different trials. The results of the meta-analysis showed that TMPs combined with chemotherapy reduced the risk of leukopenia (RR=0. 43

Subgroup Analysis of ORR and DCR
Subgroup analysis was performed on ORR and DCR according to the KPS score, drug delivery of TMPs, the number of chemotherapy drug, chemotherapy regimen, and follow-up time ( Tables 4, 5, and Figures S10-S19). The KPS score was divided into three parts: <70, ≥70, and unclear. Subgroup analysis showed that TMPs increased ORR when KPS score <70 and unclear and DCR in every part (Figures S10, S15). The drug delivery of TMPs was either intravenously or orally. Subgroup analysis showed that TMPs increased ORR and DCR regardless of whether it was administered intravenously or orally ( Figures S11, S16). Based on the number of chemotherapy drug, individuals were divided into those who used single-drug and those who used double-drugs. Subgroup analysis showed that TMPs increased ORR and DCR regardless of whether the number of chemotherapy drug used (Figures S12, S17). The chemotherapy regimen was divided into three categories: GEMbased, S-1-based, and other chemotherapy regimens. Subgroup analysis showed that TMPs increased ORR and DCR regardless of the above chemotherapy regimen used (Figures S13, S18). The follow-up time was divided into two parts: 6w≤ and <9w, and ≥9w. Subgroup analysis showed that TMPs increased ORR and DCR in every part of the follow-up time ( Figures  S14, S19).
TMPs are different combinations of multiple herbs. To determine which herbs or combination of herbs combined with chemotherapy contributed the most to APC, subgroup

Sensitivity Analysis
We analyzed the sensitivity of the main outcome indicators, including ORR and DCR, by excluding each trial to check the

Publication Bias
According to the contour-enhanced plot of ORR ( Figure S20) and DCR ( Figure S21), some trim-and-fill data fell in the area of no statistical significance, indicating that some negative results were not published, possibly leading to publication bias. Further Egger's test ( Table 7) showed no significant publication bias in the meta-analysis of ORR (p = 0.1200), whereas significant publication bias existed in DCR (p = 0.0001).

Quality of Evidence
As shown in Tables 8A and 8B, the quality of evidence was moderate for ORR, leukopenia, nausea and vomiting, hair loss, and QoL (continuous data); low for DCR, QoL (dichotomous

DISCUSSION
Natural products can serve as an important source of drug discovery. Many prescription medicines approved by the Food and Drug Administration for cancer treatment have been obtained from the natural products (55), and more than 50% of newly approved drugs between 1946 and 2019 were natural small molecules or their derivatives (56). TMPs are the products derived from the combination of natural products and traditional medicine theories. They have a complex chemical diversity that enables them to act on a variety of biological targets (enzymes, receptors, pathways, etc.) to achieve maximal efficacy in cancer therapy with minimal adverse reactions (57). Numerous studies have described the clinical efficacy and safety of TMPs for colorectal cancer (58), non-small cell lung cancer (59), and liver cancer (60), as well as for some cancerrelated symptoms such as insomnia (61), pain (62), and anemia (63). Thus, mining TMPs with scientific and systematic methods can serve as an important strategy for cancer treatment. Pancreatic cancer is a fatal malignant tumor of the digestive system, and patients are usually in their advanced stages when diagnosed. TMPs combined with chemotherapy have been widely used in patients with APC to achieve greater survival benefit and QoL, but there is no reported systematic evaluation of whether these therapeutic regimens are significantly effective. Therefore, we have conducted this meta-analysis. As far as we   Most trials had unclear risk and the trials were no high risk, but the result had good robustness. The evidence was rated down by only one level. c Most trials had unclear risk and the trials were no high risk, but the result had poor robustness. The evidence was rated down by two levels. d The sample size for each outcome was fewer than 300 cases. Therefore, the evidence was rated down by one level. e There was publication bias. The QOL was over-estimated. The evidence was rated down by one level. know, this is the first systematic review and meta-analysis of RCTs describing the potential efficacy and safety of TMPs combined with chemotherapy in treating APC. The various outcomes of this meta-analysis include tumor response, QoL, cancer biomarkers and ADRs. A total of 28 different RCTs involving 1,832 APC individuals were included in this review.
At present, various TMPs containing diverse bioactive molecules have been shown to exhibit multiple anti-pancreatic cancer effects. These compounds, including quercetin (64), baicalein (65), honokiol (66), luteolin (67), and silibinin (68), have been found to be present in numerous TMPs. They can suppress pancreatic cancer cell proliferation or induce apoptotic and autophagic by modulating various oncogenic pathways including Wnt, phosphoinositide 3-kinase/protein kinase B/ mammalian target of rapamycin, mitogen-activated protein kinases and Nuclear factor-kappa B pathways (69). For instance, fraxetin isolated from the bark of Fraxinus bungeana A.DC., piperlongumine isolated from the fruit of the pepper Piper longum, and curcumin extracted from Curcuma longa were found to significantly enhance the anti-pancreatic cancer activity of gemcitabine (70)(71)(72). Therefore, the combination of TMPs and chemotherapy as therapeutic regimens has potential clinical value in APC treatment. This view has also been confirmed by various clinical trials in recent years (29,34,49). Our results showed that TMPs combined with chemotherapy can significantly enhance the tumor response, which was consistent with the previous experimental and clinical studies.
In addition, previous studies published have shown that ginkgo biloba extract (GBE 761 ONC) (73), Phytosome complex of curcumin (74), a Chinese botanical formula (PHY906) (75) were not only safe but also efficiently translate in a good response rate in the treatment of APC when combined with chemotherapy. In addition, the use of a modified supercritical carbon dioxide extract of Nerium oleander leaves (PBI-05204) (76) and Viscum album [L.] extract (77) alone has been reported to be beneficial for prolonging overall survival of patients with APC. However, none of them were RCTs about TMPs combined with chemotherapy in treating APC. These TMPs have the potential to treat APC, but it is unclear whether they effective and safet when combined with chemotherapy. The purpose of this study is to make more researchers pay attention to the good clinical value of TMPs combined with chemotherapy in treating APC.
TMPs consist of single or multiple herbs and are widely used in the clinical treatment for APC. The results of subgroup analysis showed that the following 6 herbs had significant combined RRs and no heterogeneity at multiple combined levels: ATRACTYLODIS MACROCEPHALAE RHIZOMA, A S T R A G A L I R A D I X , G L Y C Y R R H I Z A E R A D I X E T RHIZOMA, PORIA, CODONOPSIS RADIX, and PINELLIAE RHIZOMA. Therefore, these herbs were considered to have a consistent effect on enhancing the tumor response in multiple combinations which might be especially effective for treating APC when combined with chemotherapy and were more instructive to researchers. A study reported by Zhang et al. showed that calycosin, a bioactive isoflavonoid of ASTRAGALI RADIX, inhibited the growth of pancreatic cancer cells by inducing p21 Waf1/Cip1 -induced cell cycle arrest and caspasedependent apoptosis (78). Cheng et al. concluded that a triterpene mixture extracted from PORIA inhibited the migration of pancreatic cancer cells associated with CDC20 (79). Moreover, Zhao C. found that licocoumarone, the extracts from GLYCYRRHIZAE RADIX ET RHIZOMA, suppressed human pancreatic adenocarcinoma BxPC-3 cell proliferation and induces cell apoptotic (80). However, there are less studies about the other three herbs and combinations of the six herbs in treating APC.
CA19-9 is a characteristic tumor biomarker of pancreatic cancer. The level of CA19-9 has been associated with tumor size (81), stage, and survival (82), as it is often used for diagnosis, prognosis and monitoring of patients with pancreatic cancer (83,84). It has been observed that particularly, if the duration of the decline in CA19-9 levels was greater than 3 months during the 6 months period after initiation of the treatment, it could be significantly related to the good prognosis of APC (85). The previous studies have also shown that CA19-9 can effectively accelerate the process of pancreatic cancer by causing protein modification (86), binding to E-selectin, as well as by promoting angiogenesis, and is therefore considered as a potential target and an important research area for the treatment of APC (87). Our analysis results showed that TMPs combined with chemotherapy significantly reduced the levels of CA19-9, compared with chemotherapy alone, thereby indicating a positive effect of TMPs on the treatment of APC. It has been established that ADRs during the treatment duration can influence the progress of treatment and the QoL of patients. Therefore, reducing the occurrence of ADRs is also an important task of clinicians. Our results suggested that patients treated with TMPs had a relatively lower incidence of leukopenia, decreased hemoglobin, thrombopenia, and gastrointestinal reaction, compared to the chemotherapy alone. Instead of increasing ADRs, addition of various TMPs as adjuvant and alternative drugs was found to markedly reduce ADRs which reflected the better safety profile of TMPs.
The included trials did not report TMPs-related adverse reactions. As the main compositions of TMPs in the treatment of APC, a number of previous studies have confirmed that ATRACTYLODIS MACROCEPHALAE RHIZOMA (88), ASTRAGALI RADIX (89), PORIA (90) and CODONOPSIS RADIX (91) do not exhibit significant toxicity and are safe for the clinical application. However, adverse reactions of some compositions of TMPs in included trials have been reported. F o r e x a m p l e , t he m o s t i m p o rt a n t s i d e eff e c t s of GLYCYRRHIZAE RADIX ET RHIZOMA have been found to be hypertension and hypokalemic-induced secondary disorders and which need to be used with caution during pregnancy (92). Large-scale consumption of GINSENG RADIX ET RHIZOMA may cause anaphylaxis, palpitations, hypertension, skin hypersensitivity reactions and headache (93,94). The toxicity of PINELLIAE RHIZOMA includes mucosal irritation, hepatorenal and gestational toxicity (95). While this does not mean that TMPs necessarily cause these adverse reactions, it must be used with caution before analyzing their safety through strict evaluation. It is very common to use TMPs for treatment of cancer patients. For instance, one study showed that herbal and supplementary medicine was used by 78% of patients undergoing chemotherapy, but 27% of them were assessed as at risk of adverse herb-chemotherapy interaction (96) which has become an important consideration in pharmacotherapy. Therefore, TMPs pose potential risks for interactions with chemotherapy drugs (97,98), which are often caused by TMPs-related induction or inhibition of the drug metabolizing enzyme system cytochrome P-450 (CYP) and/or the Pglycoprotein drug efflux transport system (99). Herbal products that have shown clinical interactions with chemotherapeutic drugs include ECHINACEA, ALLIUM SATIVUM, GINSENG, CITRUS PARADISI, SILYBUM MARIANUM and HYPERICUM PERFORATUM. GINSENG is a commonly used herbal products used in the treatment of patients with APC, but the findings on its inductive effect on drug-metabolizing enzymes are relatively mixed (100,101). In one case report, ginseng was observed to cause hepatotoxicity when used in combination with imatinib (102). Moreover, other herbal products commonly applied in APC, including DIOSCOREA VILLOSA, RHODIOLA ROSEA and GANODERMA, might also display strong potential for herbchemotherapy interactions although there are no clinically relevant data (103). Considering the significant application of various TMPs for treating APC, clinicians and researchers should document in detail TMPs use during chemotherapy in patients with APC and be vigilant in monitoring for any potential interactions as well as adverse effects while administering TMPs-chemotherapy combination to the patients.
Our study has some potential limitations. First, we have only searched the English and Chinese databases which might miss some key trials published in other language. Second, the assessment of the methodological bias risk showed some bias in included trials thereby leading to low or very low quality of some potential outcomes. Regardless, the primary outcome was robust and reliable. We will include high-quality RCTs to update this study regularly. Third, there is currently some debate about whether TMPs combined with chemotherapy can significantly prolong the survival time in APC patients (34,(103)(104)(105). However, this study did not define it as an observational outcome due to presence of only few reports in the published trials. Therefore, further research is needed in the future. Fourth, the time elapsed from the chemotherapy termination until the measurements of outcomes were different because of the diverse chemotherapy regimens employed in each study. Although we observed the same trend of outcomes in the included trials, this factor might also substantially influence the interpretation of the results. Fifth, the specific mechanisms of action of TMPs are not clear although great progress has been made in the study of the effects of TMPs in treating APC. Sixth, according to the CONSORT Extension for Chinese Herbal Medicine Formulas (106), the name, provenance, dosage form, preparation method, dosage and route of administration of herbal medicine formulas should be reported in detail in RCT. Besides, the name, origin, processing method and dosage of all herbs in the formula should be reported. The certification method, quality control method and safety monitoring data for herbs and formulas should also be described. However, included trials using selfprepared herbal decoctions did not report the information above which might lead to potential bias. This indicated irregular reports in RCTs about self-prepared herbal decoctions in treating APC which need to be improved. Overall, we are hopeful that this study can provide relevant clinical evidences and experimental research direction for researchers. Finally, we expect that more attention will be paid to the potential therapeutic applications of TMPs in the treatment of APC and better deigned clinical trials will be conducted in future.

CONCLUSION
Our study confirmed the clinical efficacy and safety of TMPs combined with chemotherapy for APC. This combination regimen might benefit for the prognosis of patients with APC.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding authors.